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Tomos I, Kanellopoulou P, Nastos D, Aidinis V. Pharmacological targeting of ECM homeostasis, fibroblast activation and invasion for the treatment of pulmonary fibrosis. Expert Opin Ther Targets 2025:1-15. [PMID: 39985559 DOI: 10.1080/14728222.2025.2471579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/01/2024] [Revised: 01/24/2025] [Accepted: 02/20/2025] [Indexed: 02/24/2025]
Abstract
INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with a dismal prognosis. While the standard-of-care (SOC) drugs approved for IPF represent a significant advancement in antifibrotic therapies, they primarily slow disease progression and have limited overall efficacy and many side effects. Consequently, IPF remains a condition with high unmet medical and pharmacological needs. AREAS COVERED A wide variety of molecules and mechanisms have been implicated in the pathogenesis of IPF, many of which have been targeted in clinical trials. In this review, we discuss the latest therapeutic targets that affect extracellular matrix (ECM) homeostasis and the activation of lung fibroblasts, with a specific focus on ECM invasion. EXPERT OPINION A promising new approach involves targeting ECM invasion by fibroblasts, a process that parallels cancer cell behavior. Several cancer drugs are now being tested in IPF for their ability to inhibit ECM invasion, offering significant potential for future treatments. The delivery of these therapies by inhalation is a promising development, as it may enhance local effectiveness and minimize systemic side effects, thereby improving patient safety and treatment efficacy.
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Affiliation(s)
- Ioannis Tomos
- 5th Department of Respiratory Medicine, 'SOTIRIA' Chest Diseases Hospital of Athens, Athens, Greece
| | - Paraskevi Kanellopoulou
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Dimitris Nastos
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Vassilis Aidinis
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
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Yue R, Yang T, Niu D, Zeng Z, Wang X, Pan L, Yao J. Integration of pharmacodynamics, network pharmacology and metabolomics to elucidate the effect and mechanism of Jingfang Granule in the treatment of Paraquat induced Pulmonary fibrosis. PLoS One 2025; 20:e0318246. [PMID: 39965011 PMCID: PMC11835338 DOI: 10.1371/journal.pone.0318246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/30/2023] [Accepted: 01/09/2025] [Indexed: 02/20/2025] Open
Abstract
OBJECTIVE One of the main risk factors of COVID-19 is Pulmonary fibrosis (PF). The protective effect of Jingfang Granule (JF) to bleomycin-induced PF has been confirmed in our previous studies. This work was designed to reveal the effect and mechanism of JF on PF which induced by Paraquat (PQ). METHODS In this study, the PF mice model was induced by PQ with the administration of 1, 0.5, and 0.25 g/kg JF or Nintedanib (NTNB) 45 mg/kg by oral administration. The ameliorating effects of JF were reflected by the survival curve and lung coefficient. And the pathological alterations of lung were observed by H&E, Masson and Sirius red staining. Then, the expression of fibrosis-associated protein α-SMA and TGFβ1/Smad2,3 signaling pathway was detected by immunohistochemistry and western blot. An integrated approach combined metabolomics with network pharmacology was applied to recognize the mechanism of JF on ameliorated the PQ-induced PF, and the result of integrated was verified by western blot. RESULTS The experiment results showed that JF could inhibit the progression of PQ-induced PF and delay the death of mice after PQ poisoning, and the inhibit effect was similar to NTNB. JF also reduced fibroblasts in lung tissue of the PF mice model by significantly down- regulated the expression of α-SMA and TGFβ1/Smad2,3 signaling pathway. In addition, JF intervened 16 serum metabolites compared with PQ-induced PF mice, and the differential metabolites were linked 241 corresponding targeted proteins obtained by database, which have 79 common targets to JF related targets. The integrated results of metabolomics, network pharmacology and western blot showed that apoptosis was a crucial way for JF to relieve the PQ-induced PF, and JF regulated the signals of Bcl-2, Bax, Caspase-3 protein and PI3k/Akt pathway to inhibit the apoptosis. CONCLUSION These findings demonstrate that JF down-regulated the TGFβ1/Smad2,3 signaling pathway to reduce the fibroblasts, regulate the expression of Bcl-2, Bax, Caspase-3 and PI3k/Akt pathway to inhibit the apoptosis, and display a favorable effect on inhibiting the development of pulmonary fibrosis and delaying the death of PQ-induced PF mice.
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Affiliation(s)
- Rujing Yue
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd, Linyi, China
| | - Tianye Yang
- Department of Medicine and Pharmacy, Wuhan University, Wuhan, Hubei, China
| | - Dejun Niu
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd, Linyi, China
| | - Zhen Zeng
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd, Linyi, China
| | - Xishuang Wang
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd, Linyi, China
| | - Lihong Pan
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd, Linyi, China
| | - Jingchun Yao
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd, Linyi, China
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Giuliani M, Rizzi A, Pagano M, Raveglia LF, Saccani F, Di Lascia MR, Interlandi M, Nardella TS, Marchini G, Murgo A, Tigli L, Pappani A, Capelli AM, Fernandez SX, Puccini P, Villetti G, Civelli M, Beato C, Moro E, Mundi C, Remelli R, Armani E. Novel Cyclohexyl Amido Acid Antagonists of Lysophosphatidic Acid Type 1 Receptor for the Treatment of Pulmonary Fibrosis. ACS Med Chem Lett 2025; 16:317-326. [PMID: 39967626 PMCID: PMC11831564 DOI: 10.1021/acsmedchemlett.4c00559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/21/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 02/20/2025] Open
Abstract
Lysophosphatidic acid (LPA) is a phospholipid activating different biological functions by binding to G protein-coupled receptors (LPA1-6). Among these, the role of the LPA1 receptor in modulating fibrotic processes is well-known, making it a therapeutic target for pulmonary fibrosis and other fibrotic disorders. Herein we report the search for a new class of LPA1 antagonists for the oral treatment of idiopathic pulmonary fibrosis with a focus on hepatobiliary safety. Compound 7 excelled in in vitro and in vivo efficacy, showing significant efficacy both in PD studies and in a rodent lung fibrosis model, with a promising in vitro hepatic safety profile. However, in a dose range finding (DRF) toxicity study, compound 7 did not ensure safety regarding potential hepatobiliary toxicity, leading to its development being halted.
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Affiliation(s)
- Marta Giuliani
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Andrea Rizzi
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Mafalda Pagano
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Luca F. Raveglia
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Francesca Saccani
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | | | | | | | - Gessica Marchini
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Annalisa Murgo
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Laura Tigli
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Alice Pappani
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Anna Maria Capelli
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | | | - Paola Puccini
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Gino Villetti
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Maurizio Civelli
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Claudia Beato
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Elisa Moro
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Claudia Mundi
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Rosaria Remelli
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Elisabetta Armani
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
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4
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Chen J, Zou P, Quan L, Gong C, Fang Z, Lin B, Lang J, Chen M. Huaxian formula prevents the progression of radiation-induced pulmonary fibrosis by inhibiting the pro-fibrotic effects of macrophages. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119026. [PMID: 39515679 DOI: 10.1016/j.jep.2024.119026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 08/21/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Huaxian formula (HXF), a traditional Chinese medicine (TCM) remedy, specifically targets the pathological factors of "heat toxicity" and "phlegm stasis" induced by radiation in radiation-induced pulmonary fibrosis (RIPF). It works by clearing heat and invigorating the blood, addressing these key factors in the development of RIPF. AIM OF THE STUDY The HXF has demonstrated potential in preventing RIPF, although its underlying mechanisms remain unclear. This study aims to investigate the efficacy, molecular targets, and mechanisms of action of HXF. MATERIALS AND METHODS The major constituents of the HXF were identified by ultra performance liquid chromatography and tandem mass spectrometry (UPLC-MS). C57BL/6j mice were divided into four groups: control (Ctrl), HXF alone (HXF), 17Gy-irradiation alone (IR), and irradiation plus HXF (IR + HXF). Lung damage and fibrosis were assessed by histopathological staining, and the flow cytometry and immunohistochemistry (IHC) were used to detect the macrophages phenotype of lung tissues in vivo at 16 weeks post-irradiation. Transcriptomic sequencing and bioinformatics analyses identified key genes modulated by HXF. In vitro assays included flow cytometry, western bolt, and quantitative PCR (qPCR) explored the impact of HXF on macrophage polarization and fibrotic activity, while co-culture experiments of the macrophage conditional medium and mouse embryo fibroblast NIH/3T3 investigated macrophage-fibroblast interactions. RESULTS 20 major constituents of HXF were identified. And the in vivo results revealed significant lung damage and fibrosis in the IR group, which were notably mitigated in the IR + HXF group. And HXF has been shown to significantly inhibit the infiltration of M2-type macrophages in lung tissues. Transcriptomic analysis identified differentially expressed genes (DEGs) such as Arg1, Mmp10, and Fgf23. Bioinformatics enrichment analysis indicated that these DEGs are involved in pathways related to the inhibition of extracellular matrix formation and inflammation. In vitro, HXF-containing serum reduced M2-type macrophage polarization and decreased the secretion of Arginase1 and TGFβ1. Conditioned medium from HXF-treated macrophages suppressed fibroblast activation. CONCLUSION HXF's preventive effects on RIPF involve multiple targets and mechanisms, including the modulation of Arg1, Mmp10, and Fgf23 expression. By inhibiting the pro-fibrotic capacity of macrophages, HXF suppresses fibroblast activation and collagen production, thereby alleviating lung fibrosis. These findings underscore the potential of HXF as a preventive strategy in managing RIPF.
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Affiliation(s)
- Junyang Chen
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Pingjin Zou
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Li Quan
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610032, China
| | - Cuicui Gong
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610032, China
| | - Zengyi Fang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Bing Lin
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610032, China.
| | - Jinyi Lang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China; Institute of Integrated Traditional Chinese and Western Medicine Cancer Research, Chengdu University of Traditional Chinese Medicine, Chengdu, 610032, China.
| | - Meihua Chen
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
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5
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Molyneaux PL, Spagnolo P. Targeting Autotaxin and Lysophosphatidic Acid in Pulmonary Fibrosis: Admilparant's Positive Results Show Continued Promise. Am J Respir Crit Care Med 2025; 211:148-150. [PMID: 39514842 PMCID: PMC11812539 DOI: 10.1164/rccm.202410-2018ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/18/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024] Open
Affiliation(s)
- Philip L Molyneaux
- National Heart and Lung Institute Imperial College London London, United Kingdom
- Royal Brompton and Harefield Hospitals Guy's and St Thomas' NHS Foundation Trust London, United Kingdom
| | - Paolo Spagnolo
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health University of Padua Padua, Italy
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6
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Corte TJ, Behr J, Cottin V, Glassberg MK, Kreuter M, Martinez FJ, Ogura T, Suda T, Wijsenbeek M, Berkowitz E, Elpers B, Kim S, Watanabe H, Fischer A, Maher TM. Efficacy and Safety of Admilparant, an LPA 1 Antagonist, in Pulmonary Fibrosis: A Phase 2 Randomized Clinical Trial. Am J Respir Crit Care Med 2025; 211:230-238. [PMID: 39393084 DOI: 10.1164/rccm.202405-0977oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/13/2024] [Accepted: 10/01/2024] [Indexed: 10/13/2024] Open
Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) have high morbidity and mortality; thus, novel treatments are needed. Objectives: Assess efficacy and safety of admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 antagonist, in patients with IPF and PPF. Methods: This phase 2, randomized, double-blind, placebo-controlled trial included parallel cohorts of patients with IPF (n = 278 randomized, n = 276 treated) or PPF (n = 125 randomized, n = 123 treated) who received 30 mg of admilparant, 60 mg of admilparant, or placebo (1:1:1) twice daily for 26 weeks. Background antifibrotics (both cohorts) and immunosuppressants (PPF only) were permitted. Measurements and Main Results: Rates of change in percentage of predicted FVC over 26 weeks for IPF were -2.7% (placebo), -2.8% (30 mg), and -1.2% (60 mg) and for PPF were -4.3% (placebo), -2.9% (30 mg), and -1.1% (60 mg). Treatment differences between 60-mg admilparant and placebo were 1.4% (95% confidence interval, -0.1 to 3.0) for IPF and 3.2% (95% confidence interval, 0.7 to 5.7) for PPF. Treatment effect was observed with or without background antifibrotics in both cohorts. Diarrhea occurred at similar frequencies in admilparant arms versus placebo. Transient Day 1 postdose blood pressure reductions were observed in all arms in both cohorts but were greater with admilparant. Treatment discontinuations because of adverse events were similar across IPF arms and lower with admilparant (2.5% [30 mg]; 0% [60 mg]) versus placebo (17.1%) for PPF. Conclusions: In this first phase 2 study to evaluate antifibrotic treatment in parallel IPF and PPF cohorts, 60-mg admilparant slowed lung function decline and was safe and well tolerated, supporting further evaluation in phase 3 trials. Clinical trial registered with clinicaltrials.gov identifier (NCT04308681).
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Affiliation(s)
- Tamera J Corte
- Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
- University of Sydney, Sydney, Australia
| | - Juergen Behr
- Department of Medicine V, LMU University Hospital, LMU Munich, Member of the German Center for Lung Research, Munich, Germany
| | - Vincent Cottin
- National French Reference Coordinating Center for Rare Pulmonary Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, University Claude Bernard, Lyon, France
| | - Marilyn K Glassberg
- Department of Medicine, Loyola University Chicago Stritch School of Medicine, Chicago, Illinois
| | - Michael Kreuter
- Department of Pneumology, Mainz Center for Pulmonary Medicine, Mainz University Medical Center, Mainz, Germany
- Department of Pulmonary, Critical Care, and Sleep Medicine, Marienhaus Clinic Mainz, Mainz, Germany
| | - Fernando J Martinez
- Department of Medicine, Weill Cornell Medicine/New York Presbyterian Hospital, New York, New York
| | - Takashi Ogura
- Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan
| | - Takafumi Suda
- Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Marlies Wijsenbeek
- Department of Respiratory Medicine, Center for Interstitial Lung Disease and Sarcoidosis, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | | | | | - Sinae Kim
- Bristol Myers Squibb, Princeton, New Jersey
| | | | | | - Toby M Maher
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Southern California, Los Angeles, California; and
- National Heart and Lung Institute, Imperial College, London, United Kingdom
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7
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Machahua C, Marti TM, Dorn P, Funke-Chambour M. Fibrosis in PCLS: comparing TGF-β and fibrotic cocktail. Respir Res 2025; 26:44. [PMID: 39875887 PMCID: PMC11776118 DOI: 10.1186/s12931-025-03110-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/08/2024] [Accepted: 01/10/2025] [Indexed: 01/30/2025] Open
Abstract
INTRODUCTION Fibrotic cocktail (FC) is a combination of pro-fibrotic and pro-inflammatory mediators that induces early fibrotic changes in organotypic lung models. We hypothesised that transforming growth factor beta 1 (TGF-β1) alone induces a pro-fibrotic effect similar to FC. Our aim was to compare the pro-fibrotic effects of TGF-β1 with FC in human precision-cut lung slices (PCLS). METHODS PCLS from "healthy" lung tissue of cancer patients undergoing surgery (n = 7) were incubated with TGF-β1, FC or control for 72 h. Gene expression markers for myofibroblasts differentiation, extracellular matrix (ECM), as well as TGF-β receptors were assessed (RT-qPCR). ECM proteins expression in lysates and supernatant was assessed by ELISA and immunofluorescence. RESULTS We found that TGF-β1 significantly increased gene expression of ACTA2, COL1A1, CCN2, and VIM compared to control but also compared to FC. FC showed a significant increase of matrix metalloproteinase (MMP) 7 and 1 compared to control, while TGF-β receptor 2 was lower after FC compared to TGF-β1 or control. FC or TGF-β1 showed similar fibronectin protein expression in lysates and supernatants, while type I collagen protein expression in lysates was significantly greater with TGF-β1 compared to control. CONCLUSIONS Our findings show that TGF-β1 induces consistent pro-fibrotic changes in PCLS after 72 h. Compared to TGF-β1, FC treatment resulted in reduced gene expression of TGF-β receptor 2 and increased MMPs expression, potentially mitigating the early pro-fibrotic effects. Selecting specific pro-fibrotic stimuli may be preferable depending on the research question and time point of interest in lung fibrosis studies using PCLS.
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Affiliation(s)
- Carlos Machahua
- Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
- Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
| | - Thomas M Marti
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBRM), University of Bern, Bern, Switzerland
| | - Patrick Dorn
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBRM), University of Bern, Bern, Switzerland
| | - Manuela Funke-Chambour
- Department for Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Lung Precision Medicine (LPM), Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
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8
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Ma D, Tan Z, Li S, Zhao B, Yue L, Wei X, Xu S, Jiang N, Lei H, Zhai X. Discovery of Novel 4,5,6,7-Tetrahydro-7 H-pyrazolo[3,4- c]pyridin-7-one Derivatives as Orally Efficacious ATX Allosteric Inhibitors for the Treatment of Pulmonary Fibrosis. J Med Chem 2025; 68:792-818. [PMID: 39720950 DOI: 10.1021/acs.jmedchem.4c02719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/26/2024]
Abstract
Pulmonary fibrosis (PF) is a progressive, fatal lung disease lacking effective treatments. Autotaxin (ATX) plays a crucial role in exacerbating inflammation and fibrosis, making it a promising target for fibrosis therapies. Herein, starting from PAT-409 (Cudetaxestat), a series of novel ATX inhibitors bearing 1H-indole-3-carboxamide, 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one, or 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine cores were designed based on the structure of ATX hydrophobic tunnel. The optimal 31 and 35 inhibited ATX with IC50 values of 2.8 and 0.7 nM, respectively. In a bleomycin-induced mouse PF model, both compounds significantly reduced fibrosis by regulating the TGF-β/Smad signaling pathway and downregulating collagen deposition. Furthermore, 35 exhibited both negligibly low hERG channel inhibition (IC50 > 30 μM) and remarkable microsomal stability. Notably, 35 was characterized by favorable pharmacokinetic properties (F = 69.5%) and excellent safety in vivo. Overall, 35 turned out to be a well-characterized potent and safe ATX inhibitor warranting further investigation for the treatment of PF.
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Affiliation(s)
- Deyi Ma
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zehui Tan
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Sen Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Bing Zhao
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Lingfeng Yue
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xiujian Wei
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Sha Xu
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Nan Jiang
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Hongrui Lei
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xin Zhai
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
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9
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Lu W, Teoh A, Waters M, Haug G, Shakeel I, Hassan I, Shahzad AM, Callerfelt AKL, Piccari L, Sohal SS. Pathology of idiopathic pulmonary fibrosis with particular focus on vascular endothelium and epithelial injury and their therapeutic potential. Pharmacol Ther 2025; 265:108757. [PMID: 39586361 DOI: 10.1016/j.pharmthera.2024.108757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/27/2024] [Revised: 10/15/2024] [Accepted: 11/20/2024] [Indexed: 11/27/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) remains a challenging disease with no drugs available to change the trajectory. It is a condition associated with excessive and highly progressive scarring of the lungs with remodelling and extracellular matrix deposition. It is a highly "destructive" disease of the lungs. The diagnosis of IPF is challenging due to continuous evolution of the disease, which also makes early interventions very difficult. The role of vascular endothelial cells has not been explored in IPF in great detail. We do not know much about their contribution to arterial or vascular remodelling, extracellular matrix changes and contribution to pulmonary hypertension and lung fibrosis in general. Endothelial to mesenchymal transition appears to be central to such changes in IPF. Similarly, for epithelial changes, the process of epithelial to mesenchymal transition seem to be the key both for airway epithelial cells and type-2 pneumocytes. We focus here on endothelial and epithelial cell changes and its contributions to IPF. In this review we revisit the pathology of IPF, mechanistic signalling pathways, clinical definition, update on diagnosis and new advances made in treatment of this disease. We discuss ongoing clinical trials with mode of action. A multidisciplinary collaborative approach is needed to understand this treacherous disease for new therapeutic targets.
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Affiliation(s)
- Wenying Lu
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Newnham, Tasmania 7248, Australia; National Health and Medical Research Council (NHMRC) Centre of Research Excellence (CRE) in Pulmonary Fibrosis, Respiratory Medicine and Sleep Unit, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
| | - Alan Teoh
- National Health and Medical Research Council (NHMRC) Centre of Research Excellence (CRE) in Pulmonary Fibrosis, Respiratory Medicine and Sleep Unit, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
| | - Maddison Waters
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Newnham, Tasmania 7248, Australia; Department of Respiratory Medicine, Launceston General Hospital, Launceston, Tasmania 7250, Australia
| | - Greg Haug
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Newnham, Tasmania 7248, Australia; Department of Respiratory Medicine, Launceston General Hospital, Launceston, Tasmania 7250, Australia
| | - Ilma Shakeel
- Centre For Interdisciplinary Research In Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Imtaiyaz Hassan
- Centre For Interdisciplinary Research In Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Affan Mahmood Shahzad
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Newnham, Tasmania 7248, Australia; Medical School, Oceania University of Medicine, Apia, Samoa
| | | | - Lucilla Piccari
- Department of Pulmonology, Hospital del Mar, Barcelona, Spain
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Newnham, Tasmania 7248, Australia; National Health and Medical Research Council (NHMRC) Centre of Research Excellence (CRE) in Pulmonary Fibrosis, Respiratory Medicine and Sleep Unit, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
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10
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Dietrich J, Kang A, Tielemans B, Verleden SE, Khalil H, Länger F, Bruners P, Mentzer SJ, Welte T, Dreher M, Jonigk DD, Ackermann M. The role of vascularity and the fibrovascular interface in interstitial lung diseases. Eur Respir Rev 2025; 34:240080. [PMID: 39909504 PMCID: PMC11795288 DOI: 10.1183/16000617.0080-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/12/2024] [Accepted: 10/24/2024] [Indexed: 02/07/2025] Open
Abstract
Interstitial lung disease (ILD) is a clinical term that refers to a diverse group of non-neoplastic lung diseases. This group includes idiopathic and secondary pulmonary entities that are often associated with progressive pulmonary fibrosis. Currently, therapeutic approaches based on specific structural targeting of pulmonary fibrosis are limited to nintedanib and pirfenidone, which can only slow down disease progression leading to a lower mortality rate. Lung transplantation is currently the only available curative treatment, but it is associated with high perioperative mortality. The pulmonary vasculature plays a central role in physiological lung function, and vascular remodelling is considered a hallmark of the initiation and progression of pulmonary fibrosis. Different patterns of pulmonary fibrosis commonly exhibit detectable pathological features such as morphomolecular changes, including intussusceptive and sprouting angiogenesis, vascular morphometry, broncho-systemic anastomoses, and aberrant angiogenesis-related gene expression patterns. Dynamic cellular interactions within the fibrovascular interface, such as endothelial activation and endothelial-mesenchymal transition, are also observed. This review aims to summarise the current clinical, radiological and pathological diagnostic algorithm for different ILDs, including usual interstitial pneumonia/idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, alveolar fibroelastosis/pleuroparenchymal fibroelastosis, hypersensitivity pneumonitis, systemic sclerosis-related ILD and coronavirus disease 2019 injury. It emphasises an interdisciplinary clinicopathological perspective. Additionally, the review covers current therapeutic strategies and knowledge about associated vascular abnormalities.
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Affiliation(s)
- Jana Dietrich
- Institute of Pathology, University Clinics Aachen, RWTH University of Aachen, Aachen, Germany
- J. Dietrich and A. Kang share first authorship
| | - Alice Kang
- Department of Pneumology and Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, Germany
- J. Dietrich and A. Kang share first authorship
| | - Birger Tielemans
- Institute of Pathology, University Clinics Aachen, RWTH University of Aachen, Aachen, Germany
| | - Stijn E Verleden
- Antwerp Surgical Training, Anatomy and Research Centre (ASTARC), University of Antwerp, Edegem, Belgium
- Department of Respiratory Medicine, University Hospital Antwerp, Edegem, Belgium
| | - Hassan Khalil
- Laboratory of Adaptive and Regenerative Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Thoracic Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Florian Länger
- Institute of Pathology, University Clinics Aachen, RWTH University of Aachen, Aachen, Germany
| | - Philipp Bruners
- Department of Diagnostic and Interventional Radiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Steven J Mentzer
- Laboratory of Adaptive and Regenerative Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Thoracic Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Tobias Welte
- Department of Respiratory Medicine and Infectious Disease, Hannover Medical School, Hannover, Germany
| | - Michael Dreher
- Department of Pneumology and Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | - Danny D Jonigk
- Institute of Pathology, University Clinics Aachen, RWTH University of Aachen, Aachen, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
- Institute of Pathology, Hannover Medical School, Hannover, Germany
- D.D. Jonigk and M. Ackermann share senior authorship
| | - Maximilian Ackermann
- Institute of Pathology, University Clinics Aachen, RWTH University of Aachen, Aachen, Germany
- Institute of Pathology and Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Wuppertal, Germany
- Institute of Anatomy, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
- D.D. Jonigk and M. Ackermann share senior authorship
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11
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Liu JQ, Zhou HB, Bai WF, Wang J, Li Q, Fan LY, Chang H, Shi SL. Assessment of progression of pulmonary fibrosis based on metabonomics and analysis of intestinal microbiota. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2024; 52:201-217. [PMID: 38488151 DOI: 10.1080/21691401.2024.2326616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 06/26/2023] [Accepted: 02/27/2024] [Indexed: 03/19/2024]
Abstract
The main purpose of this study was to explore the changes of biomarkers in different developmental stages of bleomycin-induced pulmonary fibrosis (PF) in rats via comprehensive pathophysiology, UPLC-QTOF/MS metabonomic technology, and 16S rRNA gene sequencing of intestinal microbiota. The rats were randomly divided into normal control and 1-, 2- and 4-week model group. The rat model of PF was established by one-time intratracheal instillation of bleomycin. The levels of inflammatory and fibrosis-related factors such as hydroxyproline (HYP), type III procollagen (COL-III), type IV collagen (COL-IV), hyaluronidase (HA), laminin (LN), interleukin (IL)-1β, IL-6, malondialdehyde (MDA) increased and superoxide dismutase (SOD) decreased as the PF cycle progressed. In the 1-, 2- and 4-week model group, 2, 19 and 18 potential metabolic biomarkers and 3, 16 and 12 potential microbial biomarkers were detected, respectively, which were significantly correlated. Glycerophospholipid metabolism pathway was observed to be an important pathway affecting PF at 1, 2 and 4 weeks; arginine and proline metabolism pathways significantly affected PF at 2 weeks. Linoleic acid metabolism pathway exhibited clear metabolic abnormalities at 2 and 4 weeks of PF, and alpha-linolenic acid metabolism pathway significantly affected PF at 4 weeks.
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Affiliation(s)
- Jia-Qi Liu
- Department of Pharmacy, Baotou Medical College, Baotou, PR China
| | - Hong-Bing Zhou
- Department of Pharmacy, Baotou Medical College, Baotou, PR China
- Institute of Bioactive Substance and Function of Mongolian Medicine and Chinese Materia Medica, Baotou Medical College, Baotou, PR China
| | - Wan-Fu Bai
- Department of Pharmacy, Baotou Medical College, Baotou, PR China
| | - Jia Wang
- Department of Pharmacy, Baotou Medical College, Baotou, PR China
| | - Qian Li
- Department of Pharmacy, Baotou Medical College, Baotou, PR China
| | - Li-Ya Fan
- Department of Pharmacy, Baotou Medical College, Baotou, PR China
| | - Hong Chang
- Department of Pharmacy, Baotou Medical College, Baotou, PR China
| | - Song-Li Shi
- Department of Pharmacy, Baotou Medical College, Baotou, PR China
- Institute of Bioactive Substance and Function of Mongolian Medicine and Chinese Materia Medica, Baotou Medical College, Baotou, PR China
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12
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Jose A, Fernando JJ, Kienesberger PC. Lysophosphatidic acid metabolism and signaling in heart disease. Can J Physiol Pharmacol 2024; 102:685-696. [PMID: 38968609 DOI: 10.1139/cjpp-2024-0077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 07/07/2024]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid that is mainly produced by the secreted lysophospholipase D, autotaxin (ATX), and signals through at least six G protein-coupled receptors (LPA1-6). Extracellular LPA is degraded through lipid phosphate phosphatases (LPP1, LPP2, and LPP3) at the plasmamembrane, terminating LPA receptor signaling. The ATX-LPA-LPP3 pathway is critically involved in a wide range of physiological processes, including cell survival, migration, proliferation, angiogenesis, and organismal development. Similarly, dysregulation of this pathway has been linked to many pathological processes, including cardiovascular disease. This review summarizes and interprets current literature examining the regulation and role of the ATX-LPA-LPP3 axis in heart disease. Specifically, the contribution of altered LPA metabolism via ATX and LPP3 and resulting changes to LPA receptor signaling in obesity cardiomyopathy, cardiac mitochondrial dysfunction, myocardial infarction/ischemia-reperfusion injury, hypertrophic cardiomyopathy, and aortic valve stenosis is discussed.
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Affiliation(s)
- Anu Jose
- Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, Canada
| | - Jeffy J Fernando
- Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, Canada
| | - Petra C Kienesberger
- Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, Canada
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13
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Tang DT, Du Z, Yang KS, Bestvater BP, Kaplan J, Neubig ME, Olen CL, Phillips B, Wang P, Hudson T, Marchand B, Chan J, Sharma M, Hu Y, Matles M, Nejati E, Chojnacka M, Adams C, Pong C, Holsapple K, Budas G, Tsui V, Venkataramani C, Lazerwith SE, Notte GT, Watkins WJ, McGlinchey E, Zagorska A, Farand J. Discovery of GS-2278, a Potent and Selective LPAR1 Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis. J Med Chem 2024. [PMID: 39570661 DOI: 10.1021/acs.jmedchem.4c02090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2024]
Abstract
We describe the discovery and preclinical characterization of a potent and selective lysophosphatidic acid receptor 1 (LPAR1) antagonist with a direct-acting antifibrotic mechanism. 18a was initially identified as a potent non-carboxylic acid LPAR1 antagonist in an LPA-induced myocardin-related transcription factor A (MRTF-A) nuclear translocation assay. Modifications to the aromatic elements in the structure allowed for improvements in metabolic stability and the mitigation of GSH adduct formation, but in vitro to in vivo clearance disconnects were observed with several potent sulfonamides (e.g., 27b) across preclinical species. Through modification of the sulfonamide, 42 (GS-2278) emerged as a potent LPAR1 antagonist with a suitable in vitro profile and desirable pharmacokinetic properties for oral QD dosing. GS-2278 dose-dependently blocked LPA-induced histamine release and demonstrated efficacy in an interventional model of bleomycin-induced lung fibrosis. However, CNS-related toxicity was observed in dogs, and based on these findings, the clinical development of GS-2278 for IPF was halted.
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Affiliation(s)
- Doris T Tang
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Zhimin Du
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Kin S Yang
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Brian P Bestvater
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Joshua Kaplan
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Megan E Neubig
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Casey L Olen
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Bart Phillips
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Peiyuan Wang
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Thomas Hudson
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Bruno Marchand
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Julie Chan
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Monika Sharma
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Yiding Hu
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Mike Matles
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Elham Nejati
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Maja Chojnacka
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Clifton Adams
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Cassie Pong
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Kevin Holsapple
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Grant Budas
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Vickie Tsui
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | | | - Scott E Lazerwith
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Gregory T Notte
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - William J Watkins
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Ellen McGlinchey
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Anna Zagorska
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Julie Farand
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
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14
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Kadam AH, Schnitzer JE. Highly Calibrated Relationship Between Bleomycin Concentrations and Facets of the Active Phase Fibrosis in Classical Mouse Bleomycin Model. Int J Mol Sci 2024; 25:12300. [PMID: 39596365 PMCID: PMC11595013 DOI: 10.3390/ijms252212300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/12/2024] [Revised: 11/09/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
The mouse bleomycin model is useful in pre-clinical IPF research to understand pathophysiological mechanisms and pharmacological interventions. In the present study, we systematically investigated the effects of bleomycin at a 60-fold dose range on experimental features of lung fibrosis in the mouse bleomycin model. We analyzed the effect of intratracheal (i.t.) dosing of 0.05-3 U/kg bleomycin on disease phenotypes, including weight loss, morbidity and mortality, pulmonary inflammation, lung collagen content, various BALF biomarkers, and histology in a 14-day mouse model when the animals are in the active phase of fibrosis. In mice, challenge with 1-2 U/kg bleomycin doses induced significant and saturated responses on fibrotic endpoints, confirmed by collagen content, BALF biomarker levels, and marked weight loss compared to the normal control (NC). We observed 100% mortality in 3 U/kg of bleomycin-treated mice. In contrast, 0.05-0.5 U/kg bleomycin doses induced a dose-dependent fibrotic phenotype. The mice challenged with doses of 0.25-0.5 U/kg bleomycin showed optimum body weight loss, a significant increase in pulmonary inflammation, and the fibrotic phenotype compared to NC. Furthermore, we showed 0.25-0.5 U/kg bleomycin increases expression levels of (pro-) fibrotic cytokines, which are the mediators involved in the activation of myofibroblast during fibrogenesis (TGF-β1, IL-13, IL-6, WISP-1, VEGF), angiogenesis (VEGF), matrix remodeling (TIMP-1), and non-invasive lung function biomarker (CRP) compared to NC. A modified Ashcroft scale quantified that the fibrotic changes in the lungs were significantly higher in the lung of mice dosed at 0.25-0.5 U/kg > 0.1 U/kg bleomycin and non-significant in mice lung dosed at 0.05 U/kg bleomycin compared to NC. We demonstrated that the changes due to 0.25-0.5 U/kg i.t. bleomycin on protein biomarkers are enough to drive robust and detectable fibrotic pathology without mortality. The 0.1 U/kg has a moderate phenotype, and 0.05 U/kg had no detectable phenotype. The Goodness of Fit (r2) and Pearson correlation coefficient (r) analyses revealed a positive linear association between change evaluated in all experimental features of fibrosis and bleomycin concentrations (0.05-0.5 U/kg). Here, we provide an examination of a highly calibrated relationship between 60-fold bleomycin concentrations and a set of in vivo readouts that covers various facets of experimental fibrosis. Our study shows that there is a dose-dependent effect of bleomycin on the features of experimental fibrosis at <1 U/kg, whereas saturated responses are achieved at >1 U/kg. Our careful experimental observations, accuracy, and comprehensive data set provided meaningful insights into the effect of bleomycin dose(s) on the fibrotic phenotype, which is valuable in preclinical drug development and lung fibrosis research. In addition, we have presented a set of reproducible frameworks of endpoints that can be used for reliable assessment of the fibrotic phenotype, and in vivo therapeutic intervention(s) with improved accuracy.
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Affiliation(s)
| | - Jan E. Schnitzer
- Proteogenomics Research Institute for Systems Medicine (PRISM), 505 Coast Blvd. South, La Jolla, CA 92037, USA;
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15
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Mondoni M, Rinaldo R, Ryerson CJ, Albrici C, Baccelli A, Tirelli C, Marchetti F, Cefalo J, Nalesso G, Ferranti G, Alfano F, Sotgiu G, Guazzi M, Centanni S. Vascular involvement in idiopathic pulmonary fibrosis. ERJ Open Res 2024; 10:00550-2024. [PMID: 39588083 PMCID: PMC11587140 DOI: 10.1183/23120541.00550-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/29/2024] [Accepted: 07/17/2024] [Indexed: 11/27/2024] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing and progressive interstitial lung disease of unknown aetiology with a pathogenesis still partly unknown. Several microvascular and macrovascular abnormalities have been demonstrated in the pathogenesis of IPF and related pulmonary hypertension (PH), a complication of the disease. Methods We carried out a non-systematic, narrative literature review aimed at describing the role of the vasculature in the natural history of IPF. Results The main molecular pathogenetic mechanisms involving vasculature (i.e. endothelial-to-mesenchymal transition, vascular remodelling, endothelial permeability, occult alveolar haemorrhage, vasoconstriction and hypoxia) and the genetic basis of vascular remodelling are described. The prevalence and clinical relevance of associated PH are highlighted with focus on the vasculature as a prognostic marker. The vascular effects of current antifibrotic therapies, the role of pulmonary vasodilators in the treatment of disease, and new pharmacological options with vascular-targeted activity are described. Conclusions The vasculature plays a key role in the natural history of IPF from the early phases of disease until development of PH in a subgroup of patients, a complication related to a worse prognosis. Pulmonary vascular volume has emerged as a novel computed tomography finding and a predictor of mortality, independent of PH. New pharmacological options with concomitant vascular-directed activity might be promising in the treatment of IPF.
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Affiliation(s)
- Michele Mondoni
- Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
| | - Rocco Rinaldo
- Department of Medical Sciences, Respiratory Diseases Unit, AOU Città della Salute e della Scienza di Torino, Molinette Hospital, University of Turin, Turin, Italy
| | - Christopher J. Ryerson
- Department of Medicine and Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada
| | - Cristina Albrici
- Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
| | - Andrea Baccelli
- Department of Respiratory Medicine, Royal Brompton Hospital, Guy's and St Thomas’ NHS Foundation Trust, London, UK
| | - Claudio Tirelli
- Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
| | - Francesca Marchetti
- Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
| | - Jacopo Cefalo
- Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
| | - Giulia Nalesso
- Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
| | - Giulia Ferranti
- Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
| | - Fausta Alfano
- Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
| | - Giovanni Sotgiu
- Dept of Medical, Clinical Epidemiology and Medical Statistics Unit, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Marco Guazzi
- Department of Cardiology, University of Milano School of Medicine, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Stefano Centanni
- Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
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16
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Bock-Pereda A, Cruz-Soca M, Gallardo FS, Córdova-Casanova A, Gutierréz-Rojas C, Faundez-Contreras J, Chun J, Casar JC, Brandan E. Involvement of lysophosphatidic acid-LPA 1-YAP signaling in healthy and pathological FAPs migration. Matrix Biol 2024; 133:103-115. [PMID: 39153517 DOI: 10.1016/j.matbio.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/05/2024] [Revised: 07/09/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024]
Abstract
Skeletal muscle fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) components and is a hallmark of muscular dystrophies. Fibro-adipogenic progenitors (FAPs) are the main source of ECM, and thus have been strongly implicated in fibrogenesis. In skeletal muscle fibrotic models, including muscular dystrophies, FAPs undergo dysregulations in terms of proliferation, differentiation, and apoptosis, however few studies have explored the impact of FAPs migration. Here, we studied fibroblast and FAPs migration and identified lysophosphatidic acid (LPA), a signaling lipid central to skeletal muscle fibrogenesis, as a significant migration inductor. We identified LPA receptor 1 (LPA1) mediated signaling as crucial for this effect through a mechanism dependent on the Hippo pathway, another pathway implicated in fibrosis across diverse tissues. This cross-talk favors the activation of the Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), leading to increased expression of fibrosis-associated genes. This study reveals the role of YAP in LPA-mediated fibrotic responses as inhibition of YAP transcriptional coactivator activity hinders LPA-induced migration in fibroblasts and FAPs. Moreover, we found that FAPs derived from the mdx4cv mice, a murine model of Duchenne muscular dystrophy, display a heightened migratory phenotype due to enhanced LPA signaling compared to wild-type FAPs. Remarkably, we found that the inhibition of LPA1 or YAP transcriptional coactivator activity in mdx4cv FAPs reverts this phenotype. In summary, the identified LPA-LPA1-YAP pathway emerges as a critical driver of skeletal muscle FAPs migration and provides insights into potential novel targets to mitigate fibrosis in muscular dystrophies.
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Affiliation(s)
- Alexia Bock-Pereda
- Facultad de Ciencias Biológicas, Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago 7750000, Chile
| | - Meilyn Cruz-Soca
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago 7750000, Chile
| | - Felipe S Gallardo
- Facultad de Ciencias Biológicas, Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago 7750000, Chile
| | | | - Cristian Gutierréz-Rojas
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago 7750000, Chile; Escuela de Kinesiología, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2340025, Chile; Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile
| | - Jennifer Faundez-Contreras
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago 7750000, Chile; Facultad de Medicina y Ciencia, Fundación Ciencia y Vida, Universidad San Sebastián, Avenida del Valle Norte 725 Huechuraba, Santiago 7510602, Chile
| | - Jerold Chun
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Juan Carlos Casar
- Departamento de Neurología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile
| | - Enrique Brandan
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago 7750000, Chile; Facultad de Medicina y Ciencia, Fundación Ciencia y Vida, Universidad San Sebastián, Avenida del Valle Norte 725 Huechuraba, Santiago 7510602, Chile.
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17
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Ha AW, Sudhadevi T, Jafri A, Mayer C, MacFarlane PM, Natarajan V, Harijith A. Bronchopulmonary dysplasia demonstrates dysregulated autotaxin/lysophosphatidic acid signaling in a neonatal mouse model. Pediatr Res 2024:10.1038/s41390-024-03610-9. [PMID: 39415037 DOI: 10.1038/s41390-024-03610-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/17/2024] [Revised: 09/10/2024] [Accepted: 09/13/2024] [Indexed: 10/18/2024]
Abstract
BACKGROUND Bronchopulmonary dysplasia (BPD) is a chronic lung disease affecting premature infants who require oxygen supplementation and ventilator therapy to support their underdeveloped lungs. Autotaxin (ATX), an enzyme that generates the bioactive phospholipid lysophosphatidic acid (LPA), which acts via G-protein coupled receptors, has been implicated in numerous pulmonary diseases. In this study, we explored the pathophysiological role of the ATX/LPA signaling pathway in BPD. METHODS Neonatal mice were exposed to normoxia or hyperoxia (85%) for 14 days from birth while being treated with vehicle, ATX inhibitor or LPA receptor 1 (LPA1) inhibitor. In vitro studies utilized human lung fibroblast (HLF) cells exposed to room air, 85% oxygen, or LPA for varying time periods. Supernatants and cells were collected for assays and Western blotting. RESULTS Animals exposed to hyperoxia showed elevated expression of ATX, ATX activity, and LPA1. Inhibiting ATX or LPA1 improved alveolarization, reduced inflammation, and mitigated extracellular matrix deposition and lysyl oxidase (LOX) expression. LPA1 inhibition leading to reduced LOX expression was associated with a reduction in phosphorylation of AKT. CONCLUSION Hyperoxia increases the expression of ATX and LPA1 associated with increased LOX in the lungs. Targeting the ATX/LPA1 pathway could be a potential therapeutic approach to BPD. IMPACT Exposure to hyperoxia increases the expression and activity of autotaxin (ATX), as well as expression of LPA receptor 1 (LPA1). Increased expression of ATX influences extra cellular matrix (ECM) remodeling. Inhibitors targeting the ATX/LPA pathway could offer a new therapeutic approach to bronchopulmonary dysplasia (BPD), potentially mitigating ECM deposition and improving lung development.
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Affiliation(s)
- Alison W Ha
- Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL, USA
| | - Tara Sudhadevi
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Anjum Jafri
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Cathy Mayer
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Peter M MacFarlane
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Viswanathan Natarajan
- Department of Pharmacology, University of Illinois, Chicago, IL, USA
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Anantha Harijith
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
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18
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Deng X, Liu J, Zhou J, Shi Y, Song S, Chen J, Li Y, Yu B, Liang SH, Zhu X. Imaging Pulmonary Fibrosis and Treatment Efficacy In Vivo with Autotaxin-Specific PET Ligand [ 18F]ATX-1905. Mol Pharm 2024; 21:5171-5181. [PMID: 39186477 DOI: 10.1021/acs.molpharmaceut.4c00571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 08/28/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by unpredictable progression and limited therapeutic options. Current diagnosis relies on high resolution computed tomography (HRCT), which may not adequately capture early signs of deterioration. The enzyme autotaxin (ATX) emerges as a prominently expressed extracellular secretory enzyme in the lungs of IPF patients. The objective of this study was to evaluate the effectiveness of 18F-labeled ATX-targeted tracer [18F]ATX-1905, in comparison with [18F]FDG, for early fibrosis diagnosis, disease evolution monitoring, and treatment efficacy assessment in bleomycin-induced pulmonary fibrosis (BPF) models. To assess treatment efficacy, mice were treated with two commonly used drugs for IPF, pirfenidone or nintedanib, from Day 9 to Day 23 postbleomycin administration. Lung tissue assessments encompassed inflammation severity via H&E staining, and Ashcroft scoring via Masson staining, alongside quantification of ATX expression through ELISA. Positron emission tomography (PET) imaging employing [18F]FDG and [18F]ATX-1905 tracked disease progression pre- and post-treatment. The extent of pulmonary fibrosis corresponded to changes in ATX expression levels in the BPF mouse model. Notably, [18F]ATX-1905 exhibited elevated uptake in BPF lungs during the progression of the disease, particularly evident at the early stage (Day 9). This uptake was inhibited by an ATX inhibitor, PF-8380, underscoring the specificity of the radiotracer. Conversely, [18F]FDG uptake, peaking at Day 15, decreased subsequently, likely reflective of diminished inflammation. A 2-week treatment regimen using either pirfenidone or nintedanib resulted in notable reductions of ATX expression levels and fibrosis degrees within lung tissues, based on ELISA and Masson staining, as evidenced by PET imaging with [18F]ATX-1905. [18F]FDG uptake also decreased following the treatment period. Additionally, PET/CT imaging extended to a nonhuman primate (NHP) BPF model. The uptake of [18F]ATX-1905 (SUVmax = 2.2) was significantly higher than that of [18F]FDG (SUVmax = 0.7) in fibrotic lung tissue. Using our novel ATX-specific radiotracer [18F]ATX-1905 and PET/CT imaging, we demonstrated excellent ability in early fibrosis detection, disease monitoring, and treatment assessment within lungs of the BPF mouse models. [18F]ATX-1905 displayed remarkable specificity for ATX expression and high sensitivity for ATX alterations, suggesting its potential for monitoring varying ATX expression in lungs of IPF patients.
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Affiliation(s)
- Xiaoyun Deng
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Junyi Liu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Jianyuan Zhou
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Yifan Shi
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Shuang Song
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Jiahui Chen
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States
| | - Yinlong Li
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States
| | - Bo Yu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Steven H Liang
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia 30322, United States
| | - Xiaohua Zhu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
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19
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Okamoto Y, Kitakaze K, Takenouchi Y, Matsui R, Koga D, Miyashima R, Ishimaru H, Tsuboi K. GPR176 promotes fibroblast-to-myofibroblast transition in organ fibrosis progression. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119798. [PMID: 39047914 DOI: 10.1016/j.bbamcr.2024.119798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 01/31/2024] [Revised: 06/20/2024] [Accepted: 07/14/2024] [Indexed: 07/27/2024]
Abstract
Fibrosis is characterized by excessive deposition of extracellular matrix proteins, particularly collagen, caused by myofibroblasts in response to chronic inflammation. Although G protein-coupled receptors (GPCRs) are among the targets of current antifibrotic drugs, no drug has yet been approved to stop fibrosis progression. Herein, we aimed to identify GPCRs with profibrotic effects. In gene expression analysis of mouse lungs with induced fibrosis, eight GPCRs were identified, showing a >2-fold increase in mRNA expression after fibrosis induction. Among them, we focused on Gpr176 owing to its significant correlation with a myofibroblast marker α-smooth muscle actin (αSMA), the profibrotic factor transforming growth factor β1 (TGFβ1), and collagen in a human lung gene expression database. Similar to the lung fibrosis model, increased Gpr176 expression was also observed in other organs affected by fibrosis, including the kidney, liver, and heart, suggesting its role in fibrosis across various organs. Furthermore, fibroblasts abundantly expressed Gpr176 compared to alveolar epithelial cells, endothelial cells, and macrophages in the fibrotic lung. GPR176 expression was unaffected by TGFβ1 stimulation in rat renal fibroblast NRK-49 cells, whereas knockdown of Gpr176 by siRNA reduced TGFβ1-induced expression of αSMA, fibronectin, and collagen as well as Smad2 phosphorylation. This suggested that Gpr176 regulates fibroblast activation. Consequently, Gpr176 acts in a profibrotic manner, and inhibiting its activity could potentially prevent myofibroblast differentiation and improve fibrosis. Developing a GPR176 inverse agonist or allosteric modulator is a promising therapeutic approach for fibrosis.
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Affiliation(s)
- Yasuo Okamoto
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
| | - Keisuke Kitakaze
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Yasuhiro Takenouchi
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Rena Matsui
- Department of Medical Technology, Kawasaki University of Medical Welfare, Kurashiki, Okayama 701-0192, Japan
| | - Daisuke Koga
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Ryo Miyashima
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Hironobu Ishimaru
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Kazuhito Tsuboi
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
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20
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Horikoshi K, Sakai N, Oshima M, Yamauchi H, Ikeda M, Hayashi K, Yanagisawa H, Yamamori F, Kajikawa S, Hayashi D, Koshino A, Sako K, Yuasa T, Tamai A, Minami T, Nakagawa S, Kitajima S, Toyama T, Hara A, Shimizu M, Oota S, Ishida Y, Wada T, Iwata Y. Autotaxin concentrations in peritoneal dialysis effluent reflect peritoneal function. Ther Apher Dial 2024. [PMID: 39326924 DOI: 10.1111/1744-9987.14211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/28/2024] [Revised: 06/13/2024] [Accepted: 09/06/2024] [Indexed: 09/28/2024]
Abstract
INTRODUCTION Peritoneal equilibration test (PET) has been used to monitor peritoneal function. A more convenient marker would be useful in clinical situations including home medical care. Autotaxin is known to leak into the interstitium as vascular permeability increases during the progression of tissue fibrosis. Therefore, we hypothesized that autotaxin concentrations in peritoneal dialysis (PD) effluent might reflect peritoneal function. METHODS This study enrolled 45 patients undergoing PD from 2016 to 2021. Autotaxin concentrations measured in PD effluent were evaluated for their associations with markers obtained from PET. RESULTS Mean age was 69 years, and 33 patients were men. Univariate and multivariate analyses revealed that autotaxin concentrations are associated with dialysate/plasma creatinine ratio, end/start dialysate glucose ratio, and the dip in the dialysate sodium concentration, a marker of ultrafiltration capacity, at baseline (all p < 0.05). CONCLUSIONS Autotaxin concentrations in PD effluent might be an adjunct marker that reflects peritoneal function.
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Affiliation(s)
- Keisuke Horikoshi
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Norihiko Sakai
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
| | - Megumi Oshima
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroyuki Yamauchi
- Department of Nephrology, Seika Town National Health Insurance Hospital, Kyoto, Japan
| | - Megumi Ikeda
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kaho Hayashi
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroyoshi Yanagisawa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Fumitaka Yamamori
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Sho Kajikawa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Daiki Hayashi
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akihiko Koshino
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Keisuke Sako
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Takahiro Yuasa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akira Tamai
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Taichiro Minami
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shiori Nakagawa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shinji Kitajima
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
| | - Tadashi Toyama
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akinori Hara
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Miho Shimizu
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Satoshi Oota
- Department of Internal medicine, Toyama City Hospital, Toyama, Japan
| | - Yoichi Ishida
- Department of Internal medicine, Toyama City Hospital, Toyama, Japan
| | - Takashi Wada
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Yasunori Iwata
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
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21
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Aribindi K, Liu GY, Albertson TE. Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF). Expert Rev Clin Pharmacol 2024; 17:817-835. [PMID: 39192604 PMCID: PMC11441789 DOI: 10.1080/17512433.2024.2396121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/29/2024] [Accepted: 08/20/2024] [Indexed: 08/29/2024]
Abstract
INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a progressive-fibrosing lung disease with a median survival of less than 5 years. Currently, two agents, pirfenidone and nintedanib are approved for this disease, and both have been shown to reduce the rate of decline in lung function in patients with IPF. However, both have significant adverse effects and neither completely arrest the decline in lung function. AREAS COVERED Thirty experimental agents with unique mechanisms of action that are being evaluated for the treatment of IPF are discussed. These agents work through various mechanisms of action, these include inhibition of transcription nuclear factor k-B on fibroblasts, reduced expression of metalloproteinase 7, the generation of more lysophosphatidic acids, blocking the effects of transforming growth factor ß, and reducing reactive oxygen species as examples of some unique mechanisms of action of these agents. EXPERT OPINION New drug development has the potential to expand the treatment options available in the treatment of IPF patients. It is expected that the adverse drug effect profiles will be more favorable than current agents. It is further anticipated that these new agents or combinations of agents will arrest the fibrosis, not just slow the fibrotic process.
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Affiliation(s)
- Katyayini Aribindi
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA
- Department of Medicine, Department of Veterans Affairs Northern California Health Care System, Mather, CA, USA
| | - Gabrielle Y Liu
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA
| | - Timothy E Albertson
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA
- Department of Medicine, Department of Veterans Affairs Northern California Health Care System, Mather, CA, USA
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22
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Walker NM, Ibuki Y, McLinden AP, Misumi K, Mitchell DC, Kleer GG, Lock AM, Vittal R, Sonenberg N, Garner AL, Lama VN. MNK-driven eIF4E phosphorylation regulates the fibrogenic transformation of mesenchymal cells and chronic lung allograft dysfunction. J Clin Invest 2024; 134:e168393. [PMID: 39145446 PMCID: PMC11324311 DOI: 10.1172/jci168393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/09/2023] [Accepted: 06/25/2024] [Indexed: 08/16/2024] Open
Abstract
Tissue fibrosis remains unamenable to meaningful therapeutic interventions and is the primary cause of chronic graft failure after organ transplantation. Eukaryotic translation initiation factor (eIF4E), a key translational regulator, serves as convergent target of multiple upstream profibrotic signaling pathways that contribute to mesenchymal cell (MC) activation. Here, we investigate the role of MAP kinase-interacting serine/threonine kinase-induced (MNK-induced) direct phosphorylation of eIF4E at serine 209 (Ser209) in maintaining fibrotic transformation of MCs and determine the contribution of the MNK/eIF4E pathway to the pathogenesis of chronic lung allograft dysfunction (CLAD). MCs from patients with CLAD demonstrated constitutively higher eIF4E phosphorylation at Ser209, and eIF4E phospho-Ser209 was found to be critical in regulating key fibrogenic protein autotaxin, leading to sustained β-catenin activation and profibrotic functions of CLAD MCs. MNK1 signaling was upregulated in CLAD MCs, and genetic or pharmacologic targeting of MNK1 activity inhibited eIF4E phospho-Ser209 and profibrotic functions of CLAD MCs in vitro. Treatment with an MNK1/2 inhibitor (eFT-508) abrogated allograft fibrosis in an orthotopic murine lung-transplant model. Together these studies identify what we believe is a previously unrecognized MNK/eIF4E/ATX/β-catenin signaling pathway of fibrotic transformation of MCs and present the first evidence, to our knowledge, for the utility of MNK inhibitors in fibrosis.
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Affiliation(s)
- Natalie M. Walker
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yuta Ibuki
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - A. Patrick McLinden
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Keizo Misumi
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Dylan C. Mitchell
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Gabriel G. Kleer
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Alison M. Lock
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Ragini Vittal
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Nahum Sonenberg
- Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada
| | - Amanda L. Garner
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Vibha N. Lama
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
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23
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Taketomi Y, Higashi T, Kano K, Miki Y, Mochizuki C, Toyoshima S, Okayama Y, Nishito Y, Nakae S, Tanaka S, Tokuoka SM, Oda Y, Shichino S, Ueha S, Matsushima K, Akahoshi N, Ishii S, Chun J, Aoki J, Murakami M. Lipid-orchestrated paracrine circuit coordinates mast cell maturation and anaphylaxis through functional interaction with fibroblasts. Immunity 2024; 57:1828-1847.e11. [PMID: 39002541 DOI: 10.1016/j.immuni.2024.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/10/2023] [Revised: 04/04/2024] [Accepted: 06/19/2024] [Indexed: 07/15/2024]
Abstract
Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA1, like that of the phospholipase PLA2G3, the prostaglandin D2 (PGD2) synthase L-PGDS, or the PGD2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD2 generation, and feedforward ATX-LPA1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation.
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Affiliation(s)
- Yoshitaka Taketomi
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Takayoshi Higashi
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yoshimi Miki
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Chika Mochizuki
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shota Toyoshima
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Center for Allergy, and Division of Internal Medicine, Department of Respiratory Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan; Department of Biochemistry & Molecular Biology, Nippon Medical School, Tokyo 113-8602, Japan
| | - Yoshimichi Okayama
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Center for Allergy, and Division of Internal Medicine, Department of Respiratory Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan; Department of Allergy and Internal Medicine, Misato Kenwa Hospital, Saitama 341-8555, Japan; Department of Internal Medicine, Division of Respiratory Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan; Advanced Medical Science Research Center, Gunma Paz University Graduate School of Health Sciences, Takasaki 370-0006, Japan
| | - Yasumasa Nishito
- Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Susumu Nakae
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8528, Japan
| | - Satoshi Tanaka
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Suzumi M Tokuoka
- Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yoshiya Oda
- Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shigeyuki Shichino
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
| | - Satoshi Ueha
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
| | - Kouji Matsushima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
| | - Noriyuki Akahoshi
- Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Satoshi Ishii
- Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Jerold Chun
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan
| | - Makoto Murakami
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
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24
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Lebel M, Cliche DO, Charbonneau M, Brochu-Gaudreau K, Adam D, Brochiero E, Dubois CM, Cantin AM. Hypoxia Promotes Invadosome Formation by Lung Fibroblasts. Cells 2024; 13:1152. [PMID: 38995003 PMCID: PMC11240699 DOI: 10.3390/cells13131152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/21/2024] [Accepted: 07/02/2024] [Indexed: 07/13/2024] Open
Abstract
Lung parenchymal hypoxia has emerged as a cardinal feature of idiopathic pulmonary fibrosis (IPF). Hypoxia promotes cancer cell invasion and metastasis through signaling that is dependent upon the lysophosphatidic acid (LPA) receptor, LPA1 (LPAR1). Abundant data indicate that LPA1-dependent signaling also enhances lung fibrogenesis in IPF. We recently reported that fibroblasts isolated from the lungs of individuals with IPF have an increased capacity to form subcellular matrix-degradative structures known as invadosomes, an event that correlates with the degree of lung fibrosis. We therefore hypothesized that hypoxia promotes invadosome formation in lung fibroblasts through LPA1-dependent signaling. Here, it is demonstrated that invadosome formation by fibroblasts from the lungs of individuals with advanced IPF is inhibited by both the tyrosine receptor kinase inhibitor nintedanib and inhibition of LPA1. In addition, exposure of normal human lung fibroblasts to either hypoxia or LPA increased their ability to form invadosomes. Mechanistically, the hypoxia-induced invadosome formation by lung fibroblasts was found to involve LPA1 and PDGFR-Akt signaling. We concluded that hypoxia increases the formation of invadosomes in lung fibroblasts through the LPA1 and PDGFR-Akt signaling axis, which represents a potential target for suppressing lung fibrosis.
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Affiliation(s)
- Mégane Lebel
- Respiratory Division, Department of Medicine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (M.L.); (D.O.C.); (A.M.C.)
| | - Dominic O. Cliche
- Respiratory Division, Department of Medicine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (M.L.); (D.O.C.); (A.M.C.)
| | - Martine Charbonneau
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12 Avenue Nord, Sherbrooke, QC J1H 5N4, Canada; (M.C.); (K.B.-G.)
| | - Karine Brochu-Gaudreau
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12 Avenue Nord, Sherbrooke, QC J1H 5N4, Canada; (M.C.); (K.B.-G.)
| | - Damien Adam
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; (D.A.); (E.B.)
| | - Emmanuelle Brochiero
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; (D.A.); (E.B.)
- Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada
| | - Claire M. Dubois
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12 Avenue Nord, Sherbrooke, QC J1H 5N4, Canada; (M.C.); (K.B.-G.)
| | - André M. Cantin
- Respiratory Division, Department of Medicine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (M.L.); (D.O.C.); (A.M.C.)
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25
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Song Y, Ali FN, Ye Z, Zarzoso J, Rogowski J, Sun Y, Xin Y. Pharmacokinetics of Fipaxalparant, a Small-Molecule Selective Negative Allosteric Modulator of Lysophosphatidic Acid Receptor 1, and the Effect of Food in Healthy Volunteers. Clin Pharmacol Drug Dev 2024; 13:819-827. [PMID: 38757472 DOI: 10.1002/cpdd.1417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/04/2023] [Accepted: 04/16/2024] [Indexed: 05/18/2024]
Abstract
Dysregulated lysophosphatidic acid receptor 1 (LPAR1) signaling is implicated in fibrotic diseases, including systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Fipaxalparant (HZN-825) is a small molecule acting as a negative allosteric modulator of LPAR1 and is in phase 2 clinical evaluations for treating diffuse cutaneous SSc and IPF. This open-label, phase 1 study examined the pharmacokinetics (PKs), food effect, and safety of fipaxalparant in healthy volunteers. Dose proportionality was evaluated for fipaxalparant single doses of 150, 300, and 450 mg under fasted conditions. Food effect was tested with a 450-mg single dose under fasted conditions or with a high-fat meal. Multiple-dose PKs for twice-daily dosing of either 300 or 450 mg with low- or high-fat meals was also assessed. Fipaxalparant was safe and well tolerated in healthy volunteers (n = 36) under all conditions. Fipaxalparant exposure increased in a less than dose-proportional manner from 150 to 450 mg. At 450 mg, a high-fat meal increased the maximum observed concentration and area under the curve by approximately 1.9- and 2.1-fold, respectively. These results, combined with prior preclinical and phase 2a data, informed dose selection of fipaxalparant 300 mg once and twice daily with a meal for phase 2b studies.
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Affiliation(s)
- Yang Song
- Amgen, Inc. (formerly Horizon Therapeutics plc), South San Francisco, CA, USA
| | - Farah N Ali
- Amgen, Inc. (formerly Horizon Therapeutics plc), Deerfield, IL, USA
| | - Zhan Ye
- Amgen, Inc. (formerly Horizon Therapeutics plc), Deerfield, IL, USA
| | - Jennifer Zarzoso
- Amgen, Inc. (formerly Horizon Therapeutics plc), South San Francisco, CA, USA
| | - John Rogowski
- Amgen, Inc. (formerly Horizon Therapeutics plc), Deerfield, IL, USA
| | - Yajing Sun
- Amgen, Inc. (formerly Horizon Therapeutics plc), South San Francisco, CA, USA
| | - Yan Xin
- Amgen, Inc. (formerly Horizon Therapeutics plc), South San Francisco, CA, USA
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Sciacca E, Muscato G, Spicuzza L, Fruciano M, Gili E, Sambataro G, Palmucci S, Vancheri C, Libra A. Pharmacological treatment in Idiopathic Pulmonary Fibrosis: current issues and future perspectives. Multidiscip Respir Med 2024; 19:982. [PMID: 38869027 PMCID: PMC11186439 DOI: 10.5826/mrm.2024.982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/02/2024] [Accepted: 05/02/2024] [Indexed: 06/14/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) represents a fibrotic interstitial lung disease characterized by uncertain etiology and poor prognosis. Over the years, the path to effective treatments has been marked by a series of advances and setbacks. The introduction of approved antifibrotic drugs, pirfenidone and nintedanib, marked a pivotal moment in the management of IPF. However, despite these advances, these drugs are not curative, although they can slow the natural progression of the disease. The history of drug therapy for IPF goes together with the increased understanding of the pathogenic mechanisms underlying the disease. Based on that, current research efforts continue to explore new therapies, possible personalized treatment strategies, drug combinations, and potential biomarkers for diagnosis and prognosis. In this review, we outline the route that led to the discover of the first effective therapies, ongoing clinical trials, and future directions in the search for more effective treatments.
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Affiliation(s)
- Enrico Sciacca
- Department of Clinical and Experimental Medicine, “Regional Referral Center for Rare Lung Diseases”, University - Hospital Policlinico “G. Rodolico- San Marco”, University of Catania, Catania, Italy
| | - Giuseppe Muscato
- Department of Clinical and Experimental Medicine, “Regional Referral Center for Rare Lung Diseases”, University - Hospital Policlinico “G. Rodolico- San Marco”, University of Catania, Catania, Italy
| | - Lucia Spicuzza
- Department of Clinical and Experimental Medicine, “Regional Referral Center for Rare Lung Diseases”, University - Hospital Policlinico “G. Rodolico- San Marco”, University of Catania, Catania, Italy
| | - Mary Fruciano
- Department of Clinical and Experimental Medicine, “Regional Referral Center for Rare Lung Diseases”, University - Hospital Policlinico “G. Rodolico- San Marco”, University of Catania, Catania, Italy
| | - Elisa Gili
- Department of Clinical and Experimental Medicine, “Regional Referral Center for Rare Lung Diseases”, University - Hospital Policlinico “G. Rodolico- San Marco”, University of Catania, Catania, Italy
| | - Gianluca Sambataro
- Artroreuma s.r.l., Rheumatology outpatient Clinic, Mascalucia (CT), Italy
- Internal Medicine Unit, Department of Clinical and Experimental Medicine, Division of Rheumatology, Cannizzaro Hospital, University of Catania, Catania, Italy
| | - Stefano Palmucci
- Department of Medical Surgical Sciences and Advanced Technologies “GF Ingrassia”, University -Hospital Policlinico “G. Rodolico-San Marco”, Unità Operativa Semplice Dipartimentale di Imaging Polmonare e Tecniche Radiologiche Avanzate (UOSD IPTRA), Catania, Italy
| | - Carlo Vancheri
- Department of Clinical and Experimental Medicine, “Regional Referral Center for Rare Lung Diseases”, University - Hospital Policlinico “G. Rodolico- San Marco”, University of Catania, Catania, Italy
| | - Alessandro Libra
- Department of Clinical and Experimental Medicine, “Regional Referral Center for Rare Lung Diseases”, University - Hospital Policlinico “G. Rodolico- San Marco”, University of Catania, Catania, Italy
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27
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Córdova-Casanova A, Cruz-Soca M, Gallardo FS, Faundez-Contreras J, Bock-Pereda A, Chun J, Vio CP, Casar JC, Brandan E. LPA-induced expression of CCN2 in muscular fibro/adipogenic progenitors (FAPs): Unraveling cellular communication networks. Matrix Biol 2024; 130:36-46. [PMID: 38723870 DOI: 10.1016/j.matbio.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/21/2024] [Revised: 04/12/2024] [Accepted: 05/06/2024] [Indexed: 06/03/2024]
Abstract
Cellular Communication Network Factor 2, CCN2, is a profibrotic cytokine implicated in physiological and pathological processes in mammals. The expression of CCN2 is markedly increased in dystrophic muscles. Interestingly, diminishing CCN2 genetically or inhibiting its function improves the phenotypes of chronic muscular fibrosis in rodent models. Elucidating the cell-specific mechanisms behind the induction of CCN2 is a fundamental step in understanding its relevance in muscular dystrophies. Here, we show that the small lipids LPA and 2S-OMPT induce CCN2 expression in fibro/adipogenic progenitors (FAPs) through the activation of the LPA1 receptor and, to a lower extent, by also the LPA6 receptor. These cells show a stronger induction than myoblasts or myotubes. We show that the LPA/LPARs axis requires ROCK kinase activity and organized actin cytoskeleton upstream of YAP/TAZ signaling effectors to upregulate CCN2 levels, suggesting that mechanical signals are part of the mechanism behind this process. In conclusion, we explored the role of the LPA/LPAR axis on CCN2 expression, showing a strong cytoskeletal-dependent response in muscular FAPs.
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Affiliation(s)
- Adriana Córdova-Casanova
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago, Chile; P Universidad Católica de Chile, Santiago, Chile
| | - Meilyn Cruz-Soca
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago, Chile; P Universidad Católica de Chile, Santiago, Chile
| | | | | | - Alexia Bock-Pereda
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago, Chile; P Universidad Católica de Chile, Santiago, Chile
| | - Jerold Chun
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Carlos P Vio
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Juan Carlos Casar
- Departamento de Neurología, Pontificia Universidad Católica de Chile, Chile
| | - Enrique Brandan
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Santiago, Chile; Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile.
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MacIsaac S, Somboonviboon D, Scallan C, Kolb M. Treatment of idiopathic pulmonary fibrosis: an update on emerging drugs in phase II & III clinical trials. Expert Opin Emerg Drugs 2024; 29:177-186. [PMID: 38588523 DOI: 10.1080/14728214.2024.2340723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/23/2024] [Accepted: 04/04/2024] [Indexed: 04/10/2024]
Abstract
INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating lung disease with poor prognosis. Although two antifibrotics have been approved in the past decade there are no curative therapies. AREAS COVERED This review highlights the current landscape of IPF research in the development of novel compounds for the treatment of IPF while also evaluating repurposed medications and their role in the management of IPF. The literature search includes studies found on PubMed, conference abstracts, and press releases until March 2024. EXPERT OPINION Disease progression in IPF is driven by a dysregulated cycle of microinjury, aberrant wound healing, and propagating fibrosis. Current drug development focuses on attenuating fibrotic responses via multiple pathways. Phosphodiesterase 4 inhibitors (PDE4i), lysophosphatidic acid (LPA) antagonists, dual-selective inhibitor of αvβ6 and αvβ1 integrins, and the prostacyclin agonist Treprostinil have had supportive phase II clinical trial results in slowing decline in forced vital capacity (FVC) in IPF. Barriers to drug development specific to IPF include the lack of a rodent model that mimics IPF pathology, the nascent understanding of the role of genetics affecting development of IPF and response to treatment, and the lack of a validated biomarker to monitor therapeutic response in patients with IPF. Successful treatment of IPF will likely include a multi-targeted approach anchored in precision medicine.
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Affiliation(s)
- Sarah MacIsaac
- Firestone Institute for Respiratory Health - Division of Respirology, McMaster University, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada
- Division of Respirology, Dalhousie University, Halifax Infirmary, Halifax Nova Scotia, Canada
| | - Dujrath Somboonviboon
- Firestone Institute for Respiratory Health - Division of Respirology, McMaster University, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada
- Division of Pulmonary and Critical Care, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand
| | - Ciaran Scallan
- Firestone Institute for Respiratory Health - Division of Respirology, McMaster University, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada
| | - Martin Kolb
- Firestone Institute for Respiratory Health - Division of Respirology, McMaster University, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada
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29
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Calver JF, Parmar NR, Harris G, Lithgo RM, Stylianou P, Zetterberg FR, Gooptu B, Mackinnon AC, Carr SB, Borthwick LA, Scott DJ, Stewart ID, Slack RJ, Jenkins RG, John AE. Defining the mechanism of galectin-3-mediated TGF-β1 activation and its role in lung fibrosis. J Biol Chem 2024; 300:107300. [PMID: 38641066 PMCID: PMC11134550 DOI: 10.1016/j.jbc.2024.107300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/16/2023] [Revised: 03/29/2024] [Accepted: 04/11/2024] [Indexed: 04/21/2024] Open
Abstract
Integrin-mediated activation of the profibrotic mediator transforming growth factor-β1 (TGF-β1), plays a critical role in idiopathic pulmonary fibrosis (IPF) pathogenesis. Galectin-3 is believed to contribute to the pathological wound healing seen in IPF, although its mechanism of action is not precisely defined. We hypothesized that galectin-3 potentiates TGF-β1 activation and/or signaling in the lung to promote fibrogenesis. We show that galectin-3 induces TGF-β1 activation in human lung fibroblasts (HLFs) and specifically that extracellular galectin-3 promotes oleoyl-L-α-lysophosphatidic acid sodium salt-induced integrin-mediated TGF-β1 activation. Surface plasmon resonance analysis confirmed that galectin-3 binds to αv integrins, αvβ1, αvβ5, and αvβ6, and to the TGFβRII subunit in a glycosylation-dependent manner. This binding is heterogeneous and not a 1:1 binding stoichiometry. Binding interactions were blocked by small molecule inhibitors of galectin-3, which target the carbohydrate recognition domain. Galectin-3 binding to β1 integrin was validated in vitro by coimmunoprecipitation in HLFs. Proximity ligation assays indicated that galectin-3 and β1 integrin colocalize closely (≤40 nm) on the cell surface and that colocalization is increased by TGF-β1 treatment and blocked by galectin-3 inhibitors. In the absence of TGF-β1 stimulation, colocalization was detectable only in HLFs from IPF patients, suggesting the proteins are inherently more closely associated in the disease state. Galectin-3 inhibitor treatment of precision cut lung slices from IPF patients' reduced Col1a1, TIMP1, and hyaluronan secretion to a similar degree as TGF-β type I receptor inhibitor. These data suggest that galectin-3 promotes TGF-β1 signaling and may induce fibrogenesis by interacting directly with components of the TGF-β1 signaling cascade.
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Affiliation(s)
- Jessica F Calver
- School of Medicine, University of Nottingham, Nottingham, United Kingdom; Stevenage Bioscience Catalyst, Galecto Biotech AB, Stevenage, United Kingdom
| | - Nimesh R Parmar
- School of Medicine, University of Nottingham, Nottingham, United Kingdom; Roche Products Limited, Welwyn Garden City, Hertfordshire, United Kingdom
| | - Gemma Harris
- Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom
| | - Ryan M Lithgo
- Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom; School of Biosciences, University of Nottingham, Loughborough, Leicestershire, United Kingdom; Membrane Protein Laboratory, Diamond Light Source, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom; Diamond Light Source, Diamond House, Rutherford Appleton Laboratories, Didcot, Oxfordshire, United Kingdom
| | - Panayiota Stylianou
- Institute for Lung Health, NIHR Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom; Leicester Institute for Structural and Chemical Biology, Henry Wellcome Building, University of Leicester, Leicester, United Kingdom
| | | | - Bibek Gooptu
- Institute for Lung Health, NIHR Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom; Leicester Institute for Structural and Chemical Biology, Henry Wellcome Building, University of Leicester, Leicester, United Kingdom
| | - Alison C Mackinnon
- Galecto Biotech AB, Nine Edinburgh BioQuarter, Edinburgh, United Kingdom
| | - Stephen B Carr
- Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom; Department of Chemistry, University of Oxford, Oxford, Oxfordshire, United Kingdom
| | - Lee A Borthwick
- Fibrofind Ltd, Newcastle upon Tyne, United Kingdom; Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - David J Scott
- Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom; School of Biosciences, University of Nottingham, Loughborough, Leicestershire, United Kingdom
| | - Iain D Stewart
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Robert J Slack
- Stevenage Bioscience Catalyst, Galecto Biotech AB, Stevenage, United Kingdom
| | - R Gisli Jenkins
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Alison E John
- National Heart and Lung Institute, Imperial College London, London, United Kingdom.
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30
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Zhou Q, Chen Y, Liang Y, Sun Y. The Role of Lysophospholipid Metabolites LPC and LPA in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Metabolites 2024; 14:317. [PMID: 38921452 PMCID: PMC11205356 DOI: 10.3390/metabo14060317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/19/2024] [Revised: 05/26/2024] [Accepted: 05/29/2024] [Indexed: 06/27/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by persistent respiratory symptoms and airflow limitation. While there are some available treatment options, the effectiveness of treatment varies depending on individual differences and the phenotypes of the disease. Therefore, exploring or identifying potential therapeutic targets for COPD is urgently needed. In recent years, there has been growing evidence showing that lysophospholipids, namely lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), can play a significant role in the pathogenesis of COPD. Exploring the metabolism of lysophospholipids holds promise for understanding the underlying mechanism of COPD development and developing novel strategies for COPD treatment. This review primarily concentrates on the involvement and signaling pathways of LPC and LPA in the development and progression of COPD. Furthermore, we reviewed their associations with clinical manifestations, phenotypes, and prognosis within the COPD context and discussed the potential of the pivotal signaling molecules as viable therapeutic targets for COPD treatment.
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Affiliation(s)
- Qiqiang Zhou
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
| | - Yahong Chen
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
| | - Ying Liang
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
| | - Yongchang Sun
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
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31
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Ziehr DR, Li F, Parnell KM, Krah NM, Leahy KJ, Guillermier C, Varon J, Baron RM, Maron BA, Philp NJ, Hariri LP, Kim EY, Steinhauser ML, Knipe RS, Rutter J, Oldham WM. Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.25.591150. [PMID: 38712233 PMCID: PMC11071479 DOI: 10.1101/2024.04.25.591150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 05/08/2024]
Abstract
Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFβ-stimulated pulmonary myofibroblast differentiation in vitro and decreases bleomycin-induced pulmonary fibrosis in vivo. Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist.
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Affiliation(s)
- David R. Ziehr
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
- Department of Medicine, Massachusetts General Hospital, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Fei Li
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | | | - Nathan M. Krah
- Department of Internal Medicine, University of Utah, Salt Lake City, UT
- Department of Biochemistry, University of Utah, Salt Lake City, UT
| | - Kevin J. Leahy
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Christelle Guillermier
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Jack Varon
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Rebecca M. Baron
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Bradley A. Maron
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
- University of Maryland Institute for Health Computing, Bethesda, MD
| | - Nancy J. Philp
- Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA
| | - Lida P. Hariri
- Department of Medicine, Harvard Medical School, Boston, MA
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Edy Y. Kim
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Matthew L. Steinhauser
- Aging Institute, University of Pittsburgh, Pittsburgh, PA
- UPMC Heart and Vascular Institute, UPMC Presbyterian, Pittsburgh, PA
| | - Rachel S. Knipe
- Department of Medicine, Massachusetts General Hospital, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Jared Rutter
- Department of Biochemistry, University of Utah, Salt Lake City, UT
- Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT
| | - William M. Oldham
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
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Fan G, Guan X, Guan B, Zhu H, Pei Y, Jiang C, Xiao Y, Li Z, Cao F. Untargeted metabolomics reveals that declined PE and PC in obesity may be associated with prostate hyperplasia. PLoS One 2024; 19:e0301011. [PMID: 38640132 PMCID: PMC11029648 DOI: 10.1371/journal.pone.0301011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/06/2023] [Accepted: 03/09/2024] [Indexed: 04/21/2024] Open
Abstract
BACKGROUND Recent studies have shown that obesity may contribute to the pathogenesis of benign prostatic hyperplasia (BPH). However, the mechanism of this pathogenesis is not fully understood. METHODS A prospective case-control study was conducted with 30 obese and 30 nonobese patients with BPH. Prostate tissues were collected and analyzed using ultra performance liquid chromatography ion mobility coupled with quadrupole time-of-flight mass spectrometry (UPLC-IMS-Q-TOF). RESULTS A total of 17 differential metabolites (3 upregulated and 14 downregulated) were identified between the obese and nonobese patients with BPH. Topological pathway analysis indicated that glycerophospholipid (GP) metabolism was the most important metabolic pathway involved in BPH pathogenesis. Seven metabolites were enriched in the GP metabolic pathway. lysoPC (P16:0/0:0), PE (20:0/20:0), PE (24:1(15Z)/18:0), PC (24:1(15Z)/14:0), PC (15:0/24:0), PE (24:0/18:0), and PC (16:0/18:3(9Z,12Z,15Z)) were all significantly downregulated in the obesity group, and the area under the curve (AUC) of LysoPC (P-16:0/0/0:0) was 0.9922. The inclusion of the seven differential metabolites in a joint prediction model had an AUC of 0.9956. Thus, both LysoPC (P-16:0/0/0:0) alone and the joint prediction model demonstrated good predictive ability for obesity-induced BPH mechanisms. CONCLUSIONS In conclusion, obese patients with BPH had a unique metabolic profile, and alterations in PE and PC in these patients be associated with the development and progression of BPH.
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Affiliation(s)
- Guorui Fan
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
| | - Xiaohai Guan
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
| | - Bo Guan
- School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Hongfei Zhu
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
| | - Yongchao Pei
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
| | - Chonghao Jiang
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
| | - Yonggui Xiao
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
| | - Zhiguo Li
- School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Fenghong Cao
- Clinical Medical College, North China University of Science and Technology, Tangshan, China
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33
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Volkmann ER, Denton CP, Kolb M, Wijsenbeek-Lourens MS, Emson C, Hudson K, Amatucci AJ, Distler O, Allanore Y, Khanna D. Lysophosphatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis. Eur Respir Rev 2024; 33:240015. [PMID: 39009409 PMCID: PMC11262619 DOI: 10.1183/16000617.0015-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/25/2024] [Accepted: 04/01/2024] [Indexed: 07/17/2024] Open
Abstract
Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1) contributes to the pathophysiology of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). These diseases are associated with high morbidity and mortality despite current treatment options. The LPA-producing enzyme autotaxin (ATX) and LPAR1 activation contribute to inflammation and mechanisms underlying fibrosis in preclinical fibrotic models. Additionally, elevated levels of LPA have been detected in bronchoalveolar lavage fluid from patients with IPF and in serum from patients with SSc. Thus, ATX and LPAR1 have gained considerable interest as pharmaceutical targets to combat fibrotic disease and inhibitors of these targets have been investigated in clinical trials for IPF and SSc. The goals of this review are to summarise the current literature on ATX and LPAR1 signalling in pulmonary fibrosis and to help differentiate the novel inhibitors in development. The mechanisms of action of ATX and LPAR1 inhibitors are described and preclinical studies and clinical trials of these agents are outlined. Because of their contribution to numerous physiologic events underlying fibrotic disease, ATX and LPAR1 inhibition presents a promising therapeutic strategy for IPF, SSc and other fibrotic diseases that may fulfil unmet needs of the current standard of care.
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Affiliation(s)
- Elizabeth R Volkmann
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | | | - Martin Kolb
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | | | - Claire Emson
- Translational Medicine, Horizon Therapeutics (now Amgen, Inc.), Rockville, MD, USA
| | - Krischan Hudson
- Clinical Development, Horizon Therapeutics (now Amgen, Inc.), Deerfield, IL, USA
| | - Anthony J Amatucci
- Global Medical Affairs, Horizon Therapeutics (now Amgen, Inc), Deerfield, IL, USA
| | - Oliver Distler
- Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Yannick Allanore
- Rheumatology Department, Cochin Hospital APHP, INSERM U1016, Université Paris Cité, Paris, France
| | - Dinesh Khanna
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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34
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Li Y, Jiang C, Zhu W, Lu S, Yu H, Meng L. Exploring therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis. Sci Prog 2024; 107:368504241247402. [PMID: 38651330 PMCID: PMC11036936 DOI: 10.1177/00368504241247402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 04/25/2024]
Abstract
Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease with a poor prognosis. Idiopathic pulmonary fibrosis is characterized by repeated alveolar epithelial damage leading to abnormal repair. The intercellular microenvironment is disturbed, leading to continuous activation of fibroblasts and myofibroblasts, deposition of extracellular matrix, and ultimately fibrosis. Moreover, pulmonary fibrosis was also found as a COVID-19 complication. Currently, two drugs, pirfenidone and nintedanib, are approved for clinical therapy worldwide. However, they can merely slow the disease's progression rather than rescue it. These two drugs have other limitations, such as lack of efficacy, adverse effects, and poor pharmacokinetics. Consequently, a growing number of molecular therapies have been actively developed. Treatment options for IPF are becoming increasingly available. This article reviews the research platform, including cell and animal models involved in molecular therapy studies of idiopathic pulmonary fibrosis as well as the promising therapeutic targets and their development progress during clinical trials. The former includes patient case/control studies, cell models, and animal models. The latter includes transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, lysophosphatidic acid, interleukin-13, Rho-associated coiled-coil forming protein kinase family, and Janus kinases/signal transducers and activators of transcription pathway. We mainly focused on the therapeutic targets that have not only entered clinical trials but were publicly published with their clinical outcomes. Moreover, this work provides an outlook on some promising targets for further validation of their possibilities to cure the disease.
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Affiliation(s)
- Yue Li
- National Regional Children's Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- First Department of Respiratory Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Congshan Jiang
- National Regional Children's Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Wenhua Zhu
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, People's Republic of China
| | - Shemin Lu
- National Regional Children's Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, People's Republic of China
| | - Hongchuan Yu
- First Department of Respiratory Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Liesu Meng
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, People's Republic of China
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Sofia C, Comes A, Sgalla G, Richeldi L. Promising advances in treatments for the management of idiopathic pulmonary fibrosis. Expert Opin Pharmacother 2024; 25:717-725. [PMID: 38832823 DOI: 10.1080/14656566.2024.2354460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/27/2024] [Accepted: 05/08/2024] [Indexed: 06/06/2024]
Abstract
INTRODUCTION Following the INPULSIS and ASCEND studies, leading to the first two approved antifibrotic therapies for patients with IPF, ongoing investigations are firmly exploring novel agents for a targeted effective and better tolerated therapy able to improve the natural history of the disease. AREAS COVERED This review aims to analyze recent advances in pharmacological research of IPF, discussing the currently available treatments and the novel drugs under investigation in phase 3 trials, with particular emphasis on BI 1015550 and inhaled treprostinil. The literature search utilized Medline and Clinicaltrials.org databases. Critical aspects of clinical trial design in IPF are discussed in light of recently completed phase III studies. EXPERT OPINION While randomized clinical trials in IPF are currently underway, future objectives should explore potential synergistic benefits when combining novel molecules with the existing therapies and identify more specific molecular targets. Moreover, refining the study design represent another crucial goal. The aim of the pharmacological research will be not only stabilizing but also potentially reversing the fibrotic changes in IPF.
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Affiliation(s)
- Carmelo Sofia
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessia Comes
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giacomo Sgalla
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Luca Richeldi
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
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Yoon D, Choi B, Kim JE, Kim EY, Chung SH, Min HJ, Sung Y, Chang EJ, Song JK. Autotaxin inhibition attenuates the aortic valve calcification by suppressing inflammation-driven fibro-calcific remodeling of valvular interstitial cells. BMC Med 2024; 22:122. [PMID: 38486246 PMCID: PMC10941471 DOI: 10.1186/s12916-024-03342-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/25/2023] [Accepted: 03/05/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Patients with fibro-calcific aortic valve disease (FCAVD) have lipid depositions in their aortic valve that engender a proinflammatory impetus toward fibrosis and calcification and ultimately valve leaflet stenosis. Although the lipoprotein(a)-autotaxin (ATX)-lysophosphatidic acid axis has been suggested as a potential therapeutic target to prevent the development of FCAVD, supportive evidence using ATX inhibitors is lacking. We here evaluated the therapeutic potency of an ATX inhibitor to attenuate valvular calcification in the FCAVD animal models. METHODS ATX level and activity in healthy participants and patients with FCAVD were analyzed using a bioinformatics approach using the Gene Expression Omnibus datasets, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and western blotting. To evaluate the efficacy of ATX inhibitor, interleukin-1 receptor antagonist-deficient (Il1rn-/-) mice and cholesterol-enriched diet-induced rabbits were used as the FCAVD models, and primary human valvular interstitial cells (VICs) from patients with calcification were employed. RESULTS The global gene expression profiles of the aortic valve tissue of patients with severe FCAVD demonstrated that ATX gene expression was significantly upregulated and correlated with lipid retention (r = 0.96) or fibro-calcific remodeling-related genes (r = 0.77) in comparison to age-matched non-FCAVD controls. Orally available ATX inhibitor, BBT-877, markedly ameliorated the osteogenic differentiation and further mineralization of primary human VICs in vitro. Additionally, ATX inhibition significantly attenuated fibrosis-related factors' production, with a detectable reduction of osteogenesis-related factors, in human VICs. Mechanistically, ATX inhibitor prohibited fibrotic changes in human VICs via both canonical and non-canonical TGF-β signaling, and subsequent induction of CTGF, a key factor in tissue fibrosis. In the in vivo FCAVD model system, ATX inhibitor exposure markedly reduced calcific lesion formation in interleukin-1 receptor antagonist-deficient mice (Il1rn-/-, P = 0.0210). This inhibition ameliorated the rate of change in the aortic valve area (P = 0.0287) and mean pressure gradient (P = 0.0249) in the FCAVD rabbit model. Moreover, transaortic maximal velocity (Vmax) was diminished with ATX inhibitor administration (mean Vmax = 1.082) compared to vehicle control (mean Vmax = 1.508, P = 0.0221). Importantly, ATX inhibitor administration suppressed the effects of a high-cholesterol diet and vitamin D2-driven fibrosis, in association with a reduction in macrophage infiltration and calcific deposition, in the aortic valves of this rabbit model. CONCLUSIONS ATX inhibition attenuates the development of FCAVD while protecting against fibrosis and calcification in VICs, suggesting the potential of using ATX inhibitors to treat FCAVD.
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Affiliation(s)
- Dohee Yoon
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Bongkun Choi
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Ji-Eun Kim
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Eun-Young Kim
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Soo-Hyun Chung
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Hyo-Jin Min
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Yoolim Sung
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Eun-Ju Chang
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
| | - Jae-Kwan Song
- Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
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Reddy KD, Bizymi N, Schweikert A, Ananth S, Lim CX, Lodge KM, Joannes A, Ubags N, van der Does AM, Cloonan SM, Mailleux A, Mansouri N, Reynaert NL, Heijink IH, Cuevas-Ocaña S. ERS International Congress 2023: highlights from the Basic and Translational Sciences Assembly. ERJ Open Res 2024; 10:00875-2023. [PMID: 38686182 PMCID: PMC11057505 DOI: 10.1183/23120541.00875-2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 05/02/2024] Open
Abstract
Early career members of Assembly 3 (Basic and Translational Sciences) of the European Respiratory Society (ERS) summarise the key messages discussed during six selected sessions that took place at the ERS International Congress 2023 in Milan, Italy. Aligned with the theme of the congress, the first session covered is "Micro- and macro-environments and respiratory health", which is followed by a summary of the "Scientific year in review" session. Next, recent advances in experimental methodologies and new technologies are discussed from the "Tissue modelling and remodelling" session and a summary provided of the translational science session, "What did you always want to know about omics analyses for clinical practice?", which was organised as part of the ERS Translational Science initiative's aims. The "Lost in translation: new insights into cell-to-cell crosstalk in lung disease" session highlighted how next-generation sequencing can be integrated with laboratory methods, and a final summary of studies is presented from the "From the transcriptome landscape to innovative preclinical models in lung diseases" session, which links the transcriptome landscape with innovative preclinical models. The wide range of topics covered in the selected sessions and the high quality of the research discussed demonstrate the strength of the basic and translational science being presented at the international respiratory conference organised by the ERS.
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Affiliation(s)
- Karosham Diren Reddy
- Epigenetics of Chronic Lung Disease Group, Forschungszentrum Borstel Leibniz Lungenzentrum, Borstel, Germany
- Division of Pediatric Pneumology and Allergology, University Medical Center Schleswig-Holstein, Lübeck, Germany
- These authors contributed equally
| | - Nikoleta Bizymi
- Laboratory of Molecular and Cellular Pneumonology, School of Medicine, University of Crete, Heraklion, Greece
- These authors contributed equally
| | - Anja Schweikert
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- These authors contributed equally
| | - Sachin Ananth
- London North West University Healthcare NHS Trust, London, UK
- These authors contributed equally
| | - Clarice X. Lim
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Lung Health, Clinic Penzing, Vienna, Austria
- These authors contributed equally
| | - Katharine M. Lodge
- National Heart and Lung Institute, Imperial College London, London, UK
- These authors contributed equally
| | - Audrey Joannes
- Université de Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, France
| | - Niki Ubags
- Division of Pulmonary Medicine, Department of Medicine, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Anne M. van der Does
- PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Suzanne M. Cloonan
- School of Medicine, Trinity Biosciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Arnaud Mailleux
- Université Paris Cité, Inserm, Physiopathologie et épidémiologie des maladies respiratoires, Paris, France
| | - Nahal Mansouri
- Division of Pulmonary Medicine, Department of Medicine, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Niki L. Reynaert
- Department of Respiratory Medicine and School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Irene H. Heijink
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands
| | - Sara Cuevas-Ocaña
- Biodiscovery Institute, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
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Lescop C, Brotschi C, Williams JT, Sager CP, Birker M, Morrison K, Froidevaux S, Delahaye S, Nayler O, Bolli MH. Discovery of a Novel Orally Active, Selective LPA Receptor Type 1 Antagonist, 4-(4-(2-Isopropylphenyl)-4-((2-methoxy-4-methylphenyl)carbamoyl)piperidin-1-yl)-4-oxobutanoic Acid, with a Distinct Molecular Scaffold. J Med Chem 2024; 67:2379-2396. [PMID: 38349223 DOI: 10.1021/acs.jmedchem.3c01826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/23/2024]
Abstract
Lysophosphatidic acid receptor 1 (LPAR1) antagonists show promise as potentially novel antifibrotic treatments. In a human LPAR1 β-arrestin recruitment-based high-throughput screening campaign, we identified urea 19 as a hit with a LPAR1 IC50 value of 5.0 μM. Hit-to-lead activities revealed that one of the urea nitrogen atoms can be replaced by carbon and establish the corresponding phenylacetic amide as a lead structure for further optimization. Medicinal chemistry efforts led to the discovery of piperidine 18 as a potent and selective LPAR1 antagonist with oral activity in a mouse model of LPA-induced skin vascular leakage. The molecular scaffold of 18 shares no obvious structural similarity with any other LPAR1 antagonist disclosed so far.
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Affiliation(s)
- Cyrille Lescop
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Christine Brotschi
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Jodi T Williams
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Christoph P Sager
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Magdalena Birker
- DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Keith Morrison
- DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Sylvie Froidevaux
- DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Stéphane Delahaye
- Preclinical DMPK, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Oliver Nayler
- DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Martin H Bolli
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
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Lescop C, Birker M, Brotschi C, Bürki C, Morrison K, Froidevaux S, Delahaye S, Nayler O, Bolli MH. Discovery of the Novel, Orally Active, and Selective LPA1 Receptor Antagonist ACT-1016-0707 as a Preclinical Candidate for the Treatment of Fibrotic Diseases. J Med Chem 2024; 67:2397-2424. [PMID: 38349250 DOI: 10.1021/acs.jmedchem.3c01827] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/23/2024]
Abstract
Piperidine 3 is a potent and selective lysophosphatidic acid receptor subtype 1 receptor (LPAR1) antagonist that has shown efficacy in a skin vascular leakage target engagement model in mice. However, compound 3 has very high human plasma protein binding and high clearance in rats, which could significantly hamper its clinical development. Continued lead optimization led to the potent, less protein bound, metabolically stable, and orally active azetidine 17. Rat pharmacokinetics (PK) studies revealed that 17 accumulated in the liver. In vitro studies indicated that 17 is an organic anion co-transporting polypeptide 1B1 (OATP1B1) substrate. Although analogue 24 was no longer a substrate of OATP1B1, PK studies suggested that the compound undergoes enterohepatic recirculation. Replacing the carboxylic acidic side chain by a non-acidic sulfamide moiety and further fine-tuning of the scaffold yielded the potent, orally active LPAR1 antagonist 49, which was selected for preclinical development for the treatment of fibrotic diseases.
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Affiliation(s)
- Cyrille Lescop
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Magdalena Birker
- DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Christine Brotschi
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Cédric Bürki
- Chemistry Process R&D, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Keith Morrison
- DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Sylvie Froidevaux
- DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Stéphane Delahaye
- Preclinical DMPK, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Oliver Nayler
- DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Martin H Bolli
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
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Wang X, Wang X, Liu Z, Liu L, Zhang J, Jiang D, Huang G. Identification of inflammation-related biomarkers in keloids. Front Immunol 2024; 15:1351513. [PMID: 38444850 PMCID: PMC10912164 DOI: 10.3389/fimmu.2024.1351513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/06/2023] [Accepted: 01/30/2024] [Indexed: 03/07/2024] Open
Abstract
Background The relationship between inflammation-related genes (IRGs) and keloid disease (KD) is currently unclear. The aim of this study was to identify a new set of inflammation-related biomarkers in KD. Methods GSE145725 and GSE7890 datasets were used in this study. A list of 3026 IRGs was obtained from the Molecular Signatures Database. Differentially expressed inflammation-related genes (DEGs) were obtained by taking the intersection of DEGs between KD and control samples and the list of IRGs. Candidate genes were selected using least absolute shrinkage and selection operator (LASSO) regression analysis. Candidate genes with consistent expression differences between KD and control in both GSE145725 and GSE7890 datasets were screened as biomarkers. An alignment diagram was constructed and validated, and in silico immune infiltration analysis and drug prediction were performed. Finally, RT-qPCR was performed on KD samples to analyze the expression of the identified biomarkers. Results A total of 889 DEGs were identified from the GSE145725 dataset, 169 of which were IRGs. Three candidate genes (TRIM32, LPAR1 and FOXF1) were identified by the LASSO regression analysis, and expression validation analysis suggested that FOXF1 and LPAR1 were down-regulated in KD samples and TRIM32 was up-regulated. All three candidate genes had consistent changes in expression in both the GSE145725 and GSE7890 datasets. An alignment diagram was constructed to predict KD. Effector memory CD4 T cells, T follicular helper cell, Myeloid derived suppressor cell, activated dendritic cell, Immature dendritic cell and Monocyte were differentially expressed between the KD and control group. Sixty-seven compounds that may act on FOXF1, 108 compounds that may act on LPAR1 and 56 compounds that may act on TRIM32 were predicted. Finally, RT-qPCR showed that the expression of LPAR1 was significantly lower in KD samples compared to normal samples whereas TRIM32 was significantly higher, while there was no difference in the expression of FOXF1. Conclusion This study provides a new perspective to study the relationship between IRGs and KD.
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Affiliation(s)
- Xiaochuan Wang
- Plastic Burn Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China
| | - Xiaoyang Wang
- Plastic Burn Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China
| | - Zhenzhong Liu
- Plastic Burn Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China
| | - Lei Liu
- Plastic Burn Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China
| | - Jixun Zhang
- Plastic Burn Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China
| | - Duyin Jiang
- Plastic Burn Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China
| | - Guobao Huang
- Burn Plastic Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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Simonetti J, Ficili M, Sgalla G, Richeldi L. Experimental autotaxin inhibitors for the treatment of idiopathic pulmonary fibrosis. Expert Opin Investig Drugs 2024; 33:133-143. [PMID: 38299617 DOI: 10.1080/13543784.2024.2305126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/23/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
INTRODUCTION Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible, and fatal lung disease with unmet medical needs. Autotaxin (ATX) is an extracellular enzyme involved in the generation of lysophosphatidic acid (LPA). Preclinical and clinical data have suggested the ATX-LPAR signaling axis plays an important role in the pathogenesis and the progression of IPF. AREAS COVERED The aim of this review is to provide an update on the available evidence on autotaxin inhibitors in IPF and further details on the ongoing clinical studies involving these molecules. EXPERT OPINION The development of autotaxin inhibitors as a potential therapy for idiopathic pulmonary fibrosis has gained attention due to evidence of their involvement in the disease. Preclinical and early-phase clinical studies have explored these inhibitors' efficacy and safety, offering a novel approach in treating this disease. Combining autotaxin inhibitors with existing anti-fibrotic agents is considered for enhanced therapeutic effects. Large phase III trials assessed Ziritaxestat but yielded disappointing results, highlighting the importance of long-term observation and clinical outcomes in clinical research. Patient stratification and personalized medicine are crucial, as pulmonary fibrosis is a heterogeneous disease. Ongoing research and collaboration are essential for this advancement.
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Affiliation(s)
- Jacopo Simonetti
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Marco Ficili
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giacomo Sgalla
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luca Richeldi
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
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Meng F, Yin Z, Lu F, Wang W, Zhang H. Disruption of LPA-LPAR1 pathway results in lung tumor growth inhibition by downregulating B7-H3 expression in fibroblasts. Thorac Cancer 2024; 15:316-326. [PMID: 38124403 PMCID: PMC10834189 DOI: 10.1111/1759-7714.15193] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/16/2023] [Revised: 12/02/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Lysophosphatidic acids (LPAs) belong to a class of bioactive lysophospholipids with multiple functions including immunomodulatory roles in tumor microenvironment (TME). LPA exerts its biological effects via its receptors that are highly expressed in fibroblasts among other cell types. As cancer-associated fibroblasts (CAFs) are a key component of the TME, it is important to understand LPA signaling and regulation of receptors in fibroblasts or CAFs and associated regulatory roles on immunomodulation-related molecules. METHODS Cluster analysis, immunoblotting, real-time quantitative-PCR, CRISPR-Cas9 gene editing system, immunohistochemical staining, coculture model, and in vivo xenograft model were used to investigate the effects of LPA-LPAR1 on B7-H3 in tumor promotion of CAFs. RESULTS In this study, we found that LPAR1 and CD276 (B7-H3) were generally highly expressed in fibroblasts with good expression correlation. LPA induced B7-H3 up-expression through LPAR1, and stimulated fibroblasts proliferation that could be inhibited by silencing LPAR1 or B7-H3 as well as small molecule LPAR1 antagonist (Ki16425). Using engineered fibroblasts and non-small cell lung carcinoma (NSCLC) cell lines, subsequent investigations demonstrated that CAFs promoted the proliferation of NSCLC in vitro and in vivo, and such effect could be inhibited by knocking out LPAR1 or B7-H3. CONCLUSION The present study provided new insights for roles of LPA in CAFs, which could lead to the development of innovative therapies targeting CAFs in the TME. It is also reasonable to postulate a combinatory approach to treat malignant fibrous tumors (such as NSCLC) with LPAR1 antagonists and B7-H3 targeting therapies.
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Affiliation(s)
- Fanyi Meng
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Zhiyue Yin
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Feifei Lu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Weipeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Hongjian Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
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Kume H, Harigane R, Rikimaru M. Involvement of Lysophospholipids in Pulmonary Vascular Functions and Diseases. Biomedicines 2024; 12:124. [PMID: 38255229 PMCID: PMC10813361 DOI: 10.3390/biomedicines12010124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/31/2023] [Revised: 12/26/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Extracellular lysophospholipids (lysophosphatidic acid, lysophosphatidylcholine, sphingosine 1-phosphate, etc.), which are synthesized from phospholipids in the cell membrane, act as lipid mediators, and mediate various cellular responses in constituent cells in the respiratory system, such as contraction, proliferation, migration, and cytoskeletal organization. In addition to these effects, the expression of the adhesion molecules is enhanced by these extracellular lysophospholipids in pulmonary endothelial cells. These effects are exerted via specific G protein-coupled receptors. Rho, Ras, and phospholipase C (PLC) have been proven to be their signaling pathways, related to Ca2+ signaling due to Ca2+ dynamics and Ca2+ sensitization. Therefore, lysophospholipids probably induce pulmonary vascular remodeling through phenotype changes in smooth muscle cells, endothelial cells, and fibroblasts, likely resulting in acute respiratory distress syndrome due to vascular leak, pulmonary hypertension, and pulmonary fibrosis. Moreover, lysophospholipids induce the recruitment of inflammatory cells to the lungs via the enhancement of adhesion molecules in endothelial cells, potentially leading to the development of asthma. These results demonstrate that lysophospholipids may be novel therapeutic targets not only for injury, fibrosis, and hypertension in the lung, but also for asthma. In this review, we discuss the mechanisms of the effects of lysophospholipids on the respiratory system, and the possibility of precision medicine targeting lysophospholipids as treatable traits of these diseases.
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Affiliation(s)
- Hiroaki Kume
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu City 969-3492, Fukushima, Japan; (R.H.); (M.R.)
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Koudstaal T, Funke-Chambour M, Kreuter M, Molyneaux PL, Wijsenbeek MS. Pulmonary fibrosis: from pathogenesis to clinical decision-making. Trends Mol Med 2023; 29:1076-1087. [PMID: 37716906 DOI: 10.1016/j.molmed.2023.08.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/14/2023] [Revised: 08/21/2023] [Accepted: 08/28/2023] [Indexed: 09/18/2023]
Abstract
Pulmonary fibrosis (PF) encompasses a spectrum of chronic lung diseases that progressively impact the interstitium, resulting in compromised gas exchange, breathlessness, diminished quality of life (QoL), and ultimately respiratory failure and mortality. Various diseases can cause PF, with their underlying causes primarily affecting the lung interstitium, leading to their referral as interstitial lung diseases (ILDs). The current understanding is that PF arises from abnormal wound healing processes triggered by various factors specific to each disease, leading to excessive inflammation and fibrosis. While significant progress has been made in understanding the molecular mechanisms of PF, its pathogenesis remains elusive. This review provides an in-depth exploration of the latest insights into PF pathophysiology, diagnosis, treatment, and future perspectives.
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Affiliation(s)
- Thomas Koudstaal
- Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - Manuela Funke-Chambour
- Department of Pulmonary Medicine, Inselspital, University Hospital Bern, Bern, Switzerland
| | - Michael Kreuter
- Mainz Center for Pulmonary Medicine, Departments of Pneumology, Mainz University Medical Center and of Pulmonary, Critical Care & Sleep Medicine, Marienhaus Clinic Mainz, Mainz, Germany
| | - Philip L Molyneaux
- Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Marlies S Wijsenbeek
- Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
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Li H, Huang Z, Yang C, Han D, Wang X, Qiu X, Zhang Z, Chen X. Association between plasma lysophosphatidic acid levels and bronchopulmonary dysplasia in extremely preterm infants: A prospective study. Pediatr Pulmonol 2023; 58:3516-3522. [PMID: 37712600 DOI: 10.1002/ppul.26685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/11/2023] [Revised: 08/19/2023] [Accepted: 09/05/2023] [Indexed: 09/16/2023]
Abstract
BACKGROUND Lysophosphatidic acid (LPA) is implicated in bronchopulmonary dysplasia (BPD) pathogenesis, but clinical evidence is lacking. This study aimed to investigate LPA levels in preterm infants with and without BPD and explore LPA as a biomarker for predicting BPD occurrence. METHODS Premature infants with a gestational age of <28 weeks or a birth weight of <1000 g were enrolled. Blood samples were collected at postnatal day (PD) 7, 28, and postmenstrual age (PMA) 36 weeks, and plasma LPA levels were measured using a commercial ELISA kit. Receiver operating characteristic curve (ROC) curve analysis determined the PD 28 cutoff for LPA, and multivariable regression analyzed LPA's independent contribution to BPD and exploratory outcomes. RESULT Among the 91 infants enrolled in this study, 35 were classified into the non-BPD group and 56 into the BPD group. Infants with BPD had higher plasma LPA levels at PD 28 (6.467 vs. 4.226 μg/mL, p = 0.034) and PMA 36 weeks (2.330 vs. 1.636 μg/mL, p = 0.001). PD 28 LPA level of 6.132 μg/mL was the cutoff for predicting BPD development. Higher PD 28 LPA levels (≥6.132 μg/mL) independently associated with BPD occurrence (OR 3.307, 95% CI 1.032-10.597, p = 0.044). Higher LPA levels correlated with longer oxygen therapy durations [regression coefficients (β) 0.147, 95% CI 0.643-16.133, p = .034]. CONCLUSIONS Infants with BPD had higher plasma LPA levels at PD 28 and PMA 36 weeks. Higher PD 28 LPA levels independently associated with an increased BPD risk.
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Affiliation(s)
- Huitao Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
- Department of Cardiac Pediatrics, Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zilu Huang
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Chuanzhong Yang
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Dongshan Han
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Xuan Wang
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Xiaomei Qiu
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Zhiwei Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Cardiac Pediatrics, Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xueyu Chen
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
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Selvarajah B, Platé M, Chambers RC. Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies. Mol Aspects Med 2023; 94:101227. [PMID: 38000335 DOI: 10.1016/j.mam.2023.101227] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/09/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023]
Abstract
Fibrosis is the concluding pathological outcome and major cause of morbidity and mortality in a number of common chronic inflammatory, immune-mediated and metabolic diseases. The progressive deposition of a collagen-rich extracellular matrix (ECM) represents the cornerstone of the fibrotic response and culminates in organ failure and premature death. Idiopathic pulmonary fibrosis (IPF) represents the most rapidly progressive and lethal of all fibrotic diseases with a dismal median survival of 3.5 years from diagnosis. Although the approval of the antifibrotic agents, pirfenidone and nintedanib, for the treatment of IPF signalled a watershed moment for the development of anti-fibrotic therapeutics, these agents slow but do not halt disease progression or improve quality of life. There therefore remains a pressing need for the development of effective therapeutic strategies. In this article, we review emerging therapeutic strategies for IPF as well as the pre-clinical and translational approaches that will underpin a greater understanding of the key pathomechanisms involved in order to transform the way we diagnose and treat pulmonary fibrosis.
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Affiliation(s)
- Brintha Selvarajah
- Oncogenes and Tumour Metabolism Laboratory, The Francis Crick Institute, London, UK
| | - Manuela Platé
- Department of Respiratory Medicine (UCL Respiratory), Division of Medicine, University College London, UK
| | - Rachel C Chambers
- Department of Respiratory Medicine (UCL Respiratory), Division of Medicine, University College London, UK.
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Sofia C, Comes A, Sgalla G, Richeldi L. An update on emerging drugs for the treatment of idiopathic pulmonary fibrosis: a look towards 2023 and beyond. Expert Opin Emerg Drugs 2023; 28:283-296. [PMID: 37953604 DOI: 10.1080/14728214.2023.2281416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/13/2023] [Accepted: 11/06/2023] [Indexed: 11/14/2023]
Abstract
INTRODUCTION Currently approved drug treatments for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, have been shown to slow lung function decline and improve clinical outcomes. Since significant advances in the understanding of pathogenetic mechanisms in IPF, novel potential agents are being tested to identify new targeted and better tolerated therapeutic strategies. AREAS COVERED This review describes the evidence from IPF phase II and III clinical trials that have been completed or are ongoing in recent years. The literature search was performed using Medline and Clinicaltrials.org databases. Particular attention is paid to the new inhibitor of phosphodiesterase 4B (BI 1015550), being studied in a more advanced research phase. Some emerging critical issues of the pharmacological research are highlighted considering the recent outstanding failures of several phase III trials. EXPERT OPINION An exponential number of randomized clinical trials are underway testing promising new molecules to increase treatment choices for patients with IPF and improve patients' quality of life. The next goals should aim at a deeper understanding of the pathogenic pathways of the disease with the challenging goal of being able not only to stabilize but also to reverse the ongoing fibrotic process in patients with IPF.
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Affiliation(s)
- Carmelo Sofia
- Dipartimento di scienze mediche e chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Alessia Comes
- Dipartimento di scienze mediche e chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giacomo Sgalla
- Dipartimento di scienze mediche e chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Luca Richeldi
- Dipartimento di scienze mediche e chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
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Cheng X, Jiang S, Pan B, Xie W, Meng J. Ectopic and visceral fat deposition in aging, obesity, and idiopathic pulmonary fibrosis: an interconnected role. Lipids Health Dis 2023; 22:201. [PMID: 38001499 PMCID: PMC10668383 DOI: 10.1186/s12944-023-01964-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/25/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is considered an age-related disease. Age-related changes, along with other factors such as obesity, hormonal imbalances, and various metabolic disorders, lead to ectopic fat deposition (EFD). This accumulation of fat outside of its normal storage sites is associated with detrimental effects such as lipotoxicity, oxidative stress, inflammation, and insulin resistance. This narrative review provides an overview of the connection between ectopic and visceral fat deposition in aging, obesity, and IPF. It also elucidates the mechanism by which ectopic fat deposition in the airways and lungs, pericardium, skeletal muscles, and pancreas contributes to lung injury and fibrosis in patients with IPF, directly or indirectly. Moreover, the review discusses the impact of EFD on the severity of the disease, quality of life, presence of comorbidities, and overall prognosis in IPF patients. The review provides detailed information on recent research regarding representative lipid-lowering drugs, hypoglycemic drugs, and lipid-targeting drugs in animal experiments and clinical studies. This may offer new therapeutic directions for patients with IPF.
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Affiliation(s)
- Xiaoyun Cheng
- Department of Pulmonary and Critical Care Medicine, The Third Xiangya Hospital of Central South University, Tongzipo Road 138, Yuelu District, Changsha, 410000, China
- Hunan Key Laboratory of Organ Fibrosis, Tongzipo Road 138, Yuelu District, Changsha, 410000, China
| | - Shuhan Jiang
- Department of Pulmonary and Critical Care Medicine, The Third Xiangya Hospital of Central South University, Tongzipo Road 138, Yuelu District, Changsha, 410000, China
- Hunan Key Laboratory of Organ Fibrosis, Tongzipo Road 138, Yuelu District, Changsha, 410000, China
| | - Boyu Pan
- Departments of Orthopedics, The Third Hospital of Changsha, Laodong West Road 176, Tianxin District, Changsha, 410000, China
| | - Wei Xie
- Department of Cardiology, Xiangya Hospital of Central South University, Furong Middle Road 36, Kaifu District, Changsha, 410000, China
| | - Jie Meng
- Department of Pulmonary and Critical Care Medicine, The Third Xiangya Hospital of Central South University, Tongzipo Road 138, Yuelu District, Changsha, 410000, China.
- Hunan Key Laboratory of Organ Fibrosis, Tongzipo Road 138, Yuelu District, Changsha, 410000, China.
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Kobayashi Y, Uneuchi F, Naruse T, Matsuda D, Okumura-Kitajima L, Kajiyama H, Wada R, Yonemoto Y, Nakano K, Toki H, Kamigaso S, Yamagishi J, Tokura S, Kakinuma H, Kuroda S. Lead generation from N-[benzyl(4-phenylbutyl)carbamoyl]amino acid as a novel LPA 1 antagonist for the treatment of systemic sclerosis. Eur J Med Chem 2023; 260:115749. [PMID: 37639822 DOI: 10.1016/j.ejmech.2023.115749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/10/2023] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 08/31/2023]
Abstract
Lysophosphatidic acid (LPA), a bioactive phospholipid, binds to the G protein-coupled LPA1 receptor on the surfaces of immune cells, to promote progression of fibrosis of the skin and organs through inducing infiltration of immune cells into tissues, chemokine production, inflammatory cytokine production, and fibroblast transformation. Anti-fibrotic effects of LPA1 blockade have been reported in animal models of scleroderma and scleroderma patients. In the study reported herein, we identified the novel urea compound 5 as a hit compound with LPA1 antagonist activity from our in-house library and synthesized the lead compound TP0541640 (18) by structural transformation utilizing a structure-based drug design (SBDD) approach. Compound 18 possessed potent in vitro LPA1 antagonist activity and exhibited a dose-dependent inhibitory effect against LPA-induced histamine release in mice. Furthermore, 18 significantly suppressed collagen production and skin thickening in a mouse model of bleomycin-induced skin fibrosis. Herein, we describe the compound design strategies and in vivo studies in greater detail.
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Affiliation(s)
- Yuki Kobayashi
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Fumito Uneuchi
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Takumi Naruse
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Daisuke Matsuda
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | | | - Hiromitsu Kajiyama
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Reiko Wada
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Yuki Yonemoto
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Koichiro Nakano
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Hidetoh Toki
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Shunsuke Kamigaso
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Jyunya Yamagishi
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Seiken Tokura
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
| | - Hiroyuki Kakinuma
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan.
| | - Shoichi Kuroda
- Taisho Pharmaceutical Co., Ltd., 1-403, Kita-Ku, Saitama, 331-9530, Japan
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Huang WC, Chuang CF, Huang YT, Chung IC, Chen ML, Chuang TY, Yang XL, Chou YY, Liu CH, Chen NY, Chen CJ, Yuan TT. Monoclonal enolase-1 blocking antibody ameliorates pulmonary inflammation and fibrosis. Respir Res 2023; 24:280. [PMID: 37964270 PMCID: PMC10647181 DOI: 10.1186/s12931-023-02583-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/07/2022] [Accepted: 10/27/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2). METHODS In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis. RESULTS Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-β upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion. CONCLUSIONS These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Nai-Yu Chen
- Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Chun-Jen Chen
- Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Ta-Tung Yuan
- HuniLife Biotechnology Inc, Taipei, Taiwan.
- Department of Research and Development, HuniLife Biotechnology Inc, Rm. 1, 6F., No. 308, Sec. 1, Neihu Rd., Neihu Dist, 114, Taipei City, Taiwan.
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