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Zhao Y, Shi Y, Zhang J, Zhang H, Wang Z, Wu S, Zhang M, Liu M, Ye X, Gu H, Jiang C, Ye X, Zhu H, Li Q, Huang X, Cao M. The potential lipid biomarker 5-HETE for acute exacerbation identified by metabolomics in patients with idiopathic pulmonary fibrosis. Respirology 2025; 30:158-167. [PMID: 39681341 DOI: 10.1111/resp.14866] [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: 05/08/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024]
Abstract
BACKGROUND AND OBJECTIVE Acute exacerbation (AE) is often the fatal complication of idiopathic pulmonary fibrosis (IPF). Emerging evidence indicates that metabolic reprogramming and dysregulation of lipid metabolism are distinctive characteristics of IPF. However, the lipid metabolic mechanisms that underlie the pathophysiology of AE-IPF remain elusive. METHODS Serum samples for pilot study were collected from 34 Controls, 37 stable IPF (S-IPF) cases and 41 AE-IPF patients. UHPLC-MS/MS was utilized to investigate metabolic variations and identify lipid biomarkers in serum. ELISA, quantitative PCR and western blot were employed to validate the identified biomarkers. RESULTS There were 32 lipid metabolites and 5 lipid metabolism pathways enriched in all IPF patients compared to Controls. In AE-IPF versus S-IPF, 19 lipid metabolites and 12 pathways were identified, with 5-hydroxyeicosatetraenoic Acid (5-HETE) significantly elevated in AE-IPF. Both in internal and external validation cohorts, the serum levels of 5-HETE were significantly elevated in AE-IPF patients compared to S-IPF subjects. Consequently, the indicators related to 5-HETE in lipid metabolic pathway were significantly changed in AE-IPF patients compared with S-IPF cases in the lung tissues. The serum level of 5-HETE was significantly correlated with the disease severity (CT score and PaO2/FiO2 ratio) and survival time. Importantly, the receiver operating characteristic (ROC) curve, Kaplan-Meier analysis and Multivariate Cox regression analysis demonstrated that 5-HETE represents a promising lipid biomarker for the diagnosis and prognosis of AE-IPF. CONCLUSION Our study highlights lipid reprogramming as a novel therapeutic approach for IPF, and 5-HETE may be a potential biomarker of AE-IPF patients.
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Affiliation(s)
- Yichao Zhao
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yanchen Shi
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ji Zhang
- Department of Lung Transplant, The First Affiliated Hospital College of Medicine, Zhejiang University, Hangzhou, China
| | - Huizhe Zhang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zimu Wang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Shufei Wu
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mingrui Zhang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mengying Liu
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xu Ye
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Huimin Gu
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Cheng Jiang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoling Ye
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Huihui Zhu
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qi Li
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xinmei Huang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
- Nanjing Institute of Respiratory Diseases, Nanjing, China
| | - Mengshu Cao
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
- Nanjing Institute of Respiratory Diseases, Nanjing, China
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Reed EB, Sitikov A, Shin KWD, Hamanaka RB, Cetin-Atalay R, Mutlu GM, Mongin AA, Dulin NO. Gα12 and Gα13 proteins are required for transforming growth factor-β-induced myofibroblast differentiation. Biochem J 2024; 481:1937-1948. [PMID: 39621448 DOI: 10.1042/bcj20240317] [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: 06/26/2024] [Revised: 11/13/2024] [Accepted: 12/02/2024] [Indexed: 12/14/2024]
Abstract
Myofibroblast differentiation, characterized by accumulation of cytoskeletal and extracellular matrix proteins by fibroblasts, is a key process in wound healing and pathogenesis of tissue fibrosis. Transforming growth factor-β (TGF-β) is the most powerful known driver of myofibroblast differentiation. TGF-β signals through transmembrane receptor serine/threonine kinases that phosphorylate Smad transcription factors (Smad2/3) leading to activation of transcription of target genes. Heterotrimeric G proteins mediate distinct signaling from seven-transmembrane G protein coupled receptors, which are not known to be linked to Smad activation. We tested whether G protein signaling plays any role in TGF-β-induced myofibroblast differentiation, using primary cultured human lung fibroblasts. Activation of Gαs by cholera toxin blocked TGF-β-induced myofibroblast differentiation without affecting Smad2/3 phosphorylation. Neither inhibition of Gαi by pertussis toxin nor siRNA-mediated combined knockdown of Gαq and Gα11 had a significant effect on TGF-β-induced myofibroblast differentiation. In contrast, combined knockdown of Gα12 and Gα13 significantly inhibited TGF-β-stimulated expression of myofibroblast marker proteins (collagen-1, fibronectin, smooth-muscle α-actin), with siGα12 being significantly more potent than siGα13. Mechanistically, combined knockdown of Gα12 and Gα13 resulted in substantially reduced phosphorylation of Smad2 and Smad3 in response to TGF-β, which was accompanied by a significant decrease in the expression of TGF-β receptors (TGFBR1, TGFBR2) and of Smad3. Thus, our study uncovers a novel role of Gα12/13 proteins in the control of TGF-β signaling and myofibroblast differentiation.
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Affiliation(s)
- Eleanor B Reed
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, U.S.A
| | - Albert Sitikov
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, U.S.A
| | - Kun Woo D Shin
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, U.S.A
| | - Robert B Hamanaka
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, U.S.A
| | - Rengül Cetin-Atalay
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, U.S.A
| | - Gökhan M Mutlu
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, U.S.A
| | - Alexander A Mongin
- Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, U.S.A
| | - Nickolai O Dulin
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, U.S.A
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Chen X, Han D, Zeng Y, Li H, Wang X, Huang Z, Yang L, Wagenaar GTM, Lin B, Yang C. Inhibition of lysophosphatidic acid receptor 2 attenuates neonatal chronic lung disease in mice by preserving vascular and alveolar development. Eur J Pharmacol 2024; 985:177120. [PMID: 39522686 DOI: 10.1016/j.ejphar.2024.177120] [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: 06/18/2024] [Revised: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
AIM Bronchopulmonary dysplasia (BPD) is a common morbidity in extremely premature infants. Previous studies demonstrated the important role of lysophosphatidic acid (LPA) in inflammation in BPD. However, the role of LPA and its receptors in hyperoxia-induced vascular malformations in BPD remains to be elucidated. METHODS AND RESULTS Elevated plasma LPA levels were observed in mice with BPD compared to controls (792 vs. 607 ng/mL, p < 0.05). Inhibition of LPA signaling protected against hyperoxia-induced lung injury in neonatal mice, demonstrated by a 2.8-fold increase in pulmonary vascular density and a 14% reduction in alveolar enlargement. In vitro studies showed that LPA suppressed tube formation in human umbilical vein endothelial cells (HUVECs) by approximately 50%. LPA receptor 2 (LPA2) was identified as a functional LPA receptor in primary endothelial cells from the lungs of hyperoxic mice and in HUVECs under hyperoxic conditions. The LPA2 antagonist H2L5186303 enhanced the tube formation ability of HUVECs exposed to LPA, both under normoxia (4-fold) and hyperoxia (5-fold). Moreover, H2L5186303 significantly protected against hyperoxia-induced vascular malformation (2-fold) and improved alveolarization in neonatal mice (12% decrease in mean linear intercept, MLI). Early growth response 1 (EGR1) was characterized as a downstream target of LPA2, silencing EGR1 restored tube formation in HUVECs exposed to LPA and hyperoxia. CONCLUSIONS Our in vitro and in vivo findings demonstrate that the inhibition of LPA/LPA2 signaling mitigates hyperoxia-induced pulmonary vascular malformations, suggesting the LPA/LPA2-dependent signaling pathway has therapeutic potential for extremely premature infants with BPD.
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Affiliation(s)
- Xueyu Chen
- Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China; Shenzhen Key Laboratory of Maternal and Child Health and Diseases, Shenzhen, China
| | - Dongshan Han
- Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China
| | - Yali Zeng
- Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China
| | - Huitao Li
- Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China
| | - Xuan Wang
- Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China
| | - Zilu Huang
- Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China
| | - Lingling Yang
- Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China
| | | | - Bingchun Lin
- Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China.
| | - Chuanzhong Yang
- Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China; Shenzhen Key Laboratory of Maternal and Child Health and Diseases, Shenzhen, China.
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Gharagozlou S, Wright NM, Murguia-Favela L, Eshleman J, Midgley J, Saygili S, Mathew G, Lesmana H, Makkoukdji N, Gans M, Saba JD. Sphingosine phosphate lyase insufficiency syndrome as a primary immunodeficiency state. Adv Biol Regul 2024; 94:101058. [PMID: 39454238 DOI: 10.1016/j.jbior.2024.101058] [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: 09/27/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024]
Abstract
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.
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Affiliation(s)
- Saber Gharagozlou
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
| | - NicolaA M Wright
- Department of Pediatrics, Cummings School of Medicine, University of Calgary, Alberta, Canada.
| | - Luis Murguia-Favela
- Department of Pediatrics, Cummings School of Medicine, University of Calgary, Alberta, Canada.
| | - Juliette Eshleman
- Department of Pediatrics, Cummings School of Medicine, University of Calgary, Alberta, Canada.
| | - Julian Midgley
- Department of Pediatrics, Cummings School of Medicine, University of Calgary, Alberta, Canada.
| | - Seha Saygili
- Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Turkey.
| | - Georgie Mathew
- Division of Pediatric Nephrology, Christian Medical College, Vellore, India.
| | - Harry Lesmana
- Department of Medical Genetics and Genomics, Department of Pediatric Hematology/Oncology and BMT, Cleveland Clinic, Cleveland, OH, USA.
| | - Nadia Makkoukdji
- Department of Pediatrics, Division of Allergy & Immunology University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, FL, USA.
| | - Melissa Gans
- Department of Pediatrics, Division of Allergy & Immunology University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, FL, USA.
| | - Julie D Saba
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
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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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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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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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8
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Tiwari P, Verma S, Washimkar KR, Nilakanth Mugale M. Immune cells crosstalk Pathways, and metabolic alterations in Idiopathic pulmonary fibrosis. Int Immunopharmacol 2024; 135:112269. [PMID: 38781610 DOI: 10.1016/j.intimp.2024.112269] [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: 03/30/2024] [Revised: 05/09/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) presents a challenging progression characterized by lung tissue scarring and abnormal extracellular matrix deposition. This review examines the influence of immune responses, emphasizing their complex role in initiating and perpetuating fibrosis. It highlights how metabolic pathways modulate immune cell function during IPF. Immune cell modulation holds promise in managing pulmonary fibrosis (PF). Inhibiting neutrophil recruitment and monitoring mast cell levels offer insights into PF progression. Low-dose IL-2 therapy and regulation of fibroblast recruitment present potential therapeutic avenues, while the role of innate lymphoid cells (ILC2s) in allergic lung inflammation sheds light on disease mechanisms. The review focuses on metabolic reprogramming's role in shaping immune cell function during IPF progression. While some immune cells use glycolysis for pro-inflammatory responses, others favor fatty acid oxidation for regulatory functions. Targeting specialized pro-resolving lipid mediators (SPMs) presents significant potential for managing fibrotic disorders. Additionally, it highlights the pivotal role of amino acid metabolism in synthesizing serine and glycine as crucial regulators of collagen production and exploring the interconnectedness of lipid metabolism, mitochondrial dysfunction, and adipokines in driving fibrotic processes. Moreover, the review discusses the impact of metabolic disorders such as obesity and diabetes on lung fibrosis. Advocating for a holistic approach, it emphasizes the importance of considering this interplay between immune cell function and metabolic pathways in developing effective and personalized treatments for IPF.
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Affiliation(s)
- Purnima Tiwari
- Division of Toxicology and Experimental Medicine, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow-226031, India
| | - Shobhit Verma
- Division of Toxicology and Experimental Medicine, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow-226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Kaveri R Washimkar
- Division of Toxicology and Experimental Medicine, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow-226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR- Central Drug Research Institute (CSIR-CDRI), Lucknow-226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
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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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10
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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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11
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Reed EB, Sitikov A, Hamanaka RB, Cetin-Atalay R, Mutlu GM, Mongin AA, Dulin NO. Critical role of Gα12 and Gα13 proteins in TGF-β-induced myofibroblast differentiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.29.596473. [PMID: 38854083 PMCID: PMC11160726 DOI: 10.1101/2024.05.29.596473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 06/11/2024]
Abstract
Myofibroblast differentiation, characterized by accumulation of cytoskeletal and extracellular matrix proteins by fibroblasts, is a key process in wound healing and pathogenesis of tissue fibrosis. Transforming growth factor-β (TGF-β) is the most powerful known driver of myofibroblast differentiation. TGF-β signals through transmembrane receptor serine/threonine kinases that phosphorylate Smad transcription factors (Smad2/3) leading to activation of transcription of target genes. Heterotrimeric G proteins mediate a distinct signaling from seven-transmembrane G protein coupled receptors, not commonly linked to Smad activation. We asked if G protein signaling plays any role in TGF-β-induced myofibroblast differentiation, using primary cultured human lung fibroblasts. Activation of Gαs by cholera toxin blocked TGF-β-induced myofibroblast differentiation without affecting Smad2/3 phosphorylation. Inhibition of Gαi by pertussis toxin, or siRNA-mediated combined knockdown of Gαq and Gα11 had no significant effect on TGF-β-induced myofibroblast differentiation. A combined knockdown of Gα12 and Gα13 resulted in a drastic inhibition of TGF-β-stimulated expression of myofibroblast marker proteins (collagen-1, fibronectin, smooth-muscle α-actin), with siGα12 being significantly more potent than siGα13. Mechanistically, a combined knockdown of Gα12 and Gα13 resulted in a substantially reduced phosphorylation of Smad2 and Smad3 in response to TGF-β, which was accompanied by a significant decrease in the expression of TGFβ receptors (TGFBR1, TGFBR2) and of Smad3 under siGα12/13 conditions. In conclusion, our study uncovers a novel role of Gα12/13 proteins in the control of TGF-β signaling and myofibroblast differentiation.
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Affiliation(s)
- Eleanor B. Reed
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, USA
| | - Albert Sitikov
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, USA
| | - Robert B. Hamanaka
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, USA
| | - Rengül Cetin-Atalay
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, USA
| | - Gökhan M. Mutlu
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, USA
| | - Alexander A. Mongin
- Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY
| | - Nickolai O. Dulin
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, USA
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12
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Bhattacharyya A, Khan R, Lee JY, Tassew G, Oskouian B, Allende ML, Proia RL, Yin X, Ortega JG, Bhattacharya M, Saba JD. Gene therapy with AAV9-SGPL1 in an animal model of lung fibrosis. J Pathol 2024; 263:22-31. [PMID: 38332723 PMCID: PMC10987276 DOI: 10.1002/path.6256] [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: 08/10/2023] [Revised: 11/29/2023] [Accepted: 12/18/2023] [Indexed: 02/10/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung that leads rapidly to respiratory failure. Novel approaches to treatment are urgently needed. The bioactive lipid sphingosine-1-phosphate (S1P) is increased in IPF lungs and promotes proinflammatory and profibrotic TGF-β signaling. Hence, decreasing lung S1P represents a potential therapeutic strategy for IPF. S1P is degraded by the intracellular enzyme S1P lyase (SPL). Here we find that a knock-in mouse with a missense SPL mutation mimicking human disease resulted in reduced SPL activity, increased S1P, increased TGF-β signaling, increased lung fibrosis, and higher mortality after injury compared to wild type (WT). We then tested adeno-associated virus 9 (AAV9)-mediated overexpression of human SGPL1 (AAV-SPL) in mice as a therapeutic modality. Intravenous treatment with AAV-SPL augmented lung SPL activity, attenuated S1P levels within the lungs, and decreased injury-induced fibrosis compared to controls treated with saline or only AAV. We confirmed that AAV-SPL treatment led to higher expression of SPL in the epithelial and fibroblast compartments during bleomycin-induced lung injury. Additionally, AAV-SPL decreased expression of the profibrotic cytokines TNFα and IL1β as well as markers of fibroblast activation, such as fibronectin (Fn1), Tgfb1, Acta2, and collagen genes in the lung. Taken together, our results provide proof of concept for the use of AAV-SPL as a therapeutic strategy for the treatment of IPF. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Aritra Bhattacharyya
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, CA, USA
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, USA
| | - Ranjha Khan
- Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Joanna Y. Lee
- Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Gizachew Tassew
- Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Babak Oskouian
- Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Maria L. Allende
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Richard L. Proia
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Xiaoyang Yin
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, CA, USA
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, USA
| | - Javier G. Ortega
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, CA, USA
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, USA
| | - Mallar Bhattacharya
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, CA, USA
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, USA
| | - Julie D. Saba
- Department of Pediatrics, University of California, San Francisco, CA, USA
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Yang W, Schoeman JC, Di X, Lamont L, Harms AC, Hankemeier T. A comprehensive UHPLC-MS/MS method for metabolomics profiling of signaling lipids: Markers of oxidative stress, immunity and inflammation. Anal Chim Acta 2024; 1297:342348. [PMID: 38438234 DOI: 10.1016/j.aca.2024.342348] [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: 09/15/2023] [Revised: 01/30/2024] [Accepted: 02/04/2024] [Indexed: 03/06/2024]
Abstract
Signaling lipids (SLs) play a crucial role in various signaling pathways, featuring diverse lipid backbone structures. Emerging evidence showing the biological significance and biomedical values of SLs has strongly spurred the advancement of analytical approaches aimed at profiling SLs. Nevertheless, the dramatic differences in endogenous abundances across lipid classes as well as multiple isomers within the same lipid class makes the development of a generic analytical method challenging. A better analytical method that combines comprehensive coverage and high sensitivity is needed to enable us to gain a deeper understanding of the biochemistry of these molecules in health and disease. In this study, we developed a fast and comprehensive targeted ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for profiling SLs. The platform enables analyses of 260 metabolites covering oxylipins (isoprostanes, prostaglandins and other oxidized lipids), free fatty acids, lysophospholipids, sphingoid bases (C16, C18), platelet activating factors (C16, C18), endocannabinoids and bile acids. Various validation parameters including linearity, limit of detection, limit of quantification, extraction recovery, matrix effect, intra-day and inter-day precision were used to characterize this method. Metabolite quantitation was successfully achieved in both NIST Standard Reference Material for human plasma (NIST SRM 1950) and pooled human plasma, with 109 and 144 metabolites quantitated. The quantitation results in NIST SRM 1950 plasma demonstrated good correlations with certified or previously reported values in published literature. This study introduced quantitative data for 37 SLs for the first time. Metabolite concentrations measured in NIST SRM 1950 will serve as essential reference data for facilitating interlaboratory comparisons. The methodology established here will be the cornerstone for in-depth profiling of signaling lipids across diverse biological samples and contexts.
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Affiliation(s)
- Wei Yang
- Metabolomics and Analytics Center, Leiden Academic Centre of Drug Research, Leiden University, 2333 CC, Leiden, the Netherlands
| | - Johannes C Schoeman
- Metabolomics and Analytics Center, Leiden Academic Centre of Drug Research, Leiden University, 2333 CC, Leiden, the Netherlands
| | - Xinyu Di
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC, Leiden, the Netherlands
| | - Lieke Lamont
- Metabolomics and Analytics Center, Leiden Academic Centre of Drug Research, Leiden University, 2333 CC, Leiden, the Netherlands
| | - Amy C Harms
- Metabolomics and Analytics Center, Leiden Academic Centre of Drug Research, Leiden University, 2333 CC, Leiden, the Netherlands
| | - Thomas Hankemeier
- Metabolomics and Analytics Center, Leiden Academic Centre of Drug Research, Leiden University, 2333 CC, Leiden, the Netherlands.
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14
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Shi X, Chen Y, Shi M, Gao F, Huang L, Wang W, Wei D, Shi C, Yu Y, Xia X, Song N, Chen X, Distler JHW, Lu C, Chen J, Wang J. The novel molecular mechanism of pulmonary fibrosis: insight into lipid metabolism from reanalysis of single-cell RNA-seq databases. Lipids Health Dis 2024; 23:98. [PMID: 38570797 PMCID: PMC10988923 DOI: 10.1186/s12944-024-02062-8] [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: 12/26/2023] [Accepted: 02/27/2024] [Indexed: 04/05/2024] Open
Abstract
Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids' biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.
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Affiliation(s)
- Xiangguang Shi
- Department of Dermatology, Huashan Hospital, and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Yahui Chen
- Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China Fudan University, Shanghai, China
| | - Mengkun Shi
- Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Fei Gao
- Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China
| | - Lihao Huang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism & Integrative Biology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Wei Wang
- Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China
- MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Dong Wei
- Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China
| | - Chenyi Shi
- MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuexin Yu
- Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China Fudan University, Shanghai, China
| | - Xueyi Xia
- Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China Fudan University, Shanghai, China
| | - Nana Song
- Department of Nephrology, Zhongshan Hospital, Fudan University, Fudan Zhangjiang Institute, Shanghai, People's Republic of China
| | - Xiaofeng Chen
- Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jörg H W Distler
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen, Nuremberg, Germany
| | - Chenqi Lu
- MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
| | - Jingyu Chen
- Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China.
- Center for Lung Transplantation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jiucun Wang
- Department of Dermatology, Huashan Hospital, and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
- Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China Fudan University, Shanghai, China.
- Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Beijing, China.
- Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
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15
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Taneja A, Jentsch G, Delage S, Randall MJ, van den Blink B, Bauer Y, Namour F. ISABELA Studies: Plasma Exposure and Target Engagement Do Not Explain the Lack of Efficacy of Ziritaxestat in Patients with Idiopathic Pulmonary Fibrosis. Clin Pharmacol Ther 2024; 115:606-615. [PMID: 38071462 DOI: 10.1002/cpt.3138] [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] [Received: 04/05/2023] [Accepted: 11/15/2023] [Indexed: 01/06/2024]
Abstract
Autotaxin (ATX) contributes to the production of lysophosphatidic acid (LPA), which is associated with fibrosis development in idiopathic pulmonary fibrosis (IPF). The ATX inhibitor ziritaxestat failed to reduce decline in forced vital capacity (FVC) in patients with IPF in ISABELA 1 and 2 (NCT03711162 and NCT03733444), two identically designed phase III studies. In the current analysis, we evaluated pharmacokinetic and pharmacodynamic data from the pooled ISABELA studies to determine whether the lack of efficacy could be attributed to insufficient exposure and/or target engagement. Nonlinear mixed effect modeling was performed to predict ziritaxestat exposure in individual patients and describe its effect on LPA C18:2 levels. We assessed whether there was a correlation between ziritaxestat and ATX concentration and evaluated the relationship between LPA C18:2 reduction and change from baseline in FVC. Ziritaxestat exposure in patients with IPF was numerically lower in those who received ziritaxestat on top of pirfenidone than in those who received ziritaxestat on top of nintedanib or ziritaxestat alone. In most patients, LPA C18:2 reduction was comparable to that reported in healthy volunteers. ATX concentrations increased over time and correlated weakly with ziritaxestat exposure and LPA C18:2 reduction. No correlation between reduction in LPA C18:2 and change from baseline in FVC was apparent. Based on these evaluations, exposure and target engagement are not thought to have contributed to the lack of efficacy observed. We hypothesize that the lack of efficacy of ziritaxestat in the ISABELA program, despite adequate LPA reduction, could be due to the involvement of an alternative pro-fibrotic pathway.
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Pattaroni C, Begka C, Cardwell B, Jaffar J, Macowan M, Harris NL, Westall GP, Marsland BJ. Multi-omics integration reveals a nonlinear signature that precedes progression of lung fibrosis. Clin Transl Immunology 2024; 13:e1485. [PMID: 38269243 PMCID: PMC10807351 DOI: 10.1002/cti2.1485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/28/2023] [Revised: 12/11/2023] [Accepted: 01/09/2024] [Indexed: 01/26/2024] Open
Abstract
Objectives Idiopathic pulmonary fibrosis (IPF) is a devastating progressive interstitial lung disease with poor outcomes. While decades of research have shed light on pathophysiological mechanisms associated with the disease, our understanding of the early molecular events driving IPF and its progression is limited. With this study, we aimed to model the leading edge of fibrosis using a data-driven approach. Methods Multiple omics modalities (transcriptomics, metabolomics and lipidomics) of healthy and IPF lung explants representing different stages of fibrosis were combined using an unbiased approach. Multi-Omics Factor Analysis of datasets revealed latent factors specifically linked with established fibrotic disease (Factor1) and disease progression (Factor2). Results Features characterising Factor1 comprised well-established hallmarks of fibrotic disease such as defects in surfactant, epithelial-mesenchymal transition, extracellular matrix deposition, mitochondrial dysfunction and purine metabolism. Comparatively, Factor2 identified a signature revealing a nonlinear trajectory towards disease progression. Molecular features characterising Factor2 included genes related to transcriptional regulation of cell differentiation, ciliogenesis and a subset of lipids from the endocannabinoid class. Machine learning models, trained upon the top transcriptomics features of each factor, accurately predicted disease status and progression when tested on two independent datasets. Conclusion This multi-omics integrative approach has revealed a unique signature which may represent the inflection point in disease progression, representing a promising avenue for the identification of therapeutic targets aimed at addressing the progressive nature of the disease.
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Affiliation(s)
- Céline Pattaroni
- Department of Immunology, School of Translational MedicineMonash UniversityMelbourneVICAustralia
| | - Christina Begka
- Department of Immunology, School of Translational MedicineMonash UniversityMelbourneVICAustralia
| | - Bailey Cardwell
- Department of Immunology, School of Translational MedicineMonash UniversityMelbourneVICAustralia
| | - Jade Jaffar
- Department of Immunology, School of Translational MedicineMonash UniversityMelbourneVICAustralia
| | - Matthew Macowan
- Department of Immunology, School of Translational MedicineMonash UniversityMelbourneVICAustralia
| | - Nicola L Harris
- Department of Immunology, School of Translational MedicineMonash UniversityMelbourneVICAustralia
| | - Glen P Westall
- Department of Immunology, School of Translational MedicineMonash UniversityMelbourneVICAustralia
- Department of Respiratory MedicineAlfred HospitalMelbourneVICAustralia
| | - Benjamin J Marsland
- Department of Immunology, School of Translational MedicineMonash UniversityMelbourneVICAustralia
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17
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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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18
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Nguyen LP, Khan RA, Kang S, Lee H, Hwang JI, Kim HR. Discovery of Chemical Scaffolds as Lysophosphatidic Acid Receptor 1 Antagonists: Virtual Screening, In Vitro Validation, and Molecular Dynamics Analysis. ACS OMEGA 2023; 8:40375-40386. [PMID: 37929144 PMCID: PMC10620911 DOI: 10.1021/acsomega.3c04798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 07/04/2023] [Accepted: 10/06/2023] [Indexed: 11/07/2023]
Abstract
Lysophosphatidic acid receptor 1 (LPAR1) is an emerging therapeutic target for numerous human diseases including fibrosis. However, the limited number of available core structures of LPAR1 antagonists has prompted the need for novel chemical templates. In this study, we conducted a high-throughput virtual screening to discover potential new scaffolds. We tested three existing crystal structures alongside an AlphaFold model to evaluate their suitability in structure-based virtual screening, finding that the crystal structures show superior performance compared with the predictive model. Furthermore, we also found that enhancing the precision in the screening process did not necessarily improve the enrichment of hits. From the screening campaign, we identified five structures that were validated using an LPAR1-dependent calcium flux assay. To gain a deeper insight into the protein-ligand interaction, we extensively analyzed the binding modes of these compounds using in silico techniques, laying the groundwork for the discovery of novel LPAR1 antagonists.
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Affiliation(s)
- Lan Phuong Nguyen
- Department of Biomedical Sciences,
College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Rasel Ahmed Khan
- Department of Biomedical Sciences,
College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Soomin Kang
- Department of Biomedical Sciences,
College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Hobin Lee
- Department of Biomedical Sciences,
College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Jong-Ik Hwang
- Department of Biomedical Sciences,
College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Hong-Rae Kim
- Department of Biomedical Sciences,
College of Medicine, Korea University, Seoul 02841, Republic of Korea
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19
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Luo YL, Li Y, Zhou W, Wang SY, Liu YQ. Inhibition of LPA-LPAR1 and VEGF-VEGFR2 Signaling in IPF Treatment. Drug Des Devel Ther 2023; 17:2679-2690. [PMID: 37680863 PMCID: PMC10482219 DOI: 10.2147/dddt.s415453] [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: 04/02/2023] [Accepted: 07/25/2023] [Indexed: 09/09/2023] Open
Abstract
Due to the complex mechanism and limited treatments available for pulmonary fibrosis, the development of targeted drugs or inhibitors based on their molecular mechanisms remains an important strategy for prevention and treatment. In this paper, the downstream signaling pathways mediated by VEGFR and LPAR1 in pulmonary cells and the role of these pathways in pulmonary fibrosis, as well as the current status of drug research on the targets of LPAR1 and VEGFR2, are described. The mechanism by which these two pathways regulate vascular leakage and collagen deposition leading to the development of pulmonary fibrosis are analyzed, and the mutual promotion of the two pathways is discussed. Here we propose the development of drugs that simultaneously target LPAR1 and VEGFR2, and discuss the important considerations in targeting and safety.
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Affiliation(s)
- Ya-Li Luo
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
| | - Yan Li
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
| | - Wen Zhou
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
| | - Si-Yu Wang
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
| | - Yong-Qi Liu
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China
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20
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Cerutis DR, Weston MD, Miyamoto T. Entering, Linked with the Sphinx: Lysophosphatidic Acids Everywhere, All at Once, in the Oral System and Cancer. Int J Mol Sci 2023; 24:10278. [PMID: 37373424 PMCID: PMC10299546 DOI: 10.3390/ijms241210278] [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: 05/04/2023] [Revised: 06/08/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Oral health is crucial to overall health, and periodontal disease (PDD) is a chronic inflammatory disease. Over the past decade, PDD has been recognized as a significant contributor to systemic inflammation. Here, we relate our seminal work defining the role of lysophosphatidic acid (LPA) and its receptors (LPARs) in the oral system with findings and parallels relevant to cancer. We discuss the largely unexplored fine-tuning potential of LPA species for biological control of complex immune responses and suggest approaches for the areas where we believe more research should be undertaken to advance our understanding of signaling at the level of the cellular microenvironment in biological processes where LPA is a key player so we can better treat diseases such as PDD, cancer, and emerging diseases.
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Affiliation(s)
- D. Roselyn Cerutis
- Department of Oral Biology, Creighton University School of Dentistry, Omaha, NE 68178, USA;
| | - Michael D. Weston
- Department of Oral Biology, Creighton University School of Dentistry, Omaha, NE 68178, USA;
| | - Takanari Miyamoto
- Department of Periodontics, Creighton University School of Dentistry, Omaha, NE 68178, USA;
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21
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Neighbors M, Li Q, Zhu SJ, Liu J, Wong WR, Jia G, Sandoval W, Tew GW. Bioactive lipid lysophosphatidic acid species are associated with disease progression in idiopathic pulmonary fibrosis. J Lipid Res 2023; 64:100375. [PMID: 37075981 PMCID: PMC10205439 DOI: 10.1016/j.jlr.2023.100375] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/05/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/21/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality. Prognostic biomarkers to identify rapid progressors are urgently needed to improve patient management. Since the lysophosphatidic acid (LPA) pathway has been implicated in lung fibrosis in preclinical models and identified as a potential therapeutic target, we aimed to investigate if bioactive lipid LPA species could be prognostic biomarkers that predict IPF disease progression. LPAs and lipidomics were measured in baseline placebo plasma of a randomized IPF-controlled trial. The association of lipids with disease progression indices were assessed using statistical models. Compared to healthy, IPF patients had significantly higher levels of five LPAs (LPA16:0, 16:1, 18:1, 18:2, 20:4) and reduced levels of two triglycerides species (TAG48:4-FA12:0, -FA18:2) (false discovery rate < 0.05, fold change > 2). Patients with higher levels of LPAs had greater declines in diffusion capacity of carbon monoxide over 52 weeks (P < 0.01); additionally, LPA20:4-high (≥median) patients had earlier time to exacerbation compared to LPA20:4-low (
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Affiliation(s)
| | - Qingling Li
- Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc., South San Francisco, USA
| | - Sha Joe Zhu
- PD Data Science, F Hoffmann-La Roche, Shanghai, China
| | - Jia Liu
- PD Data Science, F Hoffmann-La Roche, Shanghai, China
| | - Weng Ruh Wong
- Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc., South San Francisco, USA
| | - Guiquan Jia
- Department of Biomarker Discovery OMNI, Genentech Inc., South San Francisco, USA
| | - Wendy Sandoval
- Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc., South San Francisco, USA
| | - Gaik W Tew
- I2O Technology and Translational Research, Genentech Inc., South San Francisco, USA.
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22
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Jaiswal A, Rehman R, Dutta J, Singh S, Ray A, Shridhar M, Jaisankar J, Bhatt M, Khandelwal D, Sahoo B, Ram A, Mabalirajan U. Cellular Distribution of Secreted Phospholipase A2 in Lungs of IPF Patients and Its Inhibition in Bleomycin-Induced Pulmonary Fibrosis in Mice. Cells 2023; 12:cells12071044. [PMID: 37048117 PMCID: PMC10092981 DOI: 10.3390/cells12071044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/19/2022] [Revised: 01/13/2023] [Accepted: 01/29/2023] [Indexed: 04/03/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a very poor prognosis as it has a 2.5 to 5 years mean survival after proper diagnosis. Even nintedanib and pirfenidone cannot halt the progression, though they slow the progression of IPF. Hence, there is a need to understand the novel pathophysiology. Phospholipase A2 (PLA2) could be the ideal candidate to study in IPF, as they have a role in both inflammation and fibrosis. In the present study, we have shown the expression profile of various secretory Phospholipase A2 (PLA2) isoforms by analyzing publicly available transcriptome data of single cells from the lungs of healthy individuals and IPF patients. Among 11 members of sPLA2, PLA2G2A is found to be increased in the fibroblasts and mesothelial cells while PLA2G5 is found to be increased in the fibroblasts of IPF patients. We identified a subset of fibroblasts expressing high PLA2G2A with moderate expression of PLA2G5 and which are specific to IPF only; we named it as PLA2G2A+ IPF fibroblast. Pathway analysis revealed that these PLA2G2A+ IPF fibroblast have upregulation of both inflammatory and fibrosis-related pathways like the TGF-β signaling pathway, IL-17 signaling, the arachidonic acid metabolism pathway and ECM-receptor interaction. In addition to this, we found elevated levels of sPLA2-IIA in plasma samples of IPF patients in our cohort. PLA2G3, PLA2G10 and PLA2G12B are found in to be increased in certain epithelial cells of IPF patients. Thus, these findings indicate that these five isoforms have a disease-dominant role along with innate immune roles as these isoforms are found predominantly in structural cells of IPF patients. Further, we have targeted sPLA2 in mice model of bleomycin-induced lung fibrosis by pBPB, a known sPLA2 inhibitor. pBPB treatment attenuated lung fibrosis induced by bleomycin along with a reduction in TGF-β and deposition of extracellular matrix in lung. Thus, these findings indicate that these sPLA2 isoforms especially PLA2G2A may serve as a therapeutic target in lung fibrosis.
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23
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Vít O, Petrák J. Autotaxin and Lysophosphatidic Acid Signalling: the Pleiotropic Regulatory Network in Cancer. Folia Biol (Praha) 2023; 69:149-162. [PMID: 38583176 DOI: 10.14712/fb2023069050149] [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: 04/09/2024]
Abstract
Autotaxin, also known as ecto-nucleotide pyrophosphatase/phosphodiesterase family member 2, is a secreted glycoprotein that plays multiple roles in human physiology and cancer pathology. This protein, by converting lysophosphatidylcholine into lysophosphatidic acid, initiates a complex signalling cascade with significant biological implications. The article outlines the autotaxin gene and protein structure, expression regulation and physiological functions, but focuses mainly on the role of autotaxin in cancer development and progression. Autotaxin and lysophosphatidic acid signalling influence several aspects of cancer, including cell proliferation, migration, metastasis, therapy resistance, and interactions with the immune system. The potential of autotaxin as a diagnostic biomarker and promising drug target is also examined.
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Affiliation(s)
- Ondřej Vít
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
| | - Jiří Petrák
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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24
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Yue YL, Zhang MY, Liu JY, Fang LJ, Qu YQ. The role of autophagy in idiopathic pulmonary fibrosis: from mechanisms to therapies. Ther Adv Respir Dis 2022; 16:17534666221140972. [PMID: 36468453 PMCID: PMC9726854 DOI: 10.1177/17534666221140972] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/09/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial pulmonary disease with an extremely poor prognosis. Autophagy is a fundamental intracellular process involved in maintaining cellular homeostasis and regulating cell survival. Autophagy deficiency has been shown to play an important role in the progression of pulmonary fibrosis. This review focused on the six steps of autophagy, as well as the interplay between autophagy and other seven pulmonary fibrosis related mechanisms, which include extracellular matrix deposition, myofibroblast differentiation, epithelial-mesenchymal transition, pulmonary epithelial cell dysfunction, apoptosis, TGF-β1 pathway, and the renin-angiotensin system. In addition, this review also summarized autophagy-related signaling pathways such as mTOR, MAPK, JAK2/STAT3 signaling, p65, and Keap1/Nrf2 signaling during the development of IPF. Furthermore, this review also illustrated the commonly used autophagy detection methods, the currently approved antifibrotic drugs pirfenidone and nintedanib, and several prospective compounds targeting autophagy for the treatment of IPF.
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Affiliation(s)
- Yue-Liang Yue
- Shandong Key Laboratory of Infectious Respiratory Diseases, Laboratory of Basic Medical Sciences, Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Meng-Yu Zhang
- Shandong Key Laboratory of Infectious Respiratory Diseases, Laboratory of Basic Medical Sciences, Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jian-Yu Liu
- Shandong Key Laboratory of Infectious Respiratory Diseases, Laboratory of Basic Medical Sciences, Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Li-Jun Fang
- Shandong Key Laboratory of Infectious Respiratory Diseases, Laboratory of Basic Medical Sciences, Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
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25
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Li J, Zhai X, Sun X, Cao S, Yuan Q, Wang J. Metabolic reprogramming of pulmonary fibrosis. Front Pharmacol 2022; 13:1031890. [PMID: 36452229 PMCID: PMC9702072 DOI: 10.3389/fphar.2022.1031890] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/30/2022] [Accepted: 11/01/2022] [Indexed: 08/13/2023] Open
Abstract
Pulmonary fibrosis is a progressive and intractable lung disease with fibrotic features that affects alveoli elasticity, which leading to higher rates of hospitalization and mortality worldwide. Pulmonary fibrosis is initiated by repetitive localized micro-damages of the alveolar epithelium, which subsequently triggers aberrant epithelial-fibroblast communication and myofibroblasts production in the extracellular matrix, resulting in massive extracellular matrix accumulation and interstitial remodeling. The major cell types responsible for pulmonary fibrosis are myofibroblasts, alveolar epithelial cells, macrophages, and endothelial cells. Recent studies have demonstrated that metabolic reprogramming or dysregulation of these cells exerts their profibrotic role via affecting pathological mechanisms such as autophagy, apoptosis, aging, and inflammatory responses, which ultimately contributes to the development of pulmonary fibrosis. This review summarizes recent findings on metabolic reprogramming that occur in the aforementioned cells during pulmonary fibrosis, especially those associated with glucose, lipid, and amino acid metabolism, with the aim of identifying novel treatment targets for pulmonary fibrosis.
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Affiliation(s)
- Jiaxin Li
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoxuan Zhai
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao Sun
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Shengchuan Cao
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Qiuhuan Yuan
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jiali Wang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
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26
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Gu Z, Yan Y, Yao H, Lin K, Li X. Targeting the LPA1 signalling pathway for fibrosis therapy: a patent review (2010-present). Expert Opin Ther Pat 2022; 32:1097-1122. [PMID: 36175357 DOI: 10.1080/13543776.2022.2130753] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Fibrosis is a disease that damages organs and even causes death. Because of the complicated pathogenesis, the development of drugs for fibrosis is challenging. In the lysophosphatidic acid receptor type 1 (LPA1) signalling pathway, LPA1 and its downstream Rho-associated coiled-coil forming protein kinase (ROCK) are related to the process of fibrosis. Targeting LPA1 signalling pathway is a potential strategy for the treatment of fibrosis. AREA COVERED This review describes the process of fibrosis mediated by the LPA1 signalling pathway and then summarizes LPA1 antagonist patents reported since 2010 and ROCK inhibitor patents since 2017 according to their scaffolds based on the Cortellis Drug Discovery Intelligence database. Information on LPA1 antagonists entering clinical trials is integrated. EXPERT OPINION Over the past decade, a large number of antagonists targeting the LPA1 signalling pathway have been patented for fibrosis therapy. A limited number of compounds have entered clinical trials. Different companies and research groups have used different scaffolds when designing compounds for fibrosis therapy. Therefore, LPA1 and ROCK are competitive targets for the development of new therapies for fibrosis to provide a potential treatment method for fibrosis in the future.
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Affiliation(s)
- Zhihao Gu
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yong Yan
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Hequan Yao
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Kejiang Lin
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xuanyi Li
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
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27
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Seeliger B, Carleo A, Wendel-Garcia PD, Fuge J, Montes-Warboys A, Schuchardt S, Molina-Molina M, Prasse A. Changes in serum metabolomics in idiopathic pulmonary fibrosis and effect of approved antifibrotic medication. Front Pharmacol 2022; 13:837680. [PMID: 36059968 PMCID: PMC9428132 DOI: 10.3389/fphar.2022.837680] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/16/2021] [Accepted: 07/21/2022] [Indexed: 11/22/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality and morbidity. Approval of antifibrotic therapy has ameliorated disease progression, but therapy response is heterogeneous and to date, adequate biomarkers predicting therapy response are lacking. In recent years metabolomic technology has improved and is broadly applied in cancer research thus enabling its use in other fields. Recently both aberrant metabolic and lipidomic pathways have been described to influence profibrotic responses. We thus aimed to characterize the metabolomic and lipidomic changes between IPF and healthy volunteers (HV) and analyze metabolomic changes following treatment with nintedanib and pirfenidone. We collected serial serum samples from two IPF cohorts from Germany (n = 122) and Spain (n = 21) and additionally age-matched healthy volunteers (n = 16). Metabolomic analysis of 630 metabolites covering 14 small molecule and 12 different lipid classes was carried out using flow injection analysis tandem mass spectrometry for lipids and liquid chromatography tandem mass spectrometry for small molecules. Levels were correlated with survival and disease severity. We identified 109 deregulated analytes in IPF compared to HV in cohort 1 and 112 deregulated analytes in cohort 2. Metabolites which were up-regulated in both cohorts were mainly triglycerides while the main class of down-regulated metabolites were phosphatidylcholines. Only a minority of de-regulated analytes were small molecules. Triglyceride subclasses were inversely correlated with baseline disease severity (GAP-score) and a clinical compound endpoint of lung function decline or death. No changes in the metabolic profiles were observed following treatment with pirfenidone. Nintedanib treatment induced up-regulation of triglycerides and phosphatidylcholines. Patients in whom an increase in these metabolites was observed showed a trend towards better survival using the 2-years composite endpoint (HR 2.46, p = 0.06). In conclusion, we report major changes in metabolites in two independent cohorts testing a large number of patients. Specific lipidic metabolite signatures may serve as biomarkers for disease progression or favorable treatment response to nintedanib.
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Affiliation(s)
- Benjamin Seeliger
- Department of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Alfonso Carleo
- Department of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | | | - Jan Fuge
- Department of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Ana Montes-Warboys
- ILD Multidisciplinary Unit, Hospital Universitari Bellvitge, IDIBELL, Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain
| | - Sven Schuchardt
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Maria Molina-Molina
- ILD Multidisciplinary Unit, Hospital Universitari Bellvitge, IDIBELL, Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain
- Centro Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
| | - Antje Prasse
- Department of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
- *Correspondence: Antje Prasse,
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28
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Sesamol protects against liver fibrosis induced in rats by modulating lysophosphatidic acid receptor expression and TGF-β/Smad3 signaling pathway. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:1003-1016. [PMID: 35648193 PMCID: PMC9276582 DOI: 10.1007/s00210-022-02259-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/26/2022] [Accepted: 05/20/2022] [Indexed: 11/18/2022]
Abstract
The present study aimed to investigate the hepatoprotective effect of sesamol (SML), a nutritional phenolic compound obtained from sesame seeds, in liver fibrosis induced by thioacetamide (TAA) in rats and to explore the underlying mechanisms. Thirty-two male Sprague–Dawley rats were equally divided into four groups: control, TAA, TAA + SML 50 mg/kg, and TAA + SML 100 mg/kg groups. Liver functions and hepatic contents of glutathione (GSH) and malondialdehyde (MDA) were measured colorimetrically. Gene expressions of lysophosphatidic acid receptor (LPAR)-1 and -3, connective tissue growth factor (CTGF), transforming growth factor (TGF)-β1, small mothers against decapentaplegic (Smad)-3 and -7, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK19) were analyzed by qRT-PCR. Moreover, phosphorylated Smad3 (pSmad3) was quantified by ELISA. Additionally, TGF-β1, α-SMA, CK19, and vascular endothelial growth factor (VEGF) protein concentrations were semi-quantitatively analyzed by immunostaining of liver sections. SML treatment markedly improved liver index and liver functions. Moreover, SML protected against liver fibrosis in a dose-dependent manner as indicated by down-regulation of LPAR1, LPAR3, CTGF, TGF-β1/Smad3, and α-SMA expressions and a decrease in pSmad3 level, as well as an up-regulation of Smad7 expression. In addition, SML suppressed ductular reaction hinted by the decrease in CK19 expression. These results reveal the anti-fibrotic effect of SML against liver fibrosis that might be attributed to down-regulation of LPAR1/3 expressions, inhibition of TGF-β1/Smad3 pathway, and ductular reaction.
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29
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Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge. Int J Mol Sci 2022; 23:ijms23116064. [PMID: 35682743 PMCID: PMC9181498 DOI: 10.3390/ijms23116064] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/07/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 12/23/2022] Open
Abstract
CTGF is upregulated in patients with idiopathic pulmonary fibrosis (IPF), characterized by the deposition of a pathological extracellular matrix (ECM). Additionally, many omics studies confirmed that aberrant cellular senescence-associated mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, alveolar endothelial cells, fibroblasts, and macrophages). Here, we reviewed the role of the CTGF in IPF lung cells to mediate anomalous senescence-related metabolic mechanisms that support the fibrotic environment in IPF.
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30
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Korfei M, Mahavadi P, Guenther A. Targeting Histone Deacetylases in Idiopathic Pulmonary Fibrosis: A Future Therapeutic Option. Cells 2022; 11:1626. [PMID: 35626663 PMCID: PMC9139813 DOI: 10.3390/cells11101626] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/17/2022] [Revised: 05/03/2022] [Accepted: 05/09/2022] [Indexed: 02/07/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options, and there is a huge unmet need for new therapies. A growing body of evidence suggests that the histone deacetylase (HDAC) family of transcriptional corepressors has emerged as crucial mediators of IPF pathogenesis. HDACs deacetylate histones and result in chromatin condensation and epigenetic repression of gene transcription. HDACs also catalyse the deacetylation of many non-histone proteins, including transcription factors, thus also leading to changes in the transcriptome and cellular signalling. Increased HDAC expression is associated with cell proliferation, cell growth and anti-apoptosis and is, thus, a salient feature of many cancers. In IPF, induction and abnormal upregulation of Class I and Class II HDAC enzymes in myofibroblast foci, as well as aberrant bronchiolar epithelium, is an eminent observation, whereas type-II alveolar epithelial cells (AECII) of IPF lungs indicate a significant depletion of many HDACs. We thus suggest that the significant imbalance of HDAC activity in IPF lungs, with a "cancer-like" increase in fibroblastic and bronchial cells versus a lack in AECII, promotes and perpetuates fibrosis. This review focuses on the mechanisms by which Class I and Class II HDACs mediate fibrogenesis and on the mechanisms by which various HDAC inhibitors reverse the deregulated epigenetic responses in IPF, supporting HDAC inhibition as promising IPF therapy.
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Affiliation(s)
- Martina Korfei
- Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, D-35392 Giessen, Germany; (P.M.); (A.G.)
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), D-35392 Giessen, Germany
| | - Poornima Mahavadi
- Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, D-35392 Giessen, Germany; (P.M.); (A.G.)
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), D-35392 Giessen, Germany
| | - Andreas Guenther
- Biomedical Research Center Seltersberg (BFS), Justus Liebig University Giessen, D-35392 Giessen, Germany; (P.M.); (A.G.)
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), D-35392 Giessen, Germany
- Lung Clinic, Evangelisches Krankenhaus Mittelhessen, D-35398 Giessen, Germany
- European IPF Registry and Biobank, D-35392 Giessen, Germany
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31
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Molecular pathways and role of epigenetics in the idiopathic pulmonary fibrosis. Life Sci 2022; 291:120283. [PMID: 34998839 DOI: 10.1016/j.lfs.2021.120283] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/22/2021] [Revised: 12/19/2021] [Accepted: 12/27/2021] [Indexed: 12/12/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with unknown etiological factors that can progress to other dangerous diseases like lung cancer. Environmental and genetic predisposition are the two major etiological or risk factors involved in the pathology of the IPF. Among the environmental risk factors, smoking is one of the major causes for the development of IPF. Epigenetic pathways like nucleosomes remodeling, DNA methylation, histone modifications and miRNA mediated genes play a crucial role in development of IPF. Mutations in the genes make the epigenetic factors as important drug targets in IPF. Transcriptional changes due to environmental factors are also involved in the progression of IPF. The mutations in human telomerase reverse transcriptase (hTERT) have shown decreased life expectancy in IPF patients. The TERT-gene is highly expressed in chronic smokers and makes the role of epigenetics evident. Drug like nintedanib acts through vascular endothelial growth factor receptors (VEGFR), while drug pirfenidone acts through transforming growth factor (TGF), which is useful in IPF. Gefitinib, a tyrosine kinase inhibitor of EGFR, is useful as an anti-fibrosis agent in preclinical models. Newer drugs such as Celgene-CC90001 and FibroGen-FG-3019 are currently under investigations acts through the modulating epigenetic mechanisms. Thus, the study on epigenetics opens a wide window for the discovery of newer drugs. This study provides an elementary analysis of multiple regulators of epigenetics and their roles associated with the pathology of IPF. Further, this review also includes epigenetic drugs under development in preclinical and clinical stages.
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32
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Tanaka T, Koyama K, Takahashi N, Morito K, Ali H, Azuma M, Kagawa K, Kawano H, Has RY, Aihara M, Nishioka Y. Lysophosphatidic acid, ceramide 1-phosphate and sphingosine 1-phosphate in peripheral blood of patients with idiopathic pulmonary fibrosis. THE JOURNAL OF MEDICAL INVESTIGATION 2022; 69:196-203. [PMID: 36244770 DOI: 10.2152/jmi.69.196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 06/16/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonias. Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are signaling lipids that evoke growth factor-like responses to many cells. Recent studies revealed the involvement of LPA and S1P in the pathology of IPF. In this study, we determined LPA, S1P and ceramide 1-phosphate (C1P) in peripheral blood plasma of IPF patients, and examined correlation to the vital capacity of lung (VC), an indicator of development of fibrosis. Blood plasma samples were taken from eleven patients with IPF and seven healthy volunteers. The lipids of the sample were extracted and subjected to liquid chromatography-tandem mass spectrometry for analysis. Results showed that there is a significant negative correlation between VC and plasma LPA levels, indicating that IPF patients with advanced fibrosis had higher concentration of LPA in their plasma. Average of S1P levels were significantly higher in IPF patients than those in healthy subjects. Although it is not statistically significant, a similar correlation trend that observed in LPA levels also found between VC and S1P levels. These results indicated that plasma LPA and S1P may be associated with deterioration of pulmonary function of IPF patients. J. Med. Invest. 69 : 196-203, August, 2022.
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Affiliation(s)
- Tamotsu Tanaka
- Division of Bioscience and Bioindustry, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan
| | - Kazuya Koyama
- Department of Respiratory Medicine and Rheumatology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Naoko Takahashi
- Department of Pharmaceutical Health Chemistry, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Katsuya Morito
- Department of Pharmaceutical Health Chemistry, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hanif Ali
- Department of Medical Pharmacology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Momoyo Azuma
- Department of Infection Control and Prevention, Tokushima University Hospital, Tokushima, Japan
| | - Kozo Kagawa
- Department of Respiratory Medicine and Rheumatology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hiroshi Kawano
- Department of Respiratory Medicine and Rheumatology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Rumana Yesmin Has
- Division of Bioscience and Bioindustry, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan
| | - Mutsumi Aihara
- Division of Bioscience and Bioindustry, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan
| | - Yasuhiko Nishioka
- Department of Respiratory Medicine and Rheumatology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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33
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Corte TJ, Lancaster L, Swigris JJ, Maher TM, Goldin JG, Palmer SM, Suda T, Ogura T, Minnich A, Zhan X, Tirucherai GS, Elpers B, Xiao H, Watanabe H, Smith RA, Charles ED, Fischer A. Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA 1) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD). BMJ Open Respir Res 2022; 8:8/1/e001026. [PMID: 34969771 PMCID: PMC8718498 DOI: 10.1136/bmjresp-2021-001026] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/21/2021] [Accepted: 12/12/2021] [Indexed: 01/02/2023] Open
Abstract
Introduction Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1–6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD. Methods and analysis This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort. Ethics and dissemination This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. Trial registration number NCT04308681.
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Affiliation(s)
- Tamera J Corte
- Department of Respiratory Medicine, Royal Prince Alfred Hospital and Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Lisa Lancaster
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jeffrey J Swigris
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado, USA
| | - Toby M Maher
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Southern California, Los Angeles, California, USA
| | - Jonathan G Goldin
- Department of Radiological Sciences, University of California Los Angeles, Los Angeles, California, USA.,MedQIA, LLC, Los Angeles, California, USA
| | - Scott M Palmer
- Department of Medicine, Duke Clinical Research Institute, Durham, North Carolina, USA
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takashi Ogura
- Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan
| | - Anne Minnich
- Bristol Myers Squibb, Princeton, New Jersey, USA
| | | | | | | | - Hong Xiao
- Bristol Myers Squibb, Princeton, New Jersey, USA
| | | | - R Adam Smith
- Bristol Myers Squibb, Princeton, New Jersey, USA
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34
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Structure dependence and species sensitivity of in vivo hepatobiliary toxicity with lysophosphatidic acid receptor 1 (LPA 1) antagonists. Toxicol Appl Pharmacol 2021; 438:115846. [PMID: 34974053 DOI: 10.1016/j.taap.2021.115846] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/27/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 01/25/2023]
Abstract
BMS-986020, BMS-986234 and BMS-986278, are three lysophosphatidic acid receptor 1 (LPA1) antagonists that were or are being investigated for treatment of idiopathic pulmonary fibrosis (IPF). Hepatobiliary toxicity (elevated serum AST, ALT, and ALP, plasma bile acids [BAs], and cholecystitis) was observed in a Phase 2 clinical trial with BMS-986020, and development was discontinued. In dogs and rats, the species used for the pivotal toxicology studies, there was no evidence of hepatobiliary toxicity in the dog while findings in the rat were limited to increased plasma BAs levels (6.1× control), ALT (2.9×) and bilirubin (3.4×) with no histopathologic correlates. Since neither rats nor dogs predicted clinical toxicity, follow-up studies in cynomolgus monkeys revealed hepatobiliary toxicity that included increased ALT (2.0× control) and GLDH (4.9×), bile duct hyperplasia, cholangitis, cholestasis, and cholecystitis at clinically relevant BMS-986020 exposures with no changes in plasma or liver BAs. This confirmed monkey as a relevant species for identifying hepatobiliary toxicity with BMS-986020. In order to assess whether the toxicity was compound-specific or related to LPA1 antagonism, two structurally distinct LPA1 antagonists (BMS-986234 and BMS-986278), were evaluated in rat and monkey. There were no clinical or anatomic pathology changes indicative of hepatobiliary toxicity. Mixed effects on plasma bile acids in both rat and monkey has made this biomarker not a useful predictor of the hepatobiliary toxicity. In conclusion, the nonclinical data indicate the hepatobiliary toxicity observed clinically and in monkeys administered BMS-986020 is compound specific and not mediated via antagonism of LPA1.
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35
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Chang H, Meng HY, Bai WF, Meng QG. A metabolomic approach to elucidate the inhibitory effects of baicalin in pulmonary fibrosis. PHARMACEUTICAL BIOLOGY 2021; 59:1016-1025. [PMID: 34362286 PMCID: PMC8354164 DOI: 10.1080/13880209.2021.1950192] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 05/10/2023]
Abstract
CONTEXT Baicalin, a major flavonoid extracted from Scutellaria baicalensis Georgi (Lamiaceae), has been shown to exert therapeutic effects on pulmonary fibrosis (PF). OBJECTIVE To use serum metabolomics combined with biochemical and histopathological analyses to clarify anti-PF mechanisms of baicalin on metabolic pathways and the levels of potential biomarkers. MATERIALS AND METHODS Forty male Sprague-Dawley rats were randomly divided into the control, PF model, prednisolone acetate-treated (4.2 mg/kg/day) and baicalin-treated (25 and 100 mg/kg/day) groups. A rat model of PF was established using a tracheal injection of bleomycin, and the respective drugs were administered intragastrically for 4 weeks. Histomorphology of lung tissue was examined after H&E and Masson's trichrome staining. Biochemical indicators including SOD, MDA and HYP were measured. Serum-metabonomic analysis based on UPLC-Q-TOF/MS was used to clarify the changes in potential biomarkers among different groups of PF rats. RESULTS Both doses of baicalin effectively alleviated bleomycin-induced pathological changes, and increased the levels of SOD (from 69.48 to 99.50 and 112.30, respectively), reduced the levels of MDA (from 10.91 to 5.0 and 7.53, respectively) and HYP (from 0.63 to 0.41 and 0.49, respectively). Forty-eight potential biomarkers associated with PF were identified. Meanwhile, the metabolic profiles and fluctuating metabolite levels were normalized or partially reversed after baicalin treatment. Furthermore, baicalin was found to improve PF potentially by the regulation of four key biomarkers involving taurine and hypotaurine metabolism, glutathione metabolism, and glycerophospholipid metabolism. CONCLUSIONS These findings revealed the anti-fibrotic mechanisms of baicalin and it may be considered as an effective therapy for PF.
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Affiliation(s)
- Hong Chang
- Department of Pharmacy, Baotou Medical College, Baotou, China
| | - Hong-yu Meng
- Nephroendocrine Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Wan-fu Bai
- Department of Pharmacy, Baotou Medical College, Baotou, China
| | - Qing-gang Meng
- Department of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- CONTACT Qing-gang Meng Department of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11, North third Ring Road East, Chaoyang District, Beijing100700, China
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36
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Kapszewicz M, Małecka-Wojciesko E. Simple Serum Pancreatic Ductal Adenocarcinoma (PDAC) Protein Biomarkers-Is There Anything in Sight? J Clin Med 2021; 10:jcm10225463. [PMID: 34830745 PMCID: PMC8619303 DOI: 10.3390/jcm10225463] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/14/2021] [Revised: 11/07/2021] [Accepted: 11/20/2021] [Indexed: 01/04/2023] Open
Abstract
A poor PDAC prognosis is due to a lack of effective treatment and late diagnosis. The early detection of PDAC could significantly decrease mortality and save lives. Idealbiomarkers for PDAC should be cost-effective, detectable in easily accessible biological material, and present in sufficient concentration in the earliest possible phase of the disease. This review addresses newly selected, simple protein biomarkers—new ones such as thrombospondin-2, insulin-linked binding protein 2, lysophosphatidic acid, and autotaxin and conventional ones such as Ca19-9, inflammatory factors, and coagulation factors. Their possible use in the early detection of PDAC, differentiation from benign diseases, prognosis, and treatment response prediction is discussed. We also address the usefulness of possible combinations of biomarkers in diagnostic panels.
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37
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Cheng PTW, Kaltenbach RF, Zhang H, Shi J, Tao S, Li J, Kennedy LJ, Walker SJ, Shi Y, Wang Y, Dhanusu S, Reddigunta R, Kumaravel S, Jusuf S, Smith D, Krishnananthan S, Li J, Wang T, Heiry R, Sum CS, Kalinowski SS, Hung CP, Chu CH, Azzara AV, Ziegler M, Burns L, Zinker BA, Boehm S, Taylor J, Sapuppo J, Mosure K, Everlof G, Guarino V, Zhang L, Yang Y, Ruan Q, Xu C, Apedo A, Traeger SC, Cvijic ME, Lentz KA, Tirucherai G, Sivaraman L, Robl J, Ellsworth BA, Rosen G, Gordon DA, Soars MG, Gill M, Murphy BJ. Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA 1) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases. J Med Chem 2021; 64:15549-15581. [PMID: 34709814 DOI: 10.1021/acs.jmedchem.1c01256] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/29/2022]
Abstract
The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).
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Affiliation(s)
- Peter T W Cheng
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Robert F Kaltenbach
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Hao Zhang
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Jun Shi
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Shiwei Tao
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Jun Li
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Lawrence J Kennedy
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Steven J Walker
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Yan Shi
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Ying Wang
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Suresh Dhanusu
- Biocon-Bristol Myers Squibb Research & Development Center, Bangalore 560099, India
| | - Ramesh Reddigunta
- Biocon-Bristol Myers Squibb Research & Development Center, Bangalore 560099, India
| | - Selvakumar Kumaravel
- Biocon-Bristol Myers Squibb Research & Development Center, Bangalore 560099, India
| | - Sutjano Jusuf
- Computer Aided Drug Design, Molecular Structure & Design, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Daniel Smith
- Discovery Chemistry Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Subramaniam Krishnananthan
- Discovery Chemistry Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Jianqing Li
- Discovery Chemistry Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Cambridge, Massachusetts 02140, United States
| | - Tao Wang
- Lead Evaluation, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Rebekah Heiry
- Lead Evaluation, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Chi Shing Sum
- Lead Evaluation, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Stephen S Kalinowski
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Chen-Pin Hung
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Ching-Hsuen Chu
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Anthony V Azzara
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Milinda Ziegler
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Lisa Burns
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Bradley A Zinker
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Stephanie Boehm
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Joseph Taylor
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Julia Sapuppo
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Kathy Mosure
- Metabolism & Pharmacokinetics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Cambridge, Massachusetts 02140, United States
| | - Gerry Everlof
- Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Victor Guarino
- Metabolism & Pharmacokinetics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Lisa Zhang
- Metabolism & Pharmacokinetics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Yanou Yang
- Biotransformation, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Qian Ruan
- Biotransformation, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Carrie Xu
- Bioanalytical Chemistry, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Atsu Apedo
- Discovery Analytical Sciences, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Sarah C Traeger
- Discovery Analytical Sciences, Small Molecule Drug Discovery, Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Mary Ellen Cvijic
- Lead Evaluation, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Kimberley A Lentz
- Metabolism & Pharmacokinetics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Giridhar Tirucherai
- Clinical Pharmacology, Immunology, Cardiovascular and Fibrosis, Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-5326, United States
| | - Lakshmi Sivaraman
- Nonclinical Safety Evaluation, Research & Development, Bristol Myers Squibb Company, New Brunswick, New Jersey 08903-0191, United States
| | - Jeffrey Robl
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Bruce A Ellsworth
- Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Glenn Rosen
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - David A Gordon
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Matthew G Soars
- Metabolism & Pharmacokinetics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Cambridge, Massachusetts 02140, United States
| | - Michael Gill
- Discovery Toxicology, Preclinical Candidate Optimization, Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Brian J Murphy
- Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
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38
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Ntatsoulis K, Karampitsakos T, Tsitoura E, Stylianaki EA, Matralis AN, Tzouvelekis A, Antoniou K, Aidinis V. Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target. Front Immunol 2021; 12:687397. [PMID: 34671341 PMCID: PMC8522582 DOI: 10.3389/fimmu.2021.687397] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/29/2021] [Accepted: 08/13/2021] [Indexed: 12/15/2022] Open
Abstract
Severe COVID-19 is characterized by acute respiratory distress syndrome (ARDS)-like hyperinflammation and endothelial dysfunction, that can lead to respiratory and multi organ failure and death. Interstitial lung diseases (ILD) and pulmonary fibrosis confer an increased risk for severe disease, while a subset of COVID-19-related ARDS surviving patients will develop a fibroproliferative response that can persist post hospitalization. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling lysophospholipid with multiple effects in pulmonary and immune cells. In this review, we discuss the similarities of COVID-19, ARDS and ILDs, and suggest ATX as a possible pathologic link and a potential common therapeutic target.
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Affiliation(s)
- Konstantinos Ntatsoulis
- Institute of Bio-Innovation, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Theodoros Karampitsakos
- Department of Respiratory Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Eliza Tsitoura
- Laboratory of Molecular & Cellular Pneumonology, Department of Respiratory Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Elli-Anna Stylianaki
- Institute of Bio-Innovation, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Alexios N. Matralis
- Institute of Bio-Innovation, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Argyrios Tzouvelekis
- Department of Respiratory Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Katerina Antoniou
- Laboratory of Molecular & Cellular Pneumonology, Department of Respiratory Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Vassilis Aidinis
- Institute of Bio-Innovation, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
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Metzler-Zebeli BU. The Role of Dietary and Microbial Fatty Acids in the Control of Inflammation in Neonatal Piglets. Animals (Basel) 2021; 11:ani11102781. [PMID: 34679802 PMCID: PMC8532928 DOI: 10.3390/ani11102781] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/02/2021] [Revised: 09/20/2021] [Accepted: 09/20/2021] [Indexed: 11/22/2022] Open
Abstract
Simple Summary The maturation of the gut is a specific and very dynamic process in new-born piglets. Consequently, piglet’s gut is very susceptible to disturbances, especially in stressful periods of life, such as weaning, when the gut lining often becomes inflamed and leaky. Dietary fatty acids (FA) do not only serve as source of energy and essential FA, but they are important precursors for bioactive lipid mediators, which modulate inflammatory signalling in the body. The current review summarizes results on dietary sources of FA for piglets, the signalling cascades, bioactivities, the necessity to consider the autoxidation potential of polyunsaturated FA and the area of microbially produced long-chain FA. That said, porcine milk is high in fat, whereby the milk FA composition partly depends on the dietary FA composition of the sow. Therefore, manipulation of the sow diet is an efficient tool to increase the piglet’s intake of specific FA, e.g., n-3 polyunsaturated FA which show anti-inflammatory activity and may support intestinal integrity and functioning in the growing animal. Abstract Excessive inflammation and a reduced gut mucosal barrier are major causes for gut dysfunction in piglets. The fatty acid (FA) composition of the membrane lipids is crucial for mediating inflammatory signalling and is largely determined by their dietary intake. Porcine colostrum and milk are the major sources of fat in neonatal piglets. Both are rich in fat, demonstrating the dependence of the young metabolism from fat and providing the young organism with the optimum profile of lipids for growth and development. The manipulation of sow’s dietary polyunsaturated FA (PUFA) intake has been shown to be an efficient strategy to increase the transfer of specific FAs to the piglet for incorporation in enteric tissues and cell membranes. n-3 PUFAs, especially seems to be beneficial for the immune response and gut epithelial barrier function, supporting the piglet’s enteric defences in situations of increased stress such as weaning. Little is known about microbial lipid mediators and their role in gut barrier function and inhibition of inflammation in neonatal piglets. The present review summarizes the current knowledge of lipid nutrition in new-born piglets, comparing the FA ingestion from milk and plant-based lipid sources and touching the areas of host lipid signalling, inflammatory signalling and microbially derived FAs.
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Affiliation(s)
- Barbara U Metzler-Zebeli
- Unit Nutritional Physiology, Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Veterinaerplatz 1, 1210 Vienna, Austria
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Li Q, Wong W, Birnberg A, Chakrabarti A, Yang X, Choy DF, Olsson J, Verschueren E, Neighbors M, Sandoval W, Rosenberger CM, Grimbaldeston MA, Tew GW. Lysophosphatidic acid species are associated with exacerbation in chronic obstructive pulmonary disease. BMC Pulm Med 2021; 21:301. [PMID: 34556083 PMCID: PMC8461999 DOI: 10.1186/s12890-021-01670-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/18/2021] [Accepted: 09/16/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) exacerbations are heterogenous and profoundly impact the disease trajectory. Bioactive lipid lysophosphatidic acid (LPA) has been implicated in airway inflammation but the significance of LPA in COPD exacerbation is not known. The aim of the study was to investigate the utility of serum LPA species (LPA16:0, 18:0, 18:1, 18:2, 20:4) as biomarkers of COPD exacerbation. PATIENTS AND METHODS LPA species were measured in the baseline placebo sera of a COPD randomized controlled trial. Tertile levels of each LPA were used to assign patients into biomarker high, medium, and low subgroups. Exacerbation rate and risk were compared among the LPA subgroups. RESULTS The levels of LPA species were intercorrelated (rho 0.29-0.91). Patients with low and medium levels of LPA (LPA16:0, 20:4) had significantly higher exacerbation rate compared to the respective LPA-high patients [estimated rate per patient per year (95% CI)]: LPA16:0-low = 1.2 (0.8-1.9) (p = 0.019), LPA16:0-medium = 1.3 (0.8-2.0) (p = 0.013), LPA16:0-high = 0.5 (0.2-0.9); LPA20:4-low = 1.4 (0.9-2.1) (p = 0.0033), LPA20:4-medium = 1.2 (0.8-1.8) (p = 0.0089), LPA20:4-high = 0.4 (0.2-0.8). These patients also had earlier time to first exacerbation (hazard ratio (95% CI): LPA16:0-low = 2.6 (1.1-6.0) (p = 0.028), LPA16:0-medium = 2.7 (1.2-6.3) (p = 0.020); LPA20.4-low = 2.8 (1.2-6.6) (p = 0.017), LPA20:4-medium = 2.7 (1.2-6.4) (p = 0.021). Accordingly, these patients had a significant increased exacerbation risk compared to the respective LPA-high subgroups [odd ratio (95% CI)]: LPA16:0-low = 3.1 (1.1-8.8) (p = 0.030), LPA16:0-medium = 3.0 (1.1-8.3) (p = 0.031); LPA20:4-low = 3.8 (1.3-10.9) (p = 0.012), LPA20:4-medium = 3.3 (1.2-9.5) (p = 0.025). For the other LPA species (LPA18:0, 18:1, 18:2), the results were mixed; patients with low and medium levels of LPA18:0 and 18:2 had increased exacerbation rate, but only LPA18:0-low patients had significant increase in exacerbation risk and earlier time to first exacerbation compared to the LPA18:0-high subgroup. CONCLUSIONS The study provided evidence of association between systemic LPA levels and exacerbation in COPD. Patients with low and medium levels of specific LPA species (LPA16:0, 20:4) had increased exacerbation rate, risk, and earlier time to first exacerbation. These non-invasive biomarkers may aid in identifying high risk patients with dysregulated LPA pathway to inform risk management and drug development.
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Affiliation(s)
- Qingling Li
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Weng Wong
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Andrew Birnberg
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Arindam Chakrabarti
- Department of Biomarker Discovery OMNI, Genentech, Inc., South San Francisco, CA, USA
| | - Xiaoying Yang
- Department of Biostatistics, Genentech, Inc., South San Francisco, CA, USA
| | - David F Choy
- Department of Biomarker Discovery OMNI, Genentech, Inc., South San Francisco, CA, USA
| | - Julie Olsson
- Product Development Immunology, Infectious Disease and Ophthalmology, Genentech, Inc., South San Francisco, CA, USA
| | - Erik Verschueren
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Margaret Neighbors
- OMNI Biomarker Development, Genentech Inc., South San Francisco, CA, USA
| | - Wendy Sandoval
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Carrie M Rosenberger
- Department of Biomarker Discovery OMNI, Genentech, Inc., South San Francisco, CA, USA
| | | | - Gaik W Tew
- Product Development Immunology, Infectious Disease and Ophthalmology, Genentech, Inc., South San Francisco, CA, USA.
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O'Regan A, O'Brien CJ, Eivers SB. The lysophosphatidic acid axis in fibrosis: Implications for glaucoma. Wound Repair Regen 2021; 29:613-626. [PMID: 34009724 DOI: 10.1111/wrr.12929] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/28/2021] [Revised: 04/13/2021] [Accepted: 04/28/2021] [Indexed: 12/27/2022]
Abstract
Glaucoma is a common progressive optic neuropathy that results in visual field defects and can lead to irreversible blindness. The pathophysiology of glaucoma involves dysregulated extracellular matrix remodelling in both the trabecular meshwork in the anterior chamber and in the lamina cribrosa of the optic nerve head. Fibrosis in these regions leads to raised intraocular pressure and retinal ganglion cell degeneration, respectively. Lysophosphatidic acid (LPA) is a bioactive lipid mediator which acts via six G-protein coupled receptors on the cell surface to activate intracellular pathways that promote cell proliferation, transcription and survival. LPA signalling has been implicated in both normal wound healing and pathological fibrosis. LPA enhances fibroblast proliferation, migration and contraction, and induces expression of pro-fibrotic mediators such as connective tissue growth factor. The LPA axis plays a major role in diseases such as idiopathic pulmonary fibrosis, where it has been identified as an important pharmacological target. In glaucoma, LPA is present in high levels in the aqueous humour, and its signalling has been found to increase resistance to aqueous humour outflow through altered trabecular meshwork cellular contraction and extracellular matrix deposition. LPA signalling may, therefore, also represent an attractive target for treatment of glaucoma. In this review we wish to describe the role of LPA and its related proteins in tissue fibrosis and glaucoma.
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Affiliation(s)
- Amy O'Regan
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Colm J O'Brien
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, Dublin, Ireland.,Department of Ophthalmology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Sarah B Eivers
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, Dublin, Ireland
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Roque W, Romero F. Cellular metabolomics of pulmonary fibrosis, from amino acids to lipids. Am J Physiol Cell Physiol 2021; 320:C689-C695. [PMID: 33471621 PMCID: PMC8163573 DOI: 10.1152/ajpcell.00586.2020] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/08/2020] [Revised: 01/11/2021] [Accepted: 01/13/2021] [Indexed: 12/25/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease of unknown etiology with limited treatment options. It is characterized by repetitive injury to alveolar epithelial cells and aberrant activation of numerous signaling pathways. Recent evidence suggests that metabolic reprogramming, metabolic dysregulation, and mitochondria dysfunction are distinctive features of the IPF lungs. Through numerous mechanisms, metabolomic abnormalities in alveolar epithelial cells, myofibroblast, macrophages, and fibroblasts contribute to the abnormal collagen synthesis and dysregulated airway remodeling described in lung fibrosis. This review summarizes the metabolomic changes in amino acids, lipids, glucose, and heme seen in IPF lungs. Simultaneously, we provide new insights into potential therapeutic strategies by targeting a variety of metabolites.
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Affiliation(s)
- Willy Roque
- Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey
| | - Freddy Romero
- Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, Texas
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Nathan S, Zhang H, Andreoli M, Leopold PL, Crystal RG. CREB-dependent LPA-induced signaling initiates a pro-fibrotic feedback loop between small airway basal cells and fibroblasts. Respir Res 2021; 22:97. [PMID: 33794877 PMCID: PMC8015171 DOI: 10.1186/s12931-021-01677-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/24/2020] [Accepted: 03/04/2021] [Indexed: 01/20/2023] Open
Abstract
Background Lysophosphatidic acid (LPA), generated extracellularly by the action of autotaxin and phospholipase A2, functions through LPA receptors (LPARs) or sphingosine-1-phosphate receptors (S1PRs) to induce pro-fibrotic signaling in the lower respiratory tract of patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that LPA induces changes in small airway epithelial (SAE) basal cells (BC) that create cross-talk between the BC and normal human lung fibroblasts (NHLF), enhancing myofibroblast formation. Methods To assess LPA-induced signaling, BC were treated with LPA for 2.5 min and cell lysates were analyzed by phosphokinase array and Western blot. To assess transcriptional changes, BC were treated with LPA for 3 h and harvested for collection and analysis of RNA by quantitative polymerase chain reaction (qPCR). To assess signaling protein production and function, BC were washed thoroughly after LPA treatment and incubated for 24 h before collection for protein analysis by ELISA or functional analysis by transfer of conditioned medium to NHLF cultures. Transcription, protein production, and proliferation of NHLF were assessed. Results LPA treatment induced signaling by cAMP response element-binding protein (CREB), extracellular signal-related kinases 1 and 2 (Erk1/2), and epithelial growth factor receptor (EGFR) resulting in elevated expression of connective tissue growth factor (CTGF), endothelin-1 (EDN1/ET-1 protein), and platelet derived growth factor B (PDGFB) at the mRNA and protein levels. The conditioned medium from LPA-treated BC induced NHLF proliferation and increased NHLF expression of collagen I (COL1A1), smooth muscle actin (ACTA2), and autotaxin (ENPP2) at the mRNA and protein levels. Increased autotaxin secretion from NHLF correlated with increased LPA in the NHLF culture medium. Inhibition of CREB signaling blocked LPA-induced changes in BC transcription and translation as well as the pro-fibrotic effects of the conditioned medium on NHLF. Conclusion Inhibition of CREB signaling may represent a novel target for alleviating the LPA-induced pro-fibrotic feedback loop between SAE BC and NHLF. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-021-01677-0.
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Affiliation(s)
- Shyam Nathan
- Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 164, New York, NY, 10065, USA
| | - Haijun Zhang
- Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 164, New York, NY, 10065, USA
| | - Mirko Andreoli
- Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 164, New York, NY, 10065, USA
| | - Philip L Leopold
- Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 164, New York, NY, 10065, USA
| | - Ronald G Crystal
- Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 164, New York, NY, 10065, USA.
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Turi KN, McKennan C, Gebretsadik T, Snyder B, Seroogy CM, Lemanske RF, Zoratti E, Havstad S, Ober C, Lynch S, McCauley K, Yu C, Jackson DJ, Gern JE, Hartert TV. Unconjugated bilirubin is associated with protection from early-life wheeze and childhood asthma. J Allergy Clin Immunol 2021; 148:128-138. [PMID: 33434532 DOI: 10.1016/j.jaci.2020.12.639] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/27/2020] [Revised: 11/11/2020] [Accepted: 12/02/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Wheeze and allergic sensitization are the strongest early-life predictors of childhood asthma development; the molecular origins of these early-life phenotypes are poorly understood. OBJECTIVES We sought to identify metabolites associated with early-life wheeze, allergic sensitization, and childhood asthma. METHODS We conducted a nested case-control study using Environmental influences on Child Health Outcomes Program cohorts for discovery and independent replication. Wheeze and allergic sensitization were defined by number of wheeze episodes and positive specific IgE at age 1 year, respectively. Asthma was defined as physician diagnosis of asthma at age 5 or 6 years. We used untargeted metabolomics, controlling for observed and latent confounding factors, to assess associations between the plasma metabolome and early-life wheeze, allergy, and childhood asthma. RESULTS Eighteen plasma metabolites were associated with first-year wheeze in the discovery cohort (n = 338). Z,Z unconjugated bilirubin (UCB) and its related metabolites exhibited a dose-response relationship with wheeze frequency; UCB levels were 13% (β = 0.87; 95% CI, 0.74-1.02) and 22% (β = 0.78; 95% CI, 0.68-0.91) lower in children with 1 to 3 and 4+ wheeze episodes compared with those who never wheezed, respectively. UCB levels were also associated with childhood asthma (β = 0.82; 95% CI, 0.68-0.98). Similar trends were observed in 2 independent cohorts. UCB was significantly negatively correlated with eicosanoid- and oxidative stress-related metabolites. There were no significant associations between metabolites and allergic sensitization. CONCLUSIONS We identified a novel inverse, dose-dependent association between UCB and recurrent wheeze and childhood asthma. Inflammatory lipid mediators and oxidative stress byproducts inversely correlated with UCB, suggesting that UCB modulates pathways critical to the development of early-life recurrent wheeze and childhood asthma.
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Affiliation(s)
- Kedir N Turi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn
| | | | - Tebeb Gebretsadik
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tenn
| | - Brittney Snyder
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn
| | | | | | - Edward Zoratti
- Department of Internal Medicine, Henry Ford Hospital, Detroit, Mich
| | - Suzanne Havstad
- Department of Public Health Sciences, Henry Ford Hospital, Detroit, Mich
| | - Carole Ober
- Department of Human Genetics, University of Chicago, Chicago, Ill
| | - Susan Lynch
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, Calif
| | - Kathyrn McCauley
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, Calif
| | - Chang Yu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tenn
| | | | - James E Gern
- Department of Pediatrics, University of Wisconsin, Madison, Wis.
| | - Tina V Hartert
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
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Hirata T, Smith SV, Takahashi T, Miyata N, Roman RJ. Increased Levels of Renal Lysophosphatidic Acid in Rodent Models with Renal Disease. J Pharmacol Exp Ther 2020; 376:240-249. [PMID: 33277348 DOI: 10.1124/jpet.120.000353] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/24/2020] [Accepted: 12/01/2020] [Indexed: 12/29/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that has been implicated in the pathophysiology of kidney disease. However, few studies have attempted to measure changes in the levels of various LPA species in the kidney after the development of renal disease. The present study measured the renal LPA levels during the development of kidney disease in rat models of hypertension, diabetes, and obstructive nephropathy using liquid chromatography/mass spectrometry/mass spectrometry. LPA levels (sum of 16:0, 18:0, 18:1, 18:2, and 20:4 LPA) were higher in the renal cortex of hypertensive Dahl salt-sensitive (Dahl S) rats fed a high-salt diet than those in normotensive rats fed a low-salt diet (296.6 ± 22.9 vs. 196.3 ± 8.5 nmol/g protein). LPA levels were elevated in the outer medulla of the kidney of streptozotocin-induced type 1 diabetic Dahl S rats compared with control rats (624.6 ± 129.5 vs. 318.8 ± 17.1 nmol/g protein). LPA levels were also higher in the renal cortex of 18-month-old, type 2 diabetic nephropathy (T2DN) rats with more severe renal injury than in 6-month-old T2DN rats (184.9 ± 20.9 vs. 116.9 ± 6.0 nmol/g protein). LPA levels also paralleled the progression of renal fibrosis in the renal cortex of Sprague-Dawley rats after unilateral ureteral obstruction (UUO). Administration of an LPA receptor antagonist, Ki16425, reduced the degree of renal fibrosis in UUO rats. These results suggest that the production of renal LPA increases during the development of renal injury and contributes to renal fibrosis. SIGNIFICANCE STATEMENT: The present study reveals that the lysophosphatidic acid (LPA) levels increase in the kidney in rat models of hypertension, diabetes, and obstructive nephropathy, and administration of an LPA receptor antagonist attenuates renal fibrosis. Therapeutic approaches that target the formation or actions of renal LPA might be renoprotective and have therapeutic potential.
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Affiliation(s)
- Takashi Hirata
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Stanley V Smith
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Teisuke Takahashi
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Noriyuki Miyata
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Richard J Roman
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (T.H., S.V.S., R.J.R.); and Pharmacology Laboratories (T.H., T.T.) and Research Headquarters of Pharmaceutical Operation (N.M.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
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Jang KB, Purvis JM, Kim SW. Supplemental effects of dietary lysophospholipids in lactation diets on sow performance, milk composition, gut health, and gut-associated microbiome of offspring. J Anim Sci 2020; 98:5873431. [PMID: 32681642 DOI: 10.1093/jas/skaa227] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/25/2020] [Accepted: 07/13/2020] [Indexed: 12/12/2022] Open
Abstract
Dietary lysophospholipids (LPL) would influence milk composition of sows, thus positively affect intestinal health of offspring. The objective of this study was to determine effects of dietary LPL fed to lactating sows on performance, milk characteristics, gut health, and gut-associated microbiome of offspring. Sixty pregnant sows were allotted to 2 treatments in a randomized complete block design with parity and BW as blocks on day 110 of gestation. Treatments were CON (no added LPL) and LPL (0.05% LPL; Lipidol-Ultra, Pathway Intermediates, Shrewsbury, UK). Sows were fed 2 kg/d from day 110 of gestation until farrowing and ad libitum after farrowing. Diets were formulated to meet NRC requirement for lactating sows. Colostrum and milk samples from 12 sows per treatment were collected to measure nutrients and immunoglobulins on days 1 and 18 of lactation, respectively. Twelve piglets per treatment (1 piglet per litter) were euthanized on day 18 to collect tissues to measure tumor necrosis factor-α, interleukin-8 (IL-8), malondialdehyde, protein carbonyl, IgA, histomorphology, crypt cell proliferation rate, and microbiota in the jejunum and colon. Data were analyzed using the MIXED procedure of SAS, and the mortality was analyzed using the GLIMMIX procedure of SAS. There was no difference in sow BW, parity, and litter size between treatments on day 0 of lactation. Sows fed LPL had increased (P < 0.05) litter BW gain (53.9 vs. 59.4 kg) and decreased piglet mortality (13.9% vs. 10.6%) on day 18 of lactation. Sows fed LPL had increased (P < 0.05) omega-6:omega-3 (22.1 vs. 23.7) and unsaturated:saturated (1.4 vs. 1.6) fatty acids ratios with increased oleic acid (29.1% vs. 31.4%) and tended to have increased (P = 0.092) IgG (1.14 vs. 1.94 g/L) and linoleic acid (17.7% vs. 18.7%) in the milk on day 18 of lactation. Piglets from sows fed LPL had increased (P < 0.05) IL-8 (184 vs. 245 pg/mg) and crypt cell proliferation rate (39.4% vs. 40.9%) and tended to have increased (P = 0.095) Firmicutes:Bacteroidetes ratio (1.0 vs. 3.5) in the jejunum. In conclusion, sows fed with LPL had milk with increased IgG, oleic acids, and linoleic acids without changes in BW and backfat during lactation. These changes could contribute to improved survivability and intestinal health of piglets by increasing IL-8 concentration, enhancing balance among gut-associated microbiome, and increasing enterocyte proliferation in the jejunum.
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Affiliation(s)
- Ki Beom Jang
- Department of Animal Science, North Carolina State University, Raleigh, NC
| | | | - Sung Woo Kim
- Department of Animal Science, North Carolina State University, Raleigh, NC
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Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer. Int J Mol Sci 2020; 21:ijms21165938. [PMID: 32824846 PMCID: PMC7460696 DOI: 10.3390/ijms21165938] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/02/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022] Open
Abstract
Autotaxin (ATX) is a secreted enzyme that produces lysophosphatidate (LPA), which signals through six G-protein coupled receptors, promoting tumor growth, metastasis, and survival from chemotherapy and radiotherapy. Many cancer cells produce ATX, but breast cancer cells express little ATX. In breast tumors, ATX is produced by tumor-associated stroma. Breast tumors are also surrounded by adipose tissue, which is a major bodily source of ATX. In mice, a high-fat diet increases adipocyte ATX production. ATX production in obesity is also increased because of low-level inflammation in the expanded adipose tissue. This increased ATX secretion and consequent LPA signaling is associated with decreased adiponectin production, which results in adverse metabolic profiles and glucose homeostasis. Increased ATX production by inflamed adipose tissue may explain the obesity-breast cancer association. Breast tumors produce inflammatory mediators that stimulate ATX transcription in tumor-adjacent adipose tissue. This drives a feedforward inflammatory cycle since increased LPA signaling increases production of more inflammatory mediators and cyclooxygenase-2. Inhibiting ATX activity, which has implications in breast cancer adjuvant treatments, attenuates this cycle. Targeting ATX activity and LPA signaling may potentially increase chemotherapy and radiotherapy efficacy, and decrease radiation-induced fibrosis morbidity independently of breast cancer type because most ATX is not derived from breast cancer cells.
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The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes. Int J Mol Sci 2020; 21:ijms21165595. [PMID: 32764262 PMCID: PMC7460639 DOI: 10.3390/ijms21165595] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/15/2020] [Revised: 07/31/2020] [Accepted: 08/02/2020] [Indexed: 12/14/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic disease for which novel approaches are urgently required. We reported increased sphingosine kinase 1 (SPHK1) in IPF lungs and that SPHK1 inhibition using genetic and pharmacologic approaches reduces murine bleomycin-induced pulmonary fibrosis. We determined whether PF543, a specific SPHK1 inhibitor post bleomycin or asbestos challenge mitigates lung fibrosis by reducing mitochondrial (mt) DNA damage and pro-fibrotic monocyte recruitment—both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U/kg), crocidolite asbestos (100 µg/50 µL) or controls was intratracheally instilled in Wild-Type (C57Bl6) mice. PF543 (1 mg/kg) or vehicle was intraperitoneally injected once every two days from day 7−21 following bleomycin and day 14−21 or day 30−60 following asbestos. PF543 reduced bleomycin- and asbestos-induced pulmonary fibrosis at both time points as well as lung expression of profibrotic markers, lung mtDNA damage, and fibrogenic monocyte recruitment. In contrast to human lung fibroblasts, asbestos augmented lung epithelial cell (MLE) mtDNA damage and PF543 was protective. Post-exposure PF543 mitigates pulmonary fibrosis in part by reducing lung epithelial cell mtDNA damage and monocyte recruitment. We reason that SPHK1 signaling may be an innovative therapeutic target for managing patients with IPF and other forms of lung fibrosis.
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Tan Y, Li Y, Zhou F, Guo J, Wang T, Shi Y, Yang Y, Lu J, Pei G. Administration of a mixture of triterpenoids from yeyachun and phenolic acids from danshen ameliorates carbon tetrachloride-induced liver fibrosis in mice by the regulation of intestinal flora. J Pharmacol Sci 2020; 143:165-175. [DOI: 10.1016/j.jphs.2020.04.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/07/2020] [Revised: 04/17/2020] [Accepted: 04/23/2020] [Indexed: 12/12/2022] Open
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Signaling lipids as diagnostic biomarkers for ocular surface cicatrizing conjunctivitis. J Mol Med (Berl) 2020; 98:751-760. [PMID: 32313985 PMCID: PMC7220886 DOI: 10.1007/s00109-020-01907-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/30/2020] [Revised: 03/24/2020] [Accepted: 04/02/2020] [Indexed: 12/23/2022]
Abstract
Abstract Metabolomics has been applied to diagnose diseases, predict disease progression, and design therapeutic strategies in various areas of medicine. However, it remains to be applied to the ocular surface diseases, where biological samples are often of limited quantities. We successfully performed proof-of-concept metabolomics assessment of volume-limited cytology samples from a clinical form of chronic inflammatory cicatrizing conjunctivitis, i.e., ocular MMP and discovered metabolic changes of signaling lipid mediators upon disease onset and progression. The metabolomics assessment revealed active oxylipins, lysophospholipids, fatty acids, and endocannabinoids alterations, from which potential biomarkers linked to inflammatory processes were identified. Possible underlying mechanisms such as dysregulated enzyme activities (e.g., lipoxygenases, cytochrome P450, and phospholipases) were suggested which may be considered as potential therapeutic targets in future studies. Key messages
Metabolic profile of the ocular surface can be measured using impression cytology samples. Metabolomics analysis of ocular pemphigoid is presented for the first time. The metabolomics assessment of OCP patients revealed active oxylipins, lysophospholipids, fatty acids, and endocannabinoids alterations. Several oxylipins are identified as diagnostic biomarkers for OCP.
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