1
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Giuliani M, Rizzi A, Pagano M, Raveglia LF, Saccani F, Di Lascia MR, Interlandi M, Nardella TS, Marchini G, Murgo A, Tigli L, Pappani A, Capelli AM, Fernandez SX, Puccini P, Villetti G, Civelli M, Beato C, Moro E, Mundi C, Remelli R, Armani E. Novel Cyclohexyl Amido Acid Antagonists of Lysophosphatidic Acid Type 1 Receptor for the Treatment of Pulmonary Fibrosis. ACS Med Chem Lett 2025; 16:317-326. [PMID: 39967626 PMCID: PMC11831564 DOI: 10.1021/acsmedchemlett.4c00559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/21/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 02/20/2025] Open
Abstract
Lysophosphatidic acid (LPA) is a phospholipid activating different biological functions by binding to G protein-coupled receptors (LPA1-6). Among these, the role of the LPA1 receptor in modulating fibrotic processes is well-known, making it a therapeutic target for pulmonary fibrosis and other fibrotic disorders. Herein we report the search for a new class of LPA1 antagonists for the oral treatment of idiopathic pulmonary fibrosis with a focus on hepatobiliary safety. Compound 7 excelled in in vitro and in vivo efficacy, showing significant efficacy both in PD studies and in a rodent lung fibrosis model, with a promising in vitro hepatic safety profile. However, in a dose range finding (DRF) toxicity study, compound 7 did not ensure safety regarding potential hepatobiliary toxicity, leading to its development being halted.
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Affiliation(s)
- Marta Giuliani
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Andrea Rizzi
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Mafalda Pagano
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Luca F. Raveglia
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Francesca Saccani
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | | | | | | | - Gessica Marchini
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Annalisa Murgo
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Laura Tigli
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Alice Pappani
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Anna Maria Capelli
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | | | - Paola Puccini
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Gino Villetti
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Maurizio Civelli
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
| | - Claudia Beato
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Elisa Moro
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Claudia Mundi
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Rosaria Remelli
- Aptuit,
an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy
| | - Elisabetta Armani
- Chiesi
Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy
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2
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Kume H, Kazama K, Sato R, Sato Y. Possible Involvement of Lysophospholipids in Severe Asthma as Novel Lipid Mediators. Biomolecules 2025; 15:182. [PMID: 40001485 DOI: 10.3390/biom15020182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/08/2024] [Revised: 12/25/2024] [Accepted: 01/02/2025] [Indexed: 02/27/2025] Open
Abstract
In severe asthma, symptoms are unstable despite intensive treatment based on high doses of inhaled corticosteroids and on-demand use of oral corticosteroids. Although, recently, various biological agents related to Th2 cytokines have been added to intensive controller medications for severe asthma, a significant progress has not been observed in the management for symptoms (dyspnea, wheezing and cough). Medical treatment focused on Type 2 inflammation is probably insufficient to maintain good long-term management for severe asthma. Airway eosinophilia and decreased reversibility in forced expiratory volume in 1 second (FEV1) are listed as major predictors for exacerbation-prone asthma. However, it is generally considered that asthma is complex and heterogeneous. It is necessary to establish precision medicine using treatable traits based on a multidimensional approach related to asthma. Since phospholipids generate lysophospholipids and arachidonic acid by phospholipases, lysophospholipids can be associated with the pathogenesis of this disease via action on smooth muscle, endothelium, and epithelium in the airways. Lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingosine 1-phosphate (S1P) are increased in bronchoalveolar fluid after allergen challenge. LPA, LPC, and S1P recruit eosinophils to the lungs and cause β2-adrenergic desensitization. LAP and S1P cause contraction and hyperresponsiveness in airway smooth muscle. Moreover, lysophosphatidylserine and S1P are associated with the allergic reaction related to IgE/FcεRI in mast cells. Lysophospholipid action is probably comprised of corticosteroid resistance and is independent of Type 2 inflammation, and may be corelated with oxidative stress. Lysophospholipids may be a novel molecular target in advancing the management and treatment of asthma. This review discusses the clinical relevance of lysophospholipids in asthma.
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Affiliation(s)
- Hiroaki Kume
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492, Japan
| | - Kentaro Kazama
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492, Japan
| | - Riko Sato
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492, Japan
| | - Yuki Sato
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492, Japan
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3
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Tang DT, Du Z, Yang KS, Bestvater BP, Kaplan J, Neubig ME, Olen CL, Phillips B, Wang P, Hudson T, Marchand B, Chan J, Sharma M, Hu Y, Matles M, Nejati E, Chojnacka M, Adams C, Pong C, Holsapple K, Budas G, Tsui V, Venkataramani C, Lazerwith SE, Notte GT, Watkins WJ, McGlinchey E, Zagorska A, Farand J. Discovery of GS-2278, a Potent and Selective LPAR1 Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis. J Med Chem 2024. [PMID: 39570661 DOI: 10.1021/acs.jmedchem.4c02090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2024]
Abstract
We describe the discovery and preclinical characterization of a potent and selective lysophosphatidic acid receptor 1 (LPAR1) antagonist with a direct-acting antifibrotic mechanism. 18a was initially identified as a potent non-carboxylic acid LPAR1 antagonist in an LPA-induced myocardin-related transcription factor A (MRTF-A) nuclear translocation assay. Modifications to the aromatic elements in the structure allowed for improvements in metabolic stability and the mitigation of GSH adduct formation, but in vitro to in vivo clearance disconnects were observed with several potent sulfonamides (e.g., 27b) across preclinical species. Through modification of the sulfonamide, 42 (GS-2278) emerged as a potent LPAR1 antagonist with a suitable in vitro profile and desirable pharmacokinetic properties for oral QD dosing. GS-2278 dose-dependently blocked LPA-induced histamine release and demonstrated efficacy in an interventional model of bleomycin-induced lung fibrosis. However, CNS-related toxicity was observed in dogs, and based on these findings, the clinical development of GS-2278 for IPF was halted.
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Affiliation(s)
- Doris T Tang
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Zhimin Du
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Kin S Yang
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Brian P Bestvater
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Joshua Kaplan
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Megan E Neubig
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Casey L Olen
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Bart Phillips
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Peiyuan Wang
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Thomas Hudson
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Bruno Marchand
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Julie Chan
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Monika Sharma
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Yiding Hu
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Mike Matles
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Elham Nejati
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Maja Chojnacka
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Clifton Adams
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Cassie Pong
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Kevin Holsapple
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Grant Budas
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Vickie Tsui
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | | | - Scott E Lazerwith
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Gregory T Notte
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - William J Watkins
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Ellen McGlinchey
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Anna Zagorska
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Julie Farand
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
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4
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Taketomi Y, Higashi T, Kano K, Miki Y, Mochizuki C, Toyoshima S, Okayama Y, Nishito Y, Nakae S, Tanaka S, Tokuoka SM, Oda Y, Shichino S, Ueha S, Matsushima K, Akahoshi N, Ishii S, Chun J, Aoki J, Murakami M. Lipid-orchestrated paracrine circuit coordinates mast cell maturation and anaphylaxis through functional interaction with fibroblasts. Immunity 2024; 57:1828-1847.e11. [PMID: 39002541 DOI: 10.1016/j.immuni.2024.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/10/2023] [Revised: 04/04/2024] [Accepted: 06/19/2024] [Indexed: 07/15/2024]
Abstract
Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA1, like that of the phospholipase PLA2G3, the prostaglandin D2 (PGD2) synthase L-PGDS, or the PGD2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD2 generation, and feedforward ATX-LPA1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation.
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Affiliation(s)
- Yoshitaka Taketomi
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Takayoshi Higashi
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yoshimi Miki
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Chika Mochizuki
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shota Toyoshima
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Center for Allergy, and Division of Internal Medicine, Department of Respiratory Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan; Department of Biochemistry & Molecular Biology, Nippon Medical School, Tokyo 113-8602, Japan
| | - Yoshimichi Okayama
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Center for Allergy, and Division of Internal Medicine, Department of Respiratory Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan; Department of Allergy and Internal Medicine, Misato Kenwa Hospital, Saitama 341-8555, Japan; Department of Internal Medicine, Division of Respiratory Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan; Advanced Medical Science Research Center, Gunma Paz University Graduate School of Health Sciences, Takasaki 370-0006, Japan
| | - Yasumasa Nishito
- Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Susumu Nakae
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8528, Japan
| | - Satoshi Tanaka
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Suzumi M Tokuoka
- Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yoshiya Oda
- Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shigeyuki Shichino
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
| | - Satoshi Ueha
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
| | - Kouji Matsushima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
| | - Noriyuki Akahoshi
- Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Satoshi Ishii
- Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Jerold Chun
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan
| | - Makoto Murakami
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
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5
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Ahn YM, Jung J, Lee SM. Integrated Omics Analysis Uncovers the Culprit behind Exacerbated Atopic Dermatitis in a Diet-Induced Obesity Model. Int J Mol Sci 2024; 25:4143. [PMID: 38673730 PMCID: PMC11050523 DOI: 10.3390/ijms25084143] [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: 02/27/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Atopic dermatitis (AD), a chronic inflammatory skin disease, is exacerbated by obesity, yet the precise linking mechanism remains elusive. This study aimed to elucidate how obesity amplifies AD symptoms. We studied skin samples from three mouse groups: sham control, AD, and high-fat (HF) + AD. The HF + AD mice exhibited more severe AD symptoms than the AD or sham control mice. Skin lipidome analysis revealed noteworthy changes in arachidonic acid (AA) metabolism, including increased expression of pla2g4, a key enzyme in AA generation. Genes for phospholipid transport (Scarb1) and acyltransferase utilizing AA as the acyl donor (Agpat3) were upregulated in HF + AD skin. Associations were observed between AA-containing phospholipids and skin lipids containing AA and its metabolites. Furthermore, imbalanced phospholipid metabolism was identified in the HF + AD mice, marked by excessive activation of the AA and phosphatidic acid (PA)-mediated pathway. This imbalance featured increased expression of Plcb1, Plcg1, and Dgk involved in PA generation, along with a decrease in genes converting PA into diglycerol (DG) and CDP-DG (Lpin1 and cds1). This investigation revealed imbalanced phospholipid metabolism in the skin of HF + AD mice, contributing to the heightened inflammatory response observed in HF + AD, shedding light on potential mechanisms linking obesity to the exacerbation of AD symptoms.
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Lescop C, Brotschi C, Williams JT, Sager CP, Birker M, Morrison K, Froidevaux S, Delahaye S, Nayler O, Bolli MH. Discovery of a Novel Orally Active, Selective LPA Receptor Type 1 Antagonist, 4-(4-(2-Isopropylphenyl)-4-((2-methoxy-4-methylphenyl)carbamoyl)piperidin-1-yl)-4-oxobutanoic Acid, with a Distinct Molecular Scaffold. J Med Chem 2024; 67:2379-2396. [PMID: 38349223 DOI: 10.1021/acs.jmedchem.3c01826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/23/2024]
Abstract
Lysophosphatidic acid receptor 1 (LPAR1) antagonists show promise as potentially novel antifibrotic treatments. In a human LPAR1 β-arrestin recruitment-based high-throughput screening campaign, we identified urea 19 as a hit with a LPAR1 IC50 value of 5.0 μM. Hit-to-lead activities revealed that one of the urea nitrogen atoms can be replaced by carbon and establish the corresponding phenylacetic amide as a lead structure for further optimization. Medicinal chemistry efforts led to the discovery of piperidine 18 as a potent and selective LPAR1 antagonist with oral activity in a mouse model of LPA-induced skin vascular leakage. The molecular scaffold of 18 shares no obvious structural similarity with any other LPAR1 antagonist disclosed so far.
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Affiliation(s)
- Cyrille Lescop
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Christine Brotschi
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Jodi T Williams
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Christoph P Sager
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Magdalena Birker
- DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Keith Morrison
- DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Sylvie Froidevaux
- DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Stéphane Delahaye
- Preclinical DMPK, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Oliver Nayler
- DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Martin H Bolli
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
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7
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Lescop C, Birker M, Brotschi C, Bürki C, Morrison K, Froidevaux S, Delahaye S, Nayler O, Bolli MH. Discovery of the Novel, Orally Active, and Selective LPA1 Receptor Antagonist ACT-1016-0707 as a Preclinical Candidate for the Treatment of Fibrotic Diseases. J Med Chem 2024; 67:2397-2424. [PMID: 38349250 DOI: 10.1021/acs.jmedchem.3c01827] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/23/2024]
Abstract
Piperidine 3 is a potent and selective lysophosphatidic acid receptor subtype 1 receptor (LPAR1) antagonist that has shown efficacy in a skin vascular leakage target engagement model in mice. However, compound 3 has very high human plasma protein binding and high clearance in rats, which could significantly hamper its clinical development. Continued lead optimization led to the potent, less protein bound, metabolically stable, and orally active azetidine 17. Rat pharmacokinetics (PK) studies revealed that 17 accumulated in the liver. In vitro studies indicated that 17 is an organic anion co-transporting polypeptide 1B1 (OATP1B1) substrate. Although analogue 24 was no longer a substrate of OATP1B1, PK studies suggested that the compound undergoes enterohepatic recirculation. Replacing the carboxylic acidic side chain by a non-acidic sulfamide moiety and further fine-tuning of the scaffold yielded the potent, orally active LPAR1 antagonist 49, which was selected for preclinical development for the treatment of fibrotic diseases.
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Affiliation(s)
- Cyrille Lescop
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Magdalena Birker
- DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Christine Brotschi
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Cédric Bürki
- Chemistry Process R&D, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Keith Morrison
- DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Sylvie Froidevaux
- DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Stéphane Delahaye
- Preclinical DMPK, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Oliver Nayler
- DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
| | - Martin H Bolli
- DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland
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8
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De Giovanni M, Chen H, Li X, Cyster JG. GPR35 and mediators from platelets and mast cells in neutrophil migration and inflammation. Immunol Rev 2023; 317:187-202. [PMID: 36928841 PMCID: PMC10504419 DOI: 10.1111/imr.13194] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 03/18/2023]
Abstract
Neutrophil recruitment from circulation to sites of inflammation is guided by multiple chemoattractant cues emanating from tissue cells, immune cells, and platelets. Here, we focus on the function of one G-protein coupled receptor, GPR35, in neutrophil recruitment. GPR35 has been challenging to study due the description of multiple ligands and G-protein couplings. Recently, we found that GPR35-expressing hematopoietic cells respond to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). We discuss distinct response profiles of GPR35 to 5-HIAA compared to other ligands. To place the functions of 5-HIAA in context, we summarize the actions of serotonin in vascular biology and leukocyte recruitment. Important sources of serotonin and 5-HIAA are platelets and mast cells. We discuss the dynamics of cell migration into inflamed tissues and how multiple platelet and mast cell-derived mediators, including 5-HIAA, cooperate to promote neutrophil recruitment. Additional actions of GPR35 in tissue physiology are reviewed. Finally, we discuss how clinically approved drugs that modulate serotonin uptake and metabolism may influence 5-HIAA-GPR35 function, and we speculate about broader influences of the GPR35 ligand-receptor system in immunity and disease.
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Affiliation(s)
- Marco De Giovanni
- Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Hongwen Chen
- Departments of Molecular Genetics and Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xiaochun Li
- Departments of Molecular Genetics and Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jason G. Cyster
- Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
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9
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Pederson WP, Ellerman LM, Jin Y, Gu H, Ledford JG. Metabolomic Profiling in Mouse Model of Menopause-Associated Asthma. Metabolites 2023; 13:546. [PMID: 37110204 PMCID: PMC10145474 DOI: 10.3390/metabo13040546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/24/2023] [Revised: 04/06/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Menopause-associated asthma impacts a subset of women, tends to be more severe, and is less responsive to current treatments. We recently developed a model of menopause-associated asthma using 4-Vinylcyclohexene Diepoxide (VCD) and house dust mites (HDM). The goal of this study was to uncover potential biomarkers and drivers of menopause-onset asthma by assessing serum and bronchoalveolar lavage fluid (BALF) samples from mice with and without menopause and HDM challenge by large-scale targeted metabolomics. Female mice were treated with VCD/HDM to model menopause-associated asthma, and serum and BALF samples were processed for large-scale targeted metabolomic assessment. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to examine metabolites of potential biological significance. We identified over 50 individual metabolites, impacting 46 metabolic pathways, in the serum and BALF that were significantly different across the four study groups. In particular, glutamate, GABA, phosphocreatine, and pyroglutamic acid, which are involved in glutamate/glutamine, glutathione, and arginine and proline metabolisms, were significantly impacted in the menopausal HDM-challenged mice. Additionally, several metabolites had significant correlations with total airway resistance including glutamic acid, histamine, uridine, cytosine, cytidine, and acetamide. Using metabolic profiling, we identified metabolites and metabolic pathways that may aid in discriminating potential biomarkers for and drivers of menopause-associated asthma.
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Affiliation(s)
- William P. Pederson
- Physiological Sciences GIDP, University of Arizona, Tucson, AZ 85724, USA;
- Department of Physiology, University of Arizona, Tucson, AZ 85724, USA
| | | | - Yan Jin
- Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA
| | - Haiwei Gu
- Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA
| | - Julie G. Ledford
- Asthma and Airway Disease Research Center, Tucson, AZ 85724, USA
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
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10
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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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11
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Lysophosphatidic acid activates nociceptors and causes pain or itch depending on the application mode in human skin. Pain 2021; 163:445-460. [PMID: 34166323 DOI: 10.1097/j.pain.0000000000002363] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/21/2020] [Accepted: 04/13/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors e.g. from the Mrgpr family. Human nerve fibers involved in pain signaling ("nociceptors") can elicit itch if activated by focalized stimuli such as cowhage spicules.In this study, we scrutinized the effects of LPA in humans by two different application modes on the level of psychophysics and single nerve fiber recordings (microneurography). In healthy human subjects, intracutaneous LPA microinjections elicited burning pain, whereas LPA application via inactivated cowhage spicules evoked a moderate itch sensation. LPA microinjections induced heat hyperalgesia and hypersensitivity to higher electrical stimulus frequencies. Pharmacological blockade of TRPA1 or TRPV1 reduced heat hyperalgesia but not acute chemical pain. Microneurography revealed an application mode-dependent differential activation of mechano-sensitive (CM) and mechano-insensitive (CMi) C-fibers. LPA microinjections activated a greater proportion of CMi and more strongly than CM fibers; spicule-application of LPA activated CM and CMi fibers to a similar extent but excited CM more and CMi fibers less intensely than microinjections.In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C-fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents, and a specific combination of activated fiber subclasses might contribute.
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12
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Boehm T, Ristl R, Joseph S, Petroczi K, Klavins K, Valent P, Jilma B. Metabolome and lipidome derangements during a severe mast cell activation event in a patient with indolent systemic mastocytosis. J Allergy Clin Immunol 2021; 148:1533-1544. [PMID: 33864889 DOI: 10.1016/j.jaci.2021.03.043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/27/2020] [Revised: 03/02/2021] [Accepted: 03/30/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND The number of mast cells in various organs is elevated manifold in individuals with systemic mastocytosis. Degranulation can lead to life-threatening symptomatology. No data about the alterations of the metabolome and lipidome during an attack have been published. OBJECTIVE Our aim was to analyze changes in metabolomics and lipidomics during the acute phase of a severe mast cell activation event. METHODS A total of 43 metabolites and 11 lipid classes comprising 200 subvariants from multiple plasma samples in duplicate, covering 72 hours of a severe mast cell activation attack with nausea and vomiting, were compared with 2 baseline samples by using quantitative liquid chromatography-mass spectrometry. RESULTS A strong enterocyte dysfunction reflected in an almost 20-fold reduction in the functional small bowel length was extrapolated from strongly reduced ornithine and citrulline concentrations and was very likely secondary to severe endothelial cell dysfunction with hypoperfusion and extensive vascular leakage. Highly increased histamine and lactate concentrations accompanied the peak in clinical symptoms. Elevated asymmetric and symmetric dimethylarginine levels combined with reduced arginine levels compromised endothelial nitric oxide synthase activity and nitric oxide signaling. Specific and extensive depletion of many lysophosphatidylcholine variants indicates localized autotaxin activation and lysophosphatidic acid release. A strong correlation of clinical parameters with histamine concentrations and symptom reduction after 100-fold elevated plasma diamine oxidase concentrations implies that histamine is the key driver of the acute phase. CONCLUSIONS Rapid elimination of elevated histamine concentrations through use of recombinant human diamine oxidase, supplementation of lysophosphatidylcholine for immunomodulation, inhibition of autotaxin activity, and/or blockade of lysophosphatidic acid receptors might represent new treatment options for life-threatening mast cell activation events.
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Affiliation(s)
- Thomas Boehm
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
| | - Robin Ristl
- Section for Medical Statistics, Center of Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Saijo Joseph
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Karin Petroczi
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Kristaps Klavins
- CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
| | - Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
| | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
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13
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Regulation of Tumor Immunity by Lysophosphatidic Acid. Cancers (Basel) 2020; 12:cancers12051202. [PMID: 32397679 PMCID: PMC7281403 DOI: 10.3390/cancers12051202] [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: 04/24/2020] [Revised: 05/08/2020] [Accepted: 05/09/2020] [Indexed: 12/16/2022] Open
Abstract
The tumor microenvironment (TME) may be best conceptualized as an ecosystem comprised of cancer cells interacting with a multitude of stromal components such as the extracellular matrix (ECM), blood and lymphatic networks, fibroblasts, adipocytes, and cells of the immune system. At the center of this crosstalk between cancer cells and their TME is the bioactive lipid lysophosphatidic acid (LPA). High levels of LPA and the enzyme generating it, termed autotaxin (ATX), are present in many cancers. It is also well documented that LPA drives tumor progression by promoting angiogenesis, proliferation, survival, invasion and metastasis. One of the hallmarks of cancer is the ability to modulate and escape immune detection and eradication. Despite the profound role of LPA in regulating immune functions and inflammation, its role in the context of tumor immunity has not received much attention until recently where emerging studies highlight that this signaling axis may be a means that cancer cells adopt to evade immune detection and eradication. The present review aims to look at the immunomodulatory actions of LPA in baseline immunity to provide a broad understanding of the subject with a special emphasis on LPA and cancer immunity, highlighting the latest progress in this area of research.
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14
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The roles of autotaxin/lysophosphatidic acid in immune regulation and asthma. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158641. [PMID: 32004685 DOI: 10.1016/j.bbalip.2020.158641] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/18/2019] [Revised: 12/26/2019] [Accepted: 01/23/2020] [Indexed: 12/18/2022]
Abstract
Lysophosphatidic acid (LPA) species are present in almost all organ systems and play diverse roles through its receptors. Asthma is an airway disease characterized by chronic allergic inflammation where various innate and adaptive immune cells participate in establishing Th2 immune response. Here, we will review the contribution of LPA and its receptors to the functions of immune cells that play a key role in establishing allergic airway inflammation and aggravation of allergic asthma.
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15
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Chen S, Chen G, Shu S, Xu Y, Ma X. Metabolomics analysis of baicalin on ovalbumin-sensitized allergic rhinitis rats. ROYAL SOCIETY OPEN SCIENCE 2019; 6:181081. [PMID: 30891260 PMCID: PMC6408364 DOI: 10.1098/rsos.181081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 07/03/2018] [Accepted: 01/25/2019] [Indexed: 05/10/2023]
Abstract
Allergic rhinitis (AR) is a global health problem that appears in all age groups and affects approximately 15-30% of people. Baicalin has been used for the treatment of various allergic diseases, including AR. However, the metabolic mechanisms of AR and baicalin against AR have not been systematically studied. Here, ovalbumin-sensitized AR rats were used as a model, and animal behaviour, histological analysis, enzyme-linked immunosorbent assay (ELISA) and metabolomics were used to elucidate the mechanism of baicalin for AR. The results indicated that baicalin has a protective effect on AR rats by inhibiting the release of immunoglobulin E (IgE), histamine, interleukin-1 beta (IL-1β), interleukin-4 (IL-4), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). In addition, ovalbumin-induced AR included modulation of arachidonic acid, leukotriene A4 (LTA4), leukotriene B4 (LTB4), α-ketoglutaric acid, phosphatidylcholine PC (20 : 4/0 : 0), PC (16 : 0/0 : 0), citric acid, fumarate, malate, 3-methylhistidine, histamine and other amino acids that are involved in arachidonic acid, histidine metabolism, the TCA cycle and amino acid metabolism. Thus, AR could be alleviated or reversed by baicalin.
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Affiliation(s)
- Saizhen Chen
- Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, People's Republic of China
| | - Guirong Chen
- Liaoning University of Traditional Chinese Medicine, Shenyang 110847, People's Republic of China
| | - Sheng Shu
- Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, People's Republic of China
| | - Yubin Xu
- Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, People's Republic of China
- Author for correspondence: Yubin Xu e-mail:
| | - Xiande Ma
- Liaoning University of Traditional Chinese Medicine, Shenyang 110847, People's Republic of China
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16
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Affiliation(s)
- Yoshitaka Taketomi
- Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science
| | - Makoto Murakami
- Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science
- Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo
- AMED-CREST, Japan Agency for Medical Research and Development
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17
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Kritikou E, van Puijvelde GHM, van der Heijden T, van Santbrink PJ, Swart M, Schaftenaar FH, Kröner MJ, Kuiper J, Bot I. Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice. Sci Rep 2016; 6:37585. [PMID: 27883026 PMCID: PMC5121611 DOI: 10.1038/srep37585] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/01/2016] [Accepted: 10/31/2016] [Indexed: 02/08/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6Clow monocytes and CD4+ CD25+ FoxP3+ T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development.
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Affiliation(s)
- Eva Kritikou
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
| | | | | | | | - Maarten Swart
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
| | | | - Mara J Kröner
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
| | - Johan Kuiper
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
| | - Ilze Bot
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
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18
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Kozian DH, von Haeften E, Joho S, Czechtizky W, Anumala UR, Roux P, Dudda A, Evers A, Nazare M. Modulation of Hexadecyl-LPA-Mediated Activation of Mast Cells and Microglia by a Chemical Probe for LPA5. Chembiochem 2016; 17:861-5. [PMID: 26812365 DOI: 10.1002/cbic.201500559] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/21/2015] [Indexed: 11/05/2022]
Abstract
Mast cells and microglia play a critical role in innate immunity and inflammation and can be activated by a wide range of endogenous and exogenous stimuli. Lysophosphatidic acid (LPA) has recently been reported to activate mast cells and microglia. Using the human mast cell line HMC-1 and the mouse microglia cell line BV-2, we show that LPA-mediated activation can be prevented by blockade of the LPA receptor 5 (LPA5) in both cell lines. The identification of new LPA5-specific antagonists as tool compounds to probe and modulate the LPA5/LPA axis in relevant in vitro and in vivo assays should contribute to better understanding of the underlying role of LPAs in the development and progression of (neuro-) inflammatory diseases.
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Affiliation(s)
- Detlef H Kozian
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany.
| | | | - Sabrina Joho
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany
| | - Werngard Czechtizky
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany
| | - Upendra R Anumala
- Leibniz-Institut für Molekulare Pharmakologie FMP, Campus Berlin Buch, 13125, Berlin, Germany
| | - Pascale Roux
- Sanofi SA, 1541, avenue Marcel Merieux, 69280, Marcy l'Etoile, France
| | - Angela Dudda
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany
| | - Andreas Evers
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany
| | - Marc Nazare
- Leibniz-Institut für Molekulare Pharmakologie FMP, Campus Berlin Buch, 13125, Berlin, Germany.
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19
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Xu Y, Guo N, Dou D, Ran X, Ma X, Kuang H. Proteomics Study on Nonallergic Hypersensitivity Induced by Compound 4880 and Ovalbumin. PLoS One 2016; 11:e0148262. [PMID: 26829397 PMCID: PMC4734762 DOI: 10.1371/journal.pone.0148262] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/25/2015] [Accepted: 01/16/2016] [Indexed: 01/25/2023] Open
Abstract
Nonallergic hypersensitivity reaction (NHR) accounts for more than 77% of all immune-mediated immediate hypersensitivity reactions and has become a serious threat to public health. Here, proteomics was used to study the NHR mechanism of two typical substances, the compound 4880 and ovalbumin. Twelve different proteins were suggested as potential biomarkers for examining the NHR mechanism, and our results revealed that the mechanism mainly encompassed 2 processes, i.e., generation and effect processes. The generation process could be classified as direct stimulation, complement (classical and alternative), coagulation, kallikrein-kinin, and integrated pathways. Thus glutathione peroxidase 1, terminal complement complex (complement factor 4d and Bb), coagulation 13, kininogen-1, and IgE could be used as candidate biomarkers for the indication of the corresponding pathways respectively, the proteins were further confirmed by ELISA. And the effect process was mainly composed of histamine as well as proteins such as DCD and MYLPF, which could be used as important indices for the symptoms of NHR. Our study differs from previous studies in that C4880 was found to not only be involved in the direct stimulation pathway, but also in the activated complement and kallikrein-kinin pathways through the coagulation pathway. We also report for the first time that ovalbumin-induced NHR could be a combination of the coagulation, classical complement, and integrated pathways.
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Affiliation(s)
- Yubin Xu
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, Liaoning, China
| | - Na Guo
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Deqiang Dou
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, Liaoning, China
- * E-mail: (DQD); (HXK)
| | - Xiaoku Ran
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, Liaoning, China
| | - Xiande Ma
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, Liaoning, China
| | - Haixue Kuang
- College of pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
- * E-mail: (DQD); (HXK)
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Ohashi T, Yamamoto T. Antifibrotic effect of lysophosphatidic acid receptors LPA1and LPA3antagonist on experimental murine scleroderma induced by bleomycin. Exp Dermatol 2015; 24:698-702. [DOI: 10.1111/exd.12752] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 04/28/2015] [Indexed: 12/18/2022]
Affiliation(s)
- Takenobu Ohashi
- Department of Dermatology; Fukushima Medical University; Fukushima Japan
| | - Toshiyuki Yamamoto
- Department of Dermatology; Fukushima Medical University; Fukushima Japan
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21
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Potentials of the Circulating Pruritogenic Mediator Lysophosphatidic Acid in Development of Allergic Skin Inflammation in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:1593-603. [DOI: 10.1016/j.ajpath.2014.01.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 09/30/2013] [Revised: 01/05/2014] [Accepted: 01/16/2014] [Indexed: 01/03/2023]
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Knowlden S, Georas SN. The autotaxin-LPA axis emerges as a novel regulator of lymphocyte homing and inflammation. THE JOURNAL OF IMMUNOLOGY 2014; 192:851-7. [PMID: 24443508 DOI: 10.4049/jimmunol.1302831] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Academic Contribution Register] [Indexed: 12/17/2022]
Abstract
Lysophosphatidic acid (LPA) is a pleiotropic lipid molecule with potent effects on cell growth and motility. Major progress has been made in recent years in deciphering the mechanisms of LPA generation and how it acts on target cells. Most research has been conducted in other disciplines, but emerging data indicate that LPA has an important role to play in immunity. A key discovery was that autotaxin (ATX), an enzyme previously implicated in cancer cell motility, generates extracellular LPA from the precursor lysophosphatidylcholine. Steady-state ATX is expressed by only a few tissues, including high endothelial venules in lymph nodes, but inflammatory signals can upregulate ATX expression in different tissues. In this article, we review current thinking about the ATX/LPA axis in lymphocyte homing, as well as in models of allergic airway inflammation and asthma. New insights into the role of LPA in regulating immune responses should be forthcoming in the near future.
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Affiliation(s)
- Sara Knowlden
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642
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23
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Magkrioti C, Aidinis V. Autotaxin and lysophosphatidic acid signalling in lung pathophysiology. World J Respirol 2013; 3:77-103. [DOI: 10.5320/wjr.v3.i3.77] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/29/2013] [Revised: 10/03/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid (LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysiological situations in vivo and in human diseases.
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Mruwat R, Cohen Y, Yedgar S. Phospholipase A2 inhibition as potential therapy for inflammatory skin diseases. Immunotherapy 2013; 5:315-7. [DOI: 10.2217/imt.13.18] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/26/2023] Open
Affiliation(s)
- Rufayda Mruwat
- Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120
| | - Yuval Cohen
- Morria Biopharmaceuticals PLC, 53 Davies Street, London W1K 5JH, UK
| | - Saul Yedgar
- Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120
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Bot M, de Jager SCA, MacAleese L, Lagraauw HM, van Berkel TJC, Quax PHA, Kuiper J, Heeren RMA, Biessen EAL, Bot I. Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation. J Lipid Res 2013; 54:1265-74. [PMID: 23396975 DOI: 10.1194/jlr.m032862] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/20/2022] Open
Abstract
Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque. It has the capacity to activate mast cells, which potentially exacerbates plaque progression. In this study, we thus aimed to investigate whether LPA contributes to plaque destabilization by modulating mast cell function. We here show by an imaging mass spectrometry approach that several LPA species are present in atherosclerotic plaques. Subsequently, we demonstrate that LPA is a potent mast cell activator which, unlike other triggers, favors release of tryptase. Local perivascular administration of LPA to an atherosclerotic carotid artery segment increases the activation status of perivascular mast cells and promotes intraplaque hemorrhage and macrophage recruitment without impacting plaque cell apoptosis. The mast cell stabilizer cromolyn could prevent intraplaque hemorrhage elicited by LPA-mediated mast cell activation. Finally, the involvement of mast cells in these events was further emphasized by the lack of effect of perivascular LPA administration in mast cell deficient animals. We demonstrate that increased accumulation of LPA in plaques induces perivascular mast cell activation and in this way contributes to plaque destabilization in vivo. This study points to local LPA availability as an important factor in atherosclerotic plaque stability.
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Affiliation(s)
- Martine Bot
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, 2333 CC, Leiden University, Leiden, The Netherlands
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Current progress in non-Edg family LPA receptor research. Biochim Biophys Acta Mol Cell Biol Lipids 2012; 1831:33-41. [PMID: 22902318 DOI: 10.1016/j.bbalip.2012.08.003] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/29/2012] [Revised: 08/01/2012] [Accepted: 08/02/2012] [Indexed: 01/08/2023]
Abstract
Lysophosphatidic acid (LPA) is the simplest phospholipid yet possesses myriad biological functions. Until 2003, the functions of LPA were thought to be elicited exclusively by three subtypes of the endothelial differentiation gene (Edg) family of G protein-coupled receptors - LPA(1), LPA(2), and LPA(3). However, several biological functions of LPA could not be assigned to any of these receptors indicating the existence of one or more additional LPA receptor(s). More recently, the discovery of a second cluster of LPA receptors which includes LPA(4), LPA(5), and LPA(6) has paved the way for new avenues of LPA research. Analyses of these non-Edg family LPA receptors have begun to fill in gaps to understand biological functions of LPA such as platelet aggregation and vascular development that could not be ascribed to classical Edg family LPA receptors and are also unveiling new biological functions. Here we review recent progress in the non-Edg family LPA receptor research, with special emphasis on the pharmacology, signaling, and physiological roles of this family of receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
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Costello RW, Maloney M, Atiyeh M, Gleich G, Walsh MT. Mechanism of sphingosine 1-phosphate- and lysophosphatidic acid-induced up-regulation of adhesion molecules and eosinophil chemoattractant in nerve cells. Int J Mol Sci 2011; 12:3237-49. [PMID: 21686182 PMCID: PMC3116188 DOI: 10.3390/ijms12053237] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/08/2011] [Revised: 05/05/2011] [Accepted: 05/09/2011] [Indexed: 12/11/2022] Open
Abstract
The lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) act via G-protein coupled receptors S1P(1-5) and LPA(1-3) respectively, and are implicated in allergy. Eosinophils accumulate at innervating cholinergic nerves in asthma and adhere to nerve cells via intercellular adhesion molecule-1 (ICAM-1). IMR-32 neuroblastoma cells were used as an in vitro cholinergic nerve cell model. The G(i) coupled receptors S1P(1), S1P(3), LPA(1), LPA(2) and LPA(3) were expressed on IMR-32 cells. Both S1P and LPA induced ERK phosphorylation and ERK- and G(i)-dependent up-regulation of ICAM-1 expression, with differing time courses. LPA also induced ERK- and G(i)-dependent up-regulation of the eosinophil chemoattractant, CCL-26. The eosinophil granule protein eosinophil peroxidase (EPO) induced ERK-dependent up-regulation of transcription of S1P(1), LPA(1), LPA(2) and LPA(3), providing the situation whereby eosinophil granule proteins may enhance S1P- and/or LPA- induced eosinophil accumulation at nerve cells in allergic conditions.
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Affiliation(s)
- Richard W. Costello
- Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; E-Mails: (R.W.C.); (M.M.); (M.A.)
| | - Michael Maloney
- Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; E-Mails: (R.W.C.); (M.M.); (M.A.)
| | - Mazin Atiyeh
- Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; E-Mails: (R.W.C.); (M.M.); (M.A.)
| | - Gerald Gleich
- Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA; E-Mail:
| | - Marie-Therese Walsh
- Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; E-Mails: (R.W.C.); (M.M.); (M.A.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +353-1-8093803; Fax: +353-1-8093765
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Lundequist A, Boyce JA. LPA5 is abundantly expressed by human mast cells and important for lysophosphatidic acid induced MIP-1β release. PLoS One 2011; 6:e18192. [PMID: 21464938 PMCID: PMC3065470 DOI: 10.1371/journal.pone.0018192] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/11/2010] [Accepted: 02/28/2011] [Indexed: 01/08/2023] Open
Abstract
Background Lysophosphatidic acid (LPA) is a bioactive lipid inducing proliferation, differentiation as well as cytokine release by mast cells through G-protein coupled receptors. Recently GPR92/LPA5 was identified as an LPA receptor highly expressed by cells of the immune system, which prompted us to investigate its presence and influence on mast cells. Principal Findings Transcript analysis using quantitative real-time PCR revealed that LPA5 is the most prevalent LPA-receptor in human mast cells. Reduction of LPA5 levels using shRNA reduced calcium flux and abolished MIP-1β release in response to LPA. Conclusions LPA5 is a bona fide LPA receptor on human mast cells responsible for the majority of LPA induced MIP-1β release.
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Affiliation(s)
- Anders Lundequist
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
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Affiliation(s)
- Yoshitaka TAKETOMI
- Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science
| | - Makoto MURAKAMI
- Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science
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Swaney JS, Chapman C, Correa LD, Stebbins KJ, Broadhead AR, Bain G, Santini AM, Darlington J, King CD, Baccei CS, Lee C, Parr TA, Roppe JR, Seiders TJ, Ziff J, Prasit P, Hutchinson JH, Evans JF, Lorrain DS. Pharmacokinetic and Pharmacodynamic Characterization of an Oral Lysophosphatidic Acid Type 1 Receptor-Selective Antagonist. J Pharmacol Exp Ther 2010; 336:693-700. [DOI: 10.1124/jpet.110.175901] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/12/2023] Open
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Yin Z, Carbone LD, Gotoh M, Postlethwaite A, Bolen AL, Tigyi GJ, Murakami-Murofushi K, Watsky MA. Lysophosphatidic acid-activated Cl- current activity in human systemic sclerosis skin fibroblasts. Rheumatology (Oxford) 2010; 49:2290-7. [PMID: 20823096 DOI: 10.1093/rheumatology/keq260] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVES SSc (scleroderma) is an often fatal disease characterized by widespread tissue fibrosis. Fibroblasts play a key role in SSc-associated fibrosis. This study was designed to determine: (i) whether fibroblasts isolated from skin of patients with SSc have increased lysophosphatidic acid-activated Cl- current (IClLPA) activity vs healthy controls; (ii) whether myofibroblast differentiation is involved in SSc skin fibrosis; and (iii) whether SSc fibroblasts have different proliferation rates vs controls. METHODS Skin biopsies were taken from involved and uninvolved skin of SSc patients and controls. Whole-cell perforated patch-clamping was used to measure IClLPA activity in fibroblasts isolated and cultured from these biopsies. Western blotting was used to measure α-smooth muscle actin (α-SMA). Proliferation was measured using a colorimetric assay. RESULTS Fibroblasts cultured from SSc skin show significantly increased IClLPA activity following LPA exposure compared with control skin fibroblasts. α-SMA protein was significantly increased in cultured SSc skin fibroblasts vs controls. No significant differences in proliferation rates were found. CONCLUSIONS Elevated IClLPA activity is a hallmark of SSc skin fibroblasts. Blocking IClLPA activation may be a new therapeutic approach for treating SSc-associated fibrosis.
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Affiliation(s)
- Zhaohong Yin
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163, USA
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Sphingosylphosphorylcholine induces degranulation of mast cells in the skin and plasma exudation in the ears of mice. J Dermatol Sci 2010; 57:57-9. [DOI: 10.1016/j.jdermsci.2009.09.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/04/2009] [Revised: 08/31/2009] [Accepted: 09/18/2009] [Indexed: 11/24/2022]
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SARKER MOSHARRAFH, HU DEEN, FRASER PAULA. Regulation of Cerebromicrovascular Permeability by Lysophosphatidic Acid. Microcirculation 2010; 17:39-46. [DOI: 10.1111/j.1549-8719.2010.00001.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/26/2022]
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Ahn DK, Lee SY, Han SR, Ju JS, Yang GY, Lee MK, Youn DH, Bae YC. Intratrigeminal ganglionic injection of LPA causes neuropathic pain-like behavior and demyelination in rats. Pain 2009; 146:114-20. [DOI: 10.1016/j.pain.2009.07.012] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/11/2009] [Revised: 07/07/2009] [Accepted: 07/13/2009] [Indexed: 10/20/2022]
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Sánchez-Patán F, Aller MA, Cuellar C, Rodero M, Corcuera MT, Nava MP, Gómez F, Blanco MD, Guerrero S, Anchuelo R, Muñiz E, Alonso MJ, Teijón JM, Arias J. Mast cell inhibition by ketotifen reduces splanchnic inflammatory response in a portal hypertension model in rats. ACTA ACUST UNITED AC 2008; 60:347-55. [DOI: 10.1016/j.etp.2008.03.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/20/2006] [Accepted: 03/20/2008] [Indexed: 01/10/2023]
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36
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Walsh MT, Costello R. Putting fat on the fire? Lysophospholipid mediators in bronchoalveolar lavage fluid after allergen challenge. Clin Exp Allergy 2007; 37:305-7. [PMID: 17359379 DOI: 10.1111/j.1365-2222.2007.02674.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/29/2022]
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37
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Kuehn HS, Gilfillan AM. G protein-coupled receptors and the modification of FcepsilonRI-mediated mast cell activation. Immunol Lett 2007; 113:59-69. [PMID: 17919738 DOI: 10.1016/j.imlet.2007.08.007] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/10/2007] [Accepted: 08/16/2007] [Indexed: 12/17/2022]
Abstract
By releasing multiple pro-inflammatory mediators upon activation, mast cells are critical effector cells in the pathogenesis of allergic inflammation. The traditional viewpoint of antigen-dependent mast cell activation is that of a Th(2)-driven process whereby antigen-specific IgE molecules are produced by B cells followed by binding of the IgE to high affinity IgE receptors (FcepsilonRI) expressed on mast cells. Subsequent antigen-dependent aggregation of the FcepsilonRI initiates an intracellular signalling cascade that culminates in mediator release. Mast cell responses, including cell growth, survival, chemotaxis, and cell adhesion, however, can also be regulated by other receptors expressed on mast cells. Furthermore, FcepsilonRI-mediated mast cell mediator release can be significantly modified by ligation of specific classes of these receptors. One such class of receptors is the G protein-coupled receptors (GPCR). In this review, we describe how sub-populations of GPCRs can either enhance or inhibit FcepsilonRI-mediated mast cell activation depending on the particular G protein utilized for relaying signalling. Furthermore, we discuss the potential mechanisms whereby the signalling responses utilized by the FcepsilonRI for mast cell activation are influenced by those initiated by GPCRs to produce these diverse responses.
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Affiliation(s)
- Hye Sun Kuehn
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive MSC 1881, Bethesda, MD 20892-1881, USA
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38
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Bot M, Nofer JR, van Berkel TJC, Biessen EAL. Lysophospholipids: two-faced mediators in atherosclerosis. ACTA ACUST UNITED AC 2007. [DOI: 10.2217/17460875.2.3.341] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/29/2022]
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