Mechanisms of fibrosis: therapeutic translation for fibrotic disease

Nature Medicine, Journal Year: 2012, Volume and Issue: 18(7), P. 1028 - 1040

Published: July 1, 2012

Language: Английский

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Integrating mechanisms of pulmonary fibrosis

The Journal of Experimental Medicine, Journal Year: 2011, Volume and Issue: 208(7), P. 1339 - 1350

Published: July 4, 2011

Pulmonary fibrosis is a highly heterogeneous and lethal pathological process with limited therapeutic options. Although research on the pathogenesis of pulmonary has frequently focused mechanisms that regulate proliferation, activation, differentiation collagen-secreting myofibroblasts, recent studies have identified new pathogenic are critically involved in initiation progression variety settings. A more detailed integrated understanding cellular molecular could help pave way for effective therapeutics this devastating complex disease.

Language: Английский

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LPA Receptors: Subtypes and Biological Actions

The Annual Review of Pharmacology and Toxicology, Journal Year: 2010, Volume and Issue: 50(1), P. 157 - 186

Published: Jan. 8, 2010

Lysophosphatidic acid (LPA) is a small, ubiquitous phospholipid that acts as an extracellular signaling molecule by binding to and activating at least five known G protein-coupled receptors (GPCRs): LPA(1)-LPA(5). They are encoded distinct genes named LPAR1-LPAR5 in humans Lpar1-Lpar5 mice. The biological roles of LPA diverse include developmental, physiological, pathophysiological effects. This diversity mediated broad overlapping expression patterns multiple downstream pathways activated cognate receptors. Studies using cloned genetic knockout mice have been instrumental uncovering the significance this system, notably involving basic cellular processes well organ systems such nervous system. has further provided valuable proof-of-concept data support metabolic enzymes targets for treatment medically important diseases neuropsychiatric disorders, neuropathic pain, infertility, cardiovascular disease, inflammation, fibrosis, cancer.

Language: Английский

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Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression

The Journal of Cell Biology, Journal Year: 2010, Volume and Issue: 190(4), P. 693 - 706

Published: Aug. 23, 2010

Tissue stiffening is a hallmark of fibrotic disorders but has traditionally been regarded as an outcome fibrosis, not contributing factor to pathogenesis. In this study, we show that fibrosis induced by bleomycin injury in the murine lung locally increases median tissue stiffness sixfold relative normal parenchyma. Across pathophysiological range, cultured fibroblasts transition from surprisingly quiescent state progressive proliferation and matrix synthesis, accompanied coordinated decreases proteolytic gene expression. Increasing strongly suppresses fibroblast expression COX-2 (cyclooxygenase-2) synthesis prostaglandin E(2) (PGE(2)), autocrine inhibitor fibrogenesis. Exogenous PGE(2) or agonist prostanoid EP2 receptor completely counteracts proliferative synthetic effects caused increased stiffness. Together, these results demonstrate dominant role for compliance, acting part through PGE(2), maintaining quiescence reveal feedback relationship between stiffening, suppression, activation promotes amplifies fibrosis.

Language: Английский

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Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis

AJP Lung Cellular and Molecular Physiology, Journal Year: 2014, Volume and Issue: 308(4), P. L344 - L357

Published: Dec. 13, 2014

Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix both cause and consequence of fibroblast activation. However, molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog drosophila Yki) transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), effectors Hippo pathway, key stiffness-regulated coordinators activation synthesis. YAP TAZ are prominently expressed but not healthy lung tissue, particularly pronounced nuclear expression spindle-shaped fibroblastic cells. In culture, accumulate nuclei fibroblasts grown on pathologically stiff matrices physiologically compliant matrices. Knockdown together vitro attenuates functions, including synthesis, contraction, proliferation, does so exclusively Profibrotic effects operate, part, through their target plasminogen activator inhibitor-1, regulated stiffness independent transforming growth factor-β signaling. Immortalized conditionally expressing active or mutant proteins overcome soft limitations promote when adoptively transferred to murine lung, demonstrating ability YAP/TAZ drive profibrotic response vivo. Together, these results mechanoactivated matrix-driven that amplifies sustains fibrosis.

Language: Английский

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LPA receptor signaling: pharmacology, physiology, and pathophysiology

Journal of Lipid Research, Journal Year: 2014, Volume and Issue: 55(7), P. 1192 - 1214

Published: March 19, 2014

Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions demonstrates medicinal relevance. LPA's functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors named LPA1–6 signal numerous effector pathways activated heterotrimeric proteins, including Gi/o, G12/13, Gq, Gs. LPA receptor-mediated effects have been described cell types model systems, both vitro vivo, gain- loss-of-function studies. studies revealed physiological pathophysiological influences on virtually every organ system developmental stage of an organism. include the nervous, cardiovascular, reproductive, pulmonary systems. Disturbances normal may contribute to range diseases, neurodevelopmental neuropsychiatric disorders, pain, cardiovascular disease, bone fibrosis, cancer, infertility, obesity. underscore potential receptor subtypes related mechanisms provide novel therapeutic targets. glycerophospholipid (molecular mass: 430–480 Da) acts as potent molecule cognate (GPCRs) adult processes involving all All molecules consist glycerol backbone connected phosphate head group commonly ester-linked acyl chain varied length saturation. various chemical forms derived from multiple sources, such membrane lipids (1van Meer G. Voelker D.R. Feigenson G.W. Membrane lipids: where they how behave.Nat. Rev. Mol. Cell Biol. 2008; 9: 112-124Crossref PubMed Scopus (3523) Google Scholar), exist bioactive ligands produce wide number responses (Fig. 1). In 1960s, smooth muscle blood pressure hinted bioactivity (2Vogt W. Pharamacologically active acidic phospholipids glycolipids.Biochem. Pharmacol. 1963; 12: 415-420Crossref Scholar, 3Sen S. Smeby R.R. Bumpus F.M. Antihypertensive effect isolated phospholipid.Am. J. Physiol. 1968; 214: 337-341Crossref (45) Scholar). later years, species were identified soy beans (4Tokumura A. Fukuzawa K. Tsukatani H. Effects synthetic natural lysophosphatidic acids arterial different animal species.Lipids. 1978; 13: 572-574Crossref (137) This raised intriguing questions regarding this lipid's mechanism action, which was then thought perturbation (5Blankley C.J. Kaplan H.R. Biologically drugs.Drug Develop. Res. 1984; 4: 351-372Crossref calcium chelation (6Pörn M.I. Akerman K.E. Slotte J.P. High-density lipoproteins induce rapid transient release Ca2+ cultured fibroblasts.Biochem. 1991; 279: 29-33Crossref second messenger (7Gerrard J.M. Kindom S.E. Peterson D.A. Peller Krantz White J.G. acids. Influence platelet aggregation intracellular flux.Am. Pathol. 1979; 96: 423-438PubMed (8Snyder F. Platelet-activating factor acetylated biologically cellular mediators.Am. 1990; 259: C697-C708Crossref cell-surface (9van Corven E.J. Groenink Jalink Eichholtz T. Moolenaar W.H. Lysophosphatidate-induced proliferation: identification dissection mediated proteins.Cell. 1989; 59: 45-54Abstract Full Text PDF (662) contending theories clarified upon cloning first lysophospholipid receptor, LPA1. GPCR previously known "ventricular zone (VZ) gene-1" because its enriched expression embryonic neuroproliferative layer cerebral cortex (10Hecht J.H. Weiner J.A. Post S.R. Chun Ventricu­lar gene-1 (vzg-1) encodes expressed neurogenic regions developing cortex.J. 1996; 135: 1071-1083Crossref 11Chun Hla Lynch K.R. Spiegel International Union Basic Clinical Pharmacology. LXXVIII. Lysophospholipid nomenclature.Pharmacol. 2010; 62: 579-587Crossref (228) The LPA1 led deorphanization other putative genes based sequence homology (12An Bleu Huang Hallmark O.G. Coughlin Goetzl Identification cDNAs encoding two for lysosphingolipids.FEBS Lett. 1997; 417: 279-282Crossref (236) 13An Characterization subtype human acid.J. Chem. 1998; 273: 7906-7910Abstract (479) 14Bandoh Aoki Hosono Kobayashi Murakami-Murofushi Tsujimoto M. Arai Inoue Molecular characterization G-protein-coupled EDG7, 1999; 274: 27776-27785Abstract (449) particularly "endothelial differentiation gene" (EDG) members (15Fukushima N. Ishii I. Contos J.J. receptors.Annu. Toxicol. 2001; 41: 507-534Crossref (313) Scholar) sphingosine 1-phosphate (S1P) significant between S1P1 underscored early reports EDG-1 (16Lee M.J. Thangada Liu C.H. Thompson B.D. stimulates low affinity agonist.J. 22105-22112Abstract (0) At time identification, only homologous cannabinoid CB1 (encoded CNR1) interacts with endogenous anandamide 2-arachidonoylglycerol (17Devane W.A. Hanus L. Breuer Pertwee R.G. Stevenson L.A. Griffin Gibson D. Mandelbaum Etinger Mechoulam R. Isolation structure brain constituent binds receptor.Science. 1992; 258: 1946-1949Crossref 18Sugiura Kondo Sukagawa Nakane Shinoda Itoh Yamashita Waku 2-Arachidonoylglycerol: possible ligand brain.Biochem. Biophys. Commun. 1995; 215: 89-97Crossref (1664) Two receptors, LPA2 LPA3, subsequently discovered shared past ten three additional (LPA4–6) (19Noguchi Shimizu p2y9/GPR23 acid, structurally distant Edg family.J. 2003; 278: 25600-25606Abstract (460) 20Kotarsky Boketoft Bristulf Nilsson N.E. Norberg Hansson Owman C. Sillard Leeb-Lundberg L.M. Olde B. activates GPR92, highly gastrointestinal lymphocytes.J. Exp. Ther. 2006; 318: 619-628Crossref (172) 21Lee C.W. Rivera Gardell Dubin A.E. GPR92 new G12/13- Gq-coupled increases cAMP, LPA5.J. 281: 23589-23597Abstract (350) 22Pasternack S.M. von Kugelgen Aboud K.A. Lee Y-A. Ruschendorf Voss Hillmer A.M. Molderings G.J. Franz Ramirez et al.G P2Y5 involved maintenance hair growth.Nat. Genet. 40: 329-334Crossref (301) 23Yanagida Masago Nakanishi Kihara Y. Hamano Tajima Taguchi p2y5/LPA6.J. 2009; 284: 17731-17741Abstract (182) P2Y purinergic family significantly sequences than LPA1–3, yet still bind mediate effects. current class A rhodopsin-like GPCRs (7-TM) domains. Every couples one or more four Gα proteins (G12/13, Gq/11, Gs) 1), resulting canonical downstream produces Other lysophospholipids, lysophosphatidylserine (LPS), lysophosphatidylinositol, lysophosphatidylethanolamine (LPE), some reported being evaluated involvement (24Makide Kitamura Sato Okutani Emerging mediators, lysophosphatidylserine, lysophosphatidylthreonine, lysophosphatidylglycerol.Prostaglandins Lipid Mediat. 89: 135-139Crossref (83) An important aspect biology differentially activate (25Kano Arima Ohgami analogs-attractive tools elucidation drug development.Curr. Med. 15: 2122-2131Crossref (32) finding has supported secondary readouts activity, direct confirmation classical binding difficult. There major LPA. pathway, precursor (phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine) can be converted their corresponding lysophospholipids lysophosphatidylcholine (LPC), LPS, LPE. platelets, occurs via phosphatidylserine-specific phospholipase A1 (PS-PLA1) secretory A2 (sPLA2) activity. plasma, LPC produced LCAT PLA1 either location, autotaxin (ATX) activity phosphatidic (PA) D diacylglycerol kinase. Then, PA directly PLA2 (26Aoki Okudaira production.Biochim. Acta. 1781: 513-518Crossref (294) Through separate mechanism, generated acylation glycerol-3-phosphate glycerophosphate acyltransferase phosphorylation monoacylglycerol kinase (27Bektas Payne S.G. Goparaju Milstien acylglycerol modulates cross talk EGFR prostate cancer cells.J. 2005; 169: 801-811Crossref (131) Additional LPA-producing also 28Pagès Simon M-F. Valet P. Saulnier-Blache J.S. synthesis release.Prostaglandins 64: 1-10Crossref (145) generation fashions (28Pagès Intracellular intermediate de novo biosynthesis complex glycerolipids, mono-, di-, triglycerides, well Extracellular (29Okudaira Yukiura Biological production autotaxin.Biochimie. 92: 698-706Crossref (120) Furthermore, report supporting transcription PPARγ exists, although it remains examined (30McIntyre T.M. Pontsler A.V. Silva A.R. St Hilaire Xu Hinshaw J.C. Zimmerman G.A. Hama al.Identification (LPA): transcellular PPARgamma agonist.Proc. Natl. Acad. Sci. USA. 100: 131-136Crossref (439) eukaryotic tissues examined. formation depends phospholipid, vary degree term most often refers 18:1 oleoyl-LPA (1-acyl-2-hydroxy-sn-glycero-3-phosphate), used laboratory species. However, there growing recognized systems (31Aoki Mechanisms production.Semin. Dev. 2004; 477-489Crossref (226) 32Sugiura Kishimoto Yoshioka Tokumura Hanahan D.J. Occurrence alkyl ether-linked analog rat comparison activities toward neural cells.Biochim. 1440: 194-204Crossref (88) observed concentrations spanning nanomolar micromolar levels. 0.1 μM plasma up 10 serum, over apparent Kd (23Yanagida 33Aoki Taira Takanezawa Kishi Mizuno Saku Serum pathways.J. 2002; 277: 48737-48744Abstract (327) 34Hosogaya Yatomi Nakamura Ohkawa Okubo Yokota Ohta Yamazaki Koike Ozaki Measurement concentration healthy subjects: strong correlation lysophospholipase activity.Ann. Clin. Biochem. 45: 364-368Crossref (54) 35Watanabe Ikeda Kume Tanaka Tomiya al.Both serum levels increased chronic hepatitis Gastroenterol. 2007; 616-623Crossref (142) 18:2, 20:4, 16:1, 16:0, abundant (36Sano Baker Virag Wada Igarashi Tigyi Multiple linked activation result blood.J. 21197-21206Abstract (211) 37Yatomi Masuda Suzuki al.Clinical introduction assays..in: Receptors Signaling Biochemistry. Wiley, Hoboken, NJ2013: 148-164Crossref (2) 38Scherer Schmitz Liebisch High-throughput analysis 1-phosphate, sphinganine samples liquid chromatography-tandem mass spectrometry.Clin. 55: 1218-1222Crossref (112) Aside blood, quantified variety species, tissues, fluids, tissue, cerebrospinal fluid (CSF), seminal fluid, urine, saliva, aqueous humor 36Sano 39Tokumura Harada Involvement plasma.Biochim. 1986; 875: 31-38Crossref (148) 40Eichholtz Fahrenfort phospholipid released platelets.Biochem. 1993; 291: 677-680Crossref (558) 41Tanaka Kakehi Prostatic phosphatase degrades plasma.FEBS 571: 197-204Crossref (91) 42Ma Uchida Nagai Ueda Evidence spinal cord nerve injury-induced neuropathic pain.J. 333: 540-546Crossref (56) 43Yung Y.C. Mutoh Lin M.E. Noguchi Choi J.W. Kingsbury M.A. initiate fetal hydrocephalus.Sci. Transl. 2011; 3: 99ra87Crossref (94) 44Tokumura Kikuchi Tsutsumi Watsky Lysophospholipids rabbit following corneal injury.Prostaglandins 2012; 97: 83-89Crossref (7) 45Liliom Guan Z. Tseng J.L. Desiderio D.M. Growth factor-like after injury.Am. C1065-C1074Crossref (Table Current methods detect indirect enzymatic assays (34Hosogaya TLC-GC, LC-MS, LC-MS/MS (46Smyth S.S. Cheng H-Y. Miriyala Panchatcharam Morris A.J. Roles physiology disease.Biochim. 563-570Crossref (87) 47Aaltonen Laitinen J.T. Lehtonen Quantification tissue chromatography-electrospray tandem spectrometry.J. Chromatogr. B Analyt. Technol. Biomed. Life 878: 1145-1152Crossref (23) 48Lee Nishiumi Yoshida Fukusaki E. Bamba Simultaneous profiling polar supercritical chromatography/tandem spectrometry methylation.J. 2013; 1279: 98-107Crossref (68) techniques predictive, diagnostic, uses 49Dohi Miyauchi Miyazaki Nishino Nakajima Yaginuma Tamura al.Increased circulating patients acute coronary syndrome.Clin. Chim. 413: 207-212Crossref (34) 50Ikeda Enooku Plasma hepatocellular carcinoma.Hepatology. 57: 417-418Crossref (5) Scholar).TABLE 1Summary fluidsTissues/FluidsLPALPCMethod MeasurementReferencesPhysiological conditionsEmbryonic brain0.32–0.35 pmol/mgaValues nonhuman organisms.Not availableLC-MS(43Yung Scholar)Adult brain3.7–35 availableGC-MS, LC-MS/MS(32Sugiura 339Aaltonen Varonen Goterris inhibitors locally amplify signalling cryosections without affecting global degradation.BMC 7Crossref (12) 340Nakane Oka Ishima Sugiura 2-Arachidonoyl-sn-glycero-3-phosphate, arachidonic acid-containing acid: occurrence conversion 2-arachidonoyl-sn-glycerol, ligand, brain.Arch. 402: 51-58Crossref (74) Scholar)Nerve (spinal cord)0.79 availableB103 bioassay(42Ma Scholar)Plasma0.7 μMbValues humans./0.17–0.63 μMaValues organisms.100-140 humans./440 organisms.LC-MS, RH7777 bioassay(38Scherer 239Tokumura Carbone L.D. Morishige Postlethwaite Elevated arachidonoyl-lysophosphatidic sphingosine-1-phosphate systemic sclerosis.Int. 6: 168-176Crossref 299Yamada Komachi Malchinkhuu Tobo Kimura Kuwabara Yanagita Ikeya Tanahashi al.Lysophosphatidic malignant ascites motility pancreatic cells LPA1.J. 6595-6605Abstract (151) 341Barber M.N. Risis Yang Meikle P.J. Staples Febbraio Bruce C.R. reduced obesity type 2 diabetes.PLoS ONE. 7: e41456Crossref (183) Scholar)Serum4–15.5 humans.234 humans.TLC-GC, assay, LC-MS/MS(166Tokumura Miyake Nishioka Yamano Aono Production follicular fluids fertilization patients.Biol. Reprod. 61: 195-199Crossref (111) 342Kishimoto Soda Matsuyama assay plasma.Clin. 35: 411-416Crossref (71) 343Cho Park Y.Y. Huh Lim C.M. Koh Song D.K. Hong S.B. significance (LPC) data sepsis.Eur. Microbiol. Infect. Dis. 31: 1805-1810Crossref Scholar)CSF0.025–0.2 pMaValues detectedaValues organisms.RH7777 bioassay(344Sato Muraki Ishikawa Hayashi Tosaka Mochiduki Tomura Mogi neurite retraction-inducing PC12 sources.J. Neurochem. 904-914Crossref (62) Scholar)Seminal fluidNegligible8–19 humans.RH7777 bioassay, cycling(41Tanaka Scholar)Saliva0.785 nMbValues humans.Not availableFAB-MS(345Sugiura growth lipid, saliva.J. 43: 2049-2055Abstract (89) Scholar)Lacrimal gland fluid1.3 availableMS(45Liliom Scholar)Aqueous humor0.2 Scholar)Follicular fluid25.3 humans.157 humans.TLC-GC(166Tokumura Scholar)Ascites0.62 availableRH7777 bioassay(299Yamada Scholar)Fertilized hen white8.0-9.6 availableLC-MS(179Morishige Uto Hori Satouchi Yoshiomoto egg white induces vascular development extraembryonic membranes.Lipids. 48: 251-262Crossref Scholar)Pathophysiological conditionsNerve (injury)74.8 injury-i

Language: Английский

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Therapy for Fibrotic Diseases: Nearing the Starting Line

Science Translational Medicine, Journal Year: 2013, Volume and Issue: 5(167)

Published: Jan. 9, 2013

An emerging consensus indicates that fibrotic diseases in lung, liver, and kidney exhibit common underlying mechanisms, which can be targeted therapeutically.

Language: Английский

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Pathogenetic mechanisms in radiation fibrosis

Radiotherapy and Oncology, Journal Year: 2010, Volume and Issue: 97(1), P. 149 - 161

Published: Sept. 30, 2010

Language: Английский

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Lipid Mediators in Health and Disease: Enzymes and Receptors as Therapeutic Targets for the Regulation of Immunity and Inflammation

The Annual Review of Pharmacology and Toxicology, Journal Year: 2008, Volume and Issue: 49(1), P. 123 - 150

Published: Oct. 3, 2008

Prostaglandins, leukotrienes, platelet-activating factor, lysophosphatidic acid, sphingosine 1-phosphate, and endocannabinoids, collectively referred to as lipid mediators, play pivotal roles in immune regulation self-defense, the maintenance of homeostasis living systems. They are produced by multistep enzymatic pathways, which initiated de-esterification membrane phospholipids phospholipase A2s or sphingo-myelinase. Lipid mediators exert their biological effects binding cognate receptors, members G protein–coupled receptor superfamily. The synthesis subsequent induction activity is tightly regulated under normal physiological conditions, enzyme and/or dysfunction can lead a variety disease conditions. Thus, manipulation mediator signaling, through either inhibitors antagonists agonists, has great potential therapeutic approach disease. In this review, I summarize our current state knowledge function discuss genetic pharmacological ablation on various pathophysiological processes.

Language: Английский

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Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: April 21, 2020

Collagen-producing cells maintain the complex architecture of lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all collagen-producing normal fibrotic lungs. We characterize multiple subpopulations with distinct anatomical localizations different compartments murine One subpopulation, characterized by expression Cthrc1 (collagen triple helix repeat containing 1), emerges lungs expresses highest levels collagens. Single-cell human lungs, including those from idiopathic fibrosis scleroderma patients, demonstrate similar heterogeneity CTHRC1-expressing fibroblasts present uniquely Immunostaining situ hybridization show that these are concentrated within fibroblastic foci. purify find disease-relevant phenotypes Cthrc1-expressing vitro adoptive transfer experiments. Our atlas provides a roadmap for studying roles unique populations homeostasis

Language: Английский

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