title: Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-β signaling.
abstract: Idiopathic pulmonary fibrosis (IPF) is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces liver fibrosis. However, altered peroxisome functions in IPF pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and IPF patients, we found that IPF lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism (e.g., PEX13p and acyl-CoA oxidase 1). Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta (TGF-β) receptor II knockout mice indicating a role for TGF-β signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of IPF fibroblasts with the profibrotic factors TGF-β1 or tumor necrosis factor alpha (TNF-α) was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced fibrosis were further studied. Direct down-regulation of PEX13 by RNAi induced the activation of Smad-dependent TGF-β signaling accompanied by increased ROS production and resulted in the release of cytokines (e.g., IL-6, TGF-β) and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-α activators, led to peroxisome proliferation and reduced the TGF-β-induced myofibroblast differentiation and collagen protein in IPF cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of IPF and fibrosis progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.
authors.affiliation: Institute for Anatomy and Cell Biology, Medical Cell Biology, Justus Liebig University, Giessen 35392, Germany;
authors.forename: Gani
authors.initials: G
authors.lastname: Oruqaj
authors.affiliation: Institute for Anatomy and Cell Biology, Medical Cell Biology, Justus Liebig University, Giessen 35392, Germany;
authors.forename: Srikanth
authors.initials: S
authors.lastname: Karnati
authors.affiliation: Institute for Anatomy and Cell Biology, Medical Cell Biology, Justus Liebig University, Giessen 35392, Germany;
authors.forename: Vijith
authors.initials: V
authors.lastname: Vijayan
authors.affiliation: Institute for Anatomy and Cell Biology, Medical Cell Biology, Justus Liebig University, Giessen 35392, Germany;
authors.forename: Lakshmi Kanth
authors.identifier: http://orcid.org/0000-0002-5393-1736
authors.initials: LK
authors.lastname: Kotarkonda
authors.affiliation: Institute for Anatomy and Cell Biology, Medical Cell Biology, Justus Liebig University, Giessen 35392, Germany;
authors.forename: Eistine
authors.initials: E
authors.lastname: Boateng
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027; and.
authors.forename: Wenming
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Deparment of Internal Medicine, Medical Clinic II, and German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center, Giessen 35392, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Ruppert
authors.affiliation: Deparment of Internal Medicine, Medical Clinic II, and German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center, Giessen 35392, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Institute for Anatomy and Cell Biology, Medical Cell Biology, Justus Liebig University, Giessen 35392, Germany; Eveline.Baumgart-Vogt@anatomie.med.uni-giessen.de.
authors.forename: Eveline
authors.initials: E
authors.lastname: Baumgart-Vogt
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D050356:Lipid Metabolism; D008168:Lung / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008954:Models, Biological; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D018836:Inflammation Mediators; D015850:Interleukin-6; D008565:Membrane Proteins; C101884:PEX13 protein, human; D047493:PPAR alpha; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051785:Smad Proteins; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha
keywords: TGF-β1; fibrosis; inflammation; lung; peroxisome
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