It takes two peroxisome proliferator-activated receptors (PPAR-β/δ and PPAR-γ) to tango idiopathic pulmonary fibrosis.

Autor: Boateng E; Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, 35392, Giessen, Germany.; Department of Medical Education, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, 43614, USA., Bonilla-Martinez R; Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, 35392, Giessen, Germany., Ahlemeyer B; Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, 35392, Giessen, Germany., Garikapati V; Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, 35392, Giessen, Germany.; Institute of Inorganic and Analytical Chemistry, Justus Liebig University, 35392, Giessen, Germany.; Max Planck Institute of Molecular Cell Biology and Genetics, 01307, Dresden, Germany., Alam MR; Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, 35392, Giessen, Germany., Trompak O; Department of Internal Medicine VIII, Eberhard Karls University, 72076, Tübingen, Germany., Oruqaj G; Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, 35392, Giessen, Germany.; Department of Internal Medicine II, Member of the German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University, 35392, Giessen, Germany., El-Merhie N; Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, 35392, Giessen, Germany.; Institute for Lung Health (ILH), Member of the German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University, 35392, Giessen, Germany., Seimetz M; Excellence Cluster Cardio-Pulmonary System, German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center, 35392, Giessen, Germany., Ruppert C; Excellence Cluster Cardio-Pulmonary System, German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center, 35392, Giessen, Germany.; UGMLC Giessen Biobank, Universities of Giessen and Marburg Lung Center, 35392, Giessen, Germany., Günther A; Excellence Cluster Cardio-Pulmonary System, German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center, 35392, Giessen, Germany.; Center for Interstitial and Rare Lung Diseases, Department of Internal Medicine, German Center for Lung Research, Universities of Giessen and Marburg Lung Center, 35392, Giessen, Germany., Spengler B; Institute of Inorganic and Analytical Chemistry, Justus Liebig University, 35392, Giessen, Germany., Karnati S; Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, 35392, Giessen, Germany.; Institute for Anatomy and Cell Biology, Julius Maximilians University, 97070, Würzburg, Germany., Baumgart-Vogt E; Institute for Anatomy and Cell Biology, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, 35392, Giessen, Germany. Eveline.Baumgart-Vogt@anatomie.med.uni-giessen.de.
Jazyk: angličtina
Zdroj: Respiratory research [Respir Res] 2024 Sep 23; Vol. 25 (1), pp. 345. Date of Electronic Publication: 2024 Sep 23.
DOI: 10.1186/s12931-024-02935-7
Abstrakt: Background: Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung epithelial phenotypes, fibroblast activation, and increased extracellular matrix deposition. Transforming growth factor-beta (TGF-β)1-induced Smad signaling and downregulation of peroxisomal genes are involved in the pathogenesis and can be inhibited by peroxisome proliferator-activated receptor (PPAR)-α activation. However, the three PPARs, that is PPAR-α, PPAR-β/δ, and PPAR-γ, are known to interact in a complex crosstalk.
Methods: To mimic the pathogenesis of lung fibrosis, primary lung fibroblasts from control and IPF patients with comparable levels of all three PPARs were treated with TGF-β1 for 24 h, followed by the addition of PPAR ligands either alone or in combination for another 24 h. Fibrosis markers (intra- and extracellular collagen levels, expression and activity of matrix metalloproteinases) and peroxisomal biogenesis and metabolism (gene expression of peroxisomal biogenesis and matrix proteins, protein levels of PEX13 and catalase, targeted and untargeted lipidomic profiles) were analyzed after TGF-β1 treatment and the effects of the PPAR ligands were investigated.
Results: TGF-β1 induced the expected phenotype; e.g. it increased the intra- and extracellular collagen levels and decreased peroxisomal biogenesis and metabolism. Agonists of different PPARs reversed TGF-β1-induced fibrosis even when given 24 h after TGF-β1. The effects included the reversals of (1) the increase in collagen production by repressing COL1A2 promoter activity (through PPAR-β/δ activation); (2) the reduced activity of matrix metalloproteinases (through PPAR-β/δ activation); (3) the decrease in peroxisomal biogenesis and lipid metabolism (through PPAR-γ activation); and (4) the decrease in catalase protein levels in control (through PPAR-γ activation) and IPF (through a combined activation of PPAR-β/δ and PPAR-γ) fibroblasts. Further experiments to explore the role of catalase showed that an overexpression of catalase protein reduced collagen production. Additionally, the beneficial effect of PPAR-γ but not of PPAR-β/δ activation on collagen synthesis depended on catalase activity and was thus redox-sensitive.
Conclusion: Our data provide evidence that IPF patients may benefit from a combined activation of PPAR-β/δ and PPAR-γ.
(© 2024. The Author(s).)
Databáze: MEDLINE
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