title: A novel profibrotic mechanism mediated by TGFβ-stimulated collagen prolyl hydroxylase expression in fibrotic lung mesenchymal cells.
abstract: Idiopathic pulmonary fibrosis is a severe chronic lung disease with a high mortality rate. Excessive TGFβ signalling is recognized as a central player in lung fibrosis. However, the related mechanisms remain unclear. Herein we used a novel Tbx4 lung enhancer-driven Tet-On transgenic system to inhibit TGFβ signalling in mouse lung-resident mesenchymal cells at different stages of bleomycin-induced fibrosis, by conditionally knocking out TGFβ receptor II or expressing a dominant-negative TGFβ receptor II. Abrogation of mesenchymal TGFβ signalling markedly attenuated bleomycin-induced fibrotic pathology, which was independent of altered early inflammation. Furthermore, a novel TGFβ downstream target gene P4HA3 (an α-subunit of collagen prolyl hydroxylase) was identified, and its expression was significantly increased in fibroblastic foci of both bleomycin-induced fibrotic mouse lungs and idiopathic pulmonary fibrosis patients' lungs. The relationship between activated TGFβ signalling, up-regulation of P4HA3 and increased hydroxyproline/collagen production was further verified in cultured lung fibroblasts. Moreover, inhibition of collagen prolyl hydroxylase by pyridine-2,5-dicarboxylate attenuated TGFβ-stimulated collagen production in both cultured fibroblasts and bleomycin-induced mouse lung fibrosis. These data indicate that increased expression and activity of collagen prolyl hydroxylase is one of the important mechanisms underlying TGFβ-mediated profibrotic effects. Inhibition of collagen prolyl hydroxylase may be a new, promising approach for preventing and treating pulmonary fibrosis.
authors.affiliation: Saban Research Institute, Children's Hospital, Los Angeles, CA, USA.|Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Saban Research Institute, Children's Hospital, Los Angeles, CA, USA.|Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Saban Research Institute, Children's Hospital, Los Angeles, CA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Saban Research Institute, Children's Hospital, Los Angeles, CA, USA.|Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.affiliation: Saban Research Institute, Children's Hospital, Los Angeles, CA, USA.|Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dong
authors.affiliation: Department of Spine Surgery, Nanjing Drum Tower Hospital, Nanjing, People's Republic of China.
authors.forename: Bangping
authors.initials: B
authors.lastname: Qian
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias 'Ismael Cosío Villegas', México, DF, México.
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Kolb
authors.affiliation: Saban Research Institute, Children's Hospital, Los Angeles, CA, USA.|Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
mesh_terms: D000368:Aged; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D055786:Gene Knockout Techniques; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D064828:Prolyl Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D001761:Bleomycin; D003094:Collagen; D064828:Prolyl Hydroxylases
keywords: TGFβ signalling; collagen prolyl hydroxylase; lung mesenchymal cells; pulmonary fibrosis