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.
Original language | English (US) |
---|---|
Pages (from-to) | 384-394 |
Number of pages | 11 |
Journal | Journal of Pathology |
Volume | 236 |
Issue number | 3 |
DOIs | |
State | Published - Jul 1 2015 |
Keywords
- TGFβ signalling
- collagen prolyl hydroxylase
- lung mesenchymal cells
- pulmonary fibrosis
ASJC Scopus subject areas
- Pathology and Forensic Medicine