A novel profibrotic mechanism mediated by TGFβ-stimulated collagen prolyl hydroxylase expression in fibrotic lung mesenchymal cells.
A novel profibrotic mechanism mediated by TGFβ-stimulated collagen prolyl hydroxylase expression in fibrotic lung mesenchymal cells.
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DOI：
10.1002/path.4530
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发表时间：
2015-07
影响因子：
7.3
通讯作者：
Shi, Wei
中科院分区：
文献类型：
--
作者：
Luo, Yongfeng;Xu, Wei;Chen, Hui;Warburton, David;Dong, Rachel;Qian, Bangping;Selman, Moises;Gauldie, Jack;Kolb, Martin;Shi, Wei
Idiopathic pulmonary fibrosis is a severe chronic lung disease with a high mortality rate. Excessive TGF-β signaling 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 TGF-β signaling in mouse lung resident mesenchymal cells at different stages of bleomycin-induced fibrosis by conditionally knocking out TGF-β receptor II or expressing a dominant-negative TGF-β receptor II. Abrogation of mesenchymal TGF-β signaling markedly attenuated bleomycin-induced fibrotic pathology, which was independent of altered early inflammation. Furthermore, a novel TGF-β 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 TGF-β signaling, upregulation of P4HA3, as well as increased hydroxyproline/collagen production was further verified in cultured lung fibroblasts. Moreover, inhibition of collagen prolyl hydroxylase by pyridine-2,5-dicarboxylate attenuated both TGF-β-stimulated collagen production in 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 TGF-β-mediated profibrotic effects. Inhibition of collagen prolyl hydroxylase may be a new promising approach for preventing and treating pulmonary fibrosis.
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影响因子：
1.5
作者：
Chytil, A;Magnuson, MA;Moses, HL
通讯作者：
Moses, HL
DOI：
10.1183/09031936.00011810
发表时间：
2010-10
期刊：
The European respiratory journal
影响因子：
--
作者：
Tarantal AF;Chen H;Shi TT;Lu CH;Fang AB;Buckley S;Kolb M;Gauldie J;Warburton D;Shi W
通讯作者：
Shi W
DOI：
10.1152/ajplung.00298.2004
发表时间：
2005-04-01
影响因子：
4.9
作者：
Chen, H;Sun, JP;Shi, W
通讯作者：
Shi, W
影响因子：
37.8
作者：
Van den Diepstraten, C;Papay, K;Pickering, JG
通讯作者：
Pickering, JG
影响因子：
1.5
作者：
Frugier, T;Koishi, K;McLennan, IS
通讯作者：
McLennan, IS