Crosstalk between calpain activation and TGF-β1 augments collagen-I synthesis in pulmonary fibrosis
Crosstalk between calpain activation and TGF-β1 augments collagen-I synthesis in pulmonary fibrosis
复制标题
钙蛋白酶激活和 TGF-β1 之间的串扰增强了肺纤维化中胶原蛋白 I 的合成。
DOI：
10.1016/j.bbadis.2015.06.008
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发表时间：
2015-09-01
影响因子：
6.2
通讯作者：
Ye, Hong
中科院分区：
文献类型：
--
作者：
Li, Feng-Zhi;Cai, Peng-Cheng;Ye, Hong
特发性肺纤维化（IPF）是一种原因不明的慢性进行性肺部疾病，通常在诊断后3-5年内导致呼吸衰竭和死亡。tgf - 1被认为是一种主要的促纤维化因子。然而，tgf - β 1在肺纤维化病变的发病机制中是必要的，但不是充分的。最近的观察表明，钙蛋白酶在组织重塑和纤维化中起着关键作用。然而，钙蛋白酶介导肺纤维化的机制尚不清楚。本研究使用Calpain条件敲除(ER-Cre（+/-)capns1(flox/flox)）小鼠和原代人肺成纤维细胞（HLFs）来研究Calpain和tgf - β 1之间的关系。Calpain基因敲除小鼠不受博来霉素的纤维化作用。博莱霉素通过激活hlf中的calpain诱导tgf - β 1升高。此外，tgf - β 1也激活钙蛋白酶。calpain活化和tgf - β 1之间的这种串扰触发了下游信号通路，包括tgf - β 1 Smad2/3和非smad （Akt）通路，以及胶原- i合成。综上所述，我们的数据表明，calpain激活和tgf - β 1之间的串扰增强了hlf和肺纤维化中胶原- 1的合成。干预钙蛋白酶激活和tgf - β 1之间的串扰是预防肺纤维化的一种新的潜在策略。(C) 2015年作者。Elsevier B.V.出版
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause that typically leads to respiratory failure and death within 3-5 years of diagnosis. TGF-beta 1 is considered a major profibrotic factor. However, TGF-beta 1 is necessary but not sufficient to the pathogenesis of fibrotic lesion of the lungs. Recent observations have revealed that calpain, a calcium dependent protease, plays a pivotal role in tissue remodeling and fibrosis. However, the mechanism of calpain mediating pulmonary fibrosis is not understood. Calpain conditional knockout (ER-Cre(+/-)capns1(flox/flox)) mice and primary human lung fibroblasts (HLFs) were used here to investigate the relationship between calpain and TGF-beta 1. Calpain knockout mice were protected from fibrotic effects of bleomycin. Bleomycin induced increases in TGF-beta 1 via calpain activation in HLFs. Moreover, TGF-beta 1 also activated calpain. This crosstalk between calpain activation and TGF-beta 1 triggered the downstream signaling pathway including TGF-beta 1 Smad2/3 and non-Smad (Akt) pathways, as well as collagen-I synthesis. Taken together, our data indicate that the crosstalk between calpain activation and TGF-beta 1 augments collagen-I synthesis in HLFs and in pulmonary fibrosis. Intervention in the crosstalk between calpain activation and TGF-beta 1 is a novel potential strategy to prevent pulmonary fibrosis. (C) 2015 The Authors. Published by Elsevier B.V.