Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis.
Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis.
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DOI：
10.1016/j.exger.2014.11.018
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发表时间：
2015-01
影响因子：
3.9
通讯作者：
Liu, Rui-Ming
中科院分区：
文献类型：
--
作者：
Huang, Wen-Tan;Akhter, Hasina;Jiang, Chunsun;MacEwen, Mark;Ding, Qiang;Antony, Veena;Thannickal, Victor John;Liu, Rui-Ming
特发性肺纤维化(IPF)是一种病因不明、无有效治疗方法的致命性肺部疾病。IPF的发病率和死亡率随着年龄的增长而增加，提示高龄是IPF的主要危险因素。然而，老年人对IPF易感性增加的机制尚不清楚。在本研究中，我们首次发现纤溶酶原激活物抑制物1(PAI-1)在小鼠肺组织匀浆和肺成纤维细胞中的蛋白水平随着年龄的增长而显著增加。博莱霉素刺激后，老年小鼠与年轻小鼠相比，PAI-1诱导增强和肺纤维化。最有趣的是，我们发现在博莱霉素攻击后，老年小鼠肺中PAI-1水平升高的(Myo)成纤维细胞比年轻小鼠更少(Myo)成纤维细胞发生凋亡，而(Myo)成纤维细胞更多(Myo)。体外研究进一步证明，与青年鼠肺成纤维细胞相比，老年小鼠肺成纤维细胞能抵抗过氧化氢和肿瘤坏死因子α诱导的细胞凋亡，并增强对转化生长因子-β1的纤维化反应。另一方面，用PAI-1抑制剂抑制PAI-1活性，消除了与衰老相关的细胞凋亡抵抗和对转化生长因子-β1的敏感性。此外，我们还发现，用PAI-1siRNA抑制人肺成纤维细胞对PAI-1的表达可显著提高其对凋亡的敏感性，并抑制其对转化生长因子-β-1的反应。
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder with unknown cause and no effective treatment. The incidence of and mortality from IPF increase with age, suggesting that advanced age is a major risk factor for IPF. The mechanism underlying the increased susceptibility of the elderly to IPF, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 (PAI-1), a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung fibrosis as compared to young mice. Most interestingly, we show that fewer (myo)fibroblasts underwent apoptosis and more (myo)fibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-β1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-β1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-β1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung fibrosis in part by protecting fibroblasts from apoptosis.
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影响因子：
15.9
作者：
Eitzman, DT;McCoy, RD;Simon, RH
通讯作者：
Simon, RH
影响因子：
6
作者：
Chuang-Tsai, S;Sisson, TH;Simon, RH
通讯作者：
Simon, RH
影响因子：
7.3
作者：
Boucher J;Macotela Y;Bezy O;Mori MA;Kriauciunas K;Kahn CR
通讯作者：
Kahn CR
影响因子：
3.1
作者：
Cesari M;Pahor M;Incalzi RA
通讯作者：
Incalzi RA
影响因子：
3.3
作者：
Huang, Kewu;Mitzner, Wayne;Tankersley, Clarke G.
通讯作者：
Tankersley, Clarke G.