Lipopolysaccharide induces lung fibroblast proliferation through Toll-like receptor 4 signaling and the phosphoinositide3-kinase-Akt pathway.
Lipopolysaccharide induces lung fibroblast proliferation through Toll-like receptor 4 signaling and the phosphoinositide3-kinase-Akt pathway.
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脂多糖通过 Toll 样受体 4 信号传导和磷酸肌醇 3-激酶-Akt 途径诱导肺成纤维细胞增殖
DOI：
10.1371/journal.pone.0035926
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
He Z;Gao Y;Deng Y;Li W;Chen Y;Xing S;Zhao X;Ding J;Wang X
肺纤维化的特征是肺成纤维细胞增殖和胶原蛋白分泌。在脂多糖（LPS）诱导的急性肺损伤（ALI）中，疾病早期就开始出现肺成纤维细胞的异常增殖，但其潜在机制仍不明确。在本研究中，我们使用TLR4 - 小干扰RNA（siRNA）慢病毒敲低培养的小鼠肺成纤维细胞中Toll样受体4（TLR4）的表达，以研究LPS刺激对肺成纤维细胞增殖、磷酸肌醇3 - 激酶（PI3K）-Akt通路激活以及磷酸酶和张力蛋白同源物（PTEN）表达的影响。通过BrdU检测发现，在长达24小时内，1微克/毫升的LPS刺激对肺成纤维细胞增殖没有影响，但在72小时时，细胞增殖显著增加。这种增殖可被siRNA介导的TLR4敲低或PI3K抑制剂Ly294002处理所抑制。此外，通过实时荧光定量PCR和蛋白质免疫印迹分析检测发现，siRNA介导的TLR4敲低可抑制LPS在72小时时诱导的TLR4上调、PTEN下调以及PI3K - Akt通路的激活（磷酸化Akt过表达）。用PTEN抑制剂bpV（phen）处理可导致PI3K - Akt通路激活。肺成纤维细胞中PTEN的基础表达以及LPS诱导的PTEN下调均不受PI3K激活状态的影响。抑制PTEN足以发挥LPS对肺成纤维细胞增殖的作用，而抑制PI3K - Akt通路则可逆转这一过程。综上所述，这些结果表明，LPS可通过一种涉及PTEN表达下调和PI3K - Akt通路激活的TLR4信号机制促进肺成纤维细胞增殖。此外，PI3K - Akt通路激活是PTEN抑制的下游效应，在肺成纤维细胞增殖中起关键作用。这一机制可能在ALI/ARDS早期促成并有可能加速肺纤维化进程。
Pulmonary fibrosis is characterized by lung fibroblast proliferation and collagen secretion. In lipopolysaccharide (LPS)-induced acute lung injury (ALI), aberrant proliferation of lung fibroblasts is initiated in early disease stages, but the underlying mechanism remains unknown. In this study, we knocked down Toll-like receptor 4 (TLR4) expression in cultured mouse lung fibroblasts using TLR4-siRNA-lentivirus in order to investigate the effects of LPS challenge on lung fibroblast proliferation, phosphoinositide3-kinase (PI3K)-Akt pathway activation, and phosphatase and tensin homolog (PTEN) expression. Lung fibroblast proliferation, detected by BrdU assay, was unaffected by 1 mug/mL LPS challenge up to 24 hours, but at 72 hours, cell proliferation increased significantly. This proliferation was inhibited by siRNA-mediated TLR4 knockdown or treatment with the PI3K inhibitor, Ly294002. In addition, siRNA-mediated knockdown of TLR4 inhibited the LPS-induced up-regulation of TLR4, down-regulation of PTEN, and activation of the PI3K-Akt pathway (overexpression of phospho-Akt) at 72 hours, as detected by real-time PCR and Western blot analysis. Treatment with the PTEN inhibitor, bpV(phen), led to activation of the PI3K-Akt pathway. Neither the baseline expression nor LPS-induced down-regulation of PTEN in lung fibroblasts was influenced by PI3K activation state. PTEN inhibition was sufficient to exert the LPS effect on lung fibroblast proliferation, and PI3K-Akt pathway inhibition could reverse this process. Collectively, these results indicate that LPS can promote lung fibroblast proliferation via a TLR4 signaling mechanism that involves PTEN expression down-regulation and PI3K-Akt pathway activation. Moreover, PI3K-Akt pathway activation is a downstream effect of PTEN inhibition and plays a critical role in lung fibroblast proliferation. This mechanism could contribute to, and possibly accelerate, pulmonary fibrosis in the early stages of ALI/ARDS.
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影响因子：
5
作者：
Gutierrez-Venegas, Gloria;Kawasaki-Cardenas, Perla;Maldonado-Frias, Silvia
通讯作者：
Maldonado-Frias, Silvia
影响因子：
15.9
作者：
CHEN, B;POLUNOVSKY, V;BITTERMAN, P
通讯作者：
BITTERMAN, P
DOI：
10.1006/bbrc.1997.7680
发表时间：
1997-11-17
影响因子：
3.1
作者：
Chakravortty, D;Kumar, KSN
通讯作者：
Kumar, KSN
影响因子：
5.6
作者：
Churg, Andrew;Mueller, Nestor L.;Wright, Joanne L.
通讯作者：
Wright, Joanne L.
DOI：
10.1097/00005373-198907000-00011
发表时间：
1989-07-01
影响因子：
--
作者：
BANKEY, P;FIEGEL, V;CERRA, F
通讯作者：
CERRA, F