mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts.
mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts.
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MTORC1激活减少了衰老和特发性肺纤维化的自噬，并有助于IPF成纤维细胞的凋亡抗性。
DOI：
10.1111/acel.12514
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发表时间：
2016-12
期刊：
影响因子：
7.8
通讯作者：
Pardo A
中科院分区：
文献类型：
--
作者：
Romero Y;Bueno M;Ramirez R;Álvarez D;Sembrat JC;Goncharova EA;Rojas M;Selman M;Mora AL;Pardo A
特发性肺纤维化（IPF）是一种慢性、进行性且通常致命的与衰老相关的疾病。然而，导致IPF发病机制的衰老过程的分子机制尚未阐明。IPF的特征在于大量高活性成纤维细胞和抗凋亡的肌成纤维细胞灶。值得注意的是，在肺成纤维细胞的自噬活性及其与细胞凋亡的关系，作为适应性反应，老化的作用，以前没有在这种疾病中进行评估。在本研究中，我们分析了IPF的原代肺成纤维细胞与年轻和年龄匹配的正常肺成纤维细胞相比的自噬动力学。我们的研究结果表明，衰老有助于在基础条件下和饥饿条件下诱导较低的自噬，这是由mTOR通路激活介导的。用靶向PI 3 K/AKT/mTOR信号通路的雷帕霉素和PP 242治疗，改变了IPF成纤维细胞中饥饿诱导的自噬和凋亡。有趣的是，我们发现饥饿条件下该途径的持续激活有助于IPF成纤维细胞的凋亡抗性。这些发现表明，衰老通过激活肺成纤维细胞中的mTORC 1来影响对压力的适应性反应，从而减少自噬。该途径的激活也有助于IPF肺成纤维细胞对细胞死亡的抵抗。
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal disease associated with aging. However, the molecular mechanisms of the aging process that contribute to the pathogenesis of IPF have not been elucidated. IPF is characterized by abundant foci of highly active fibroblasts and myofibroblasts resistant to apoptosis. Remarkably, the role of aging in the autophagy activity of lung fibroblasts and its relationship with apoptosis, as adaptive responses, has not been evaluated previously in this disease. In the present study, we analyzed the dynamics of autophagy in primary lung fibroblasts from IPF compared to young and age‐matched normal lung fibroblasts. Our results showed that aging contributes for a lower induction of autophagy on basal conditions and under starvation which is mediated by mTOR pathway activation. Treatment with rapamycin and PP242, that target the PI3K/AKT/mTOR signaling pathway, modified starvation‐induced autophagy and apoptosis in IPF fibroblasts. Interestingly, we found a persistent activation of this pathway under starvation that contributes to the apoptosis resistance in IPF fibroblasts. These findings indicate that aging affects adaptive responses to stress decreasing autophagy through activation of mTORC1 in lung fibroblasts. The activation of this pathway also contributes to the resistance to cell death in IPF lung fibroblasts.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
30.8
作者：
Fingerlin, Tasha E.;Murphy, Elissa;Zhang, Weiming;Peljto, Anna L.;Brown, Kevin K.;Steele, Mark P.;Loyd, James E.;Cosgrove, Gregory P.;Lynch, David;Groshong, Steve;Collard, Harold R.;Wolters, Paul J.;Bradford, Williamson Z.;Kossen, Karl;Seiwert, Scott D.;du Bois, Roland M.;Garcia, Christine Kim;Devine, Megan S.;Gudmundsson, Gunnar;Isaksson, Helgi J.;Kaminski, Naftali;Zhang, Yingze;Gibson, Kevin F.;Lancaster, Lisa H.;Cogan, Joy D.;Mason, Wendi R.;Maher, Toby M.;Molyneaux, Philip L.;Wells, Athol U.;Moffatt, Miriam F.;Selman, Moises;Pardo, Annie;Kim, Dong Soon;Crapo, James D.;Make, Barry J.;Regan, Elizabeth A.;Walek, Dinesha S.;Daniel, Jerry J.;Kamatani, Yoichiro;Zelenika, Diana;Smith, Keith;McKean, David;Pedersen, Brent S.;Talbert, Janet;Kidd, Raven N.;Markin, Cheryl R.;Beckman, Kenneth B.;Lathrop, Mark;Schwarz, Marvin I.;Schwartz, David A.
通讯作者：
Schwartz, David A.
影响因子：
21.3
作者：
通讯作者：
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DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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