Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGFβ1.
Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGFβ1.
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DOI：
10.1111/acel.12357
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发表时间：
2015-10
期刊：
影响因子：
7.8
通讯作者：
Sanchez CG
中科院分区：
文献类型：
--
作者：
Sosulski ML;Gongora R;Danchuk S;Dong C;Luo F;Sanchez CG
衰老是纤维化的一个重要危险因素，特发性肺纤维化（IPF）通常与年龄增长相关。我们认为，年龄依赖性的蛋白质质量和细胞器分解代谢缺陷可能与肺纤维化有因果关系。我们的研究发现，与年轻动物相比，老年小鼠和中年小鼠的肺损伤导致自噬减少，氧化蛋白和脂褐素水平相应升高。更重要的是，遭受肺损伤的老年小鼠的特点是自噬反应不足，并且自噬对线粒体的选择性靶向减少（线粒体自噬）。成纤维细胞向肌成纤维细胞分化（FMD）是肺纤维化的一个重要特征，其中促纤维化细胞因子 TGFβ1 发挥着关键作用。促进自噬对于维持正常肺成纤维细胞的命运是必要且充分的。相反，TGFβ1 介导的 FMD 的特点是自噬通量减少、线粒体自噬改变和线粒体功能缺陷。与这些发现一致，博来霉素和肺纤维化 TGFβ1 腺病毒模型中 PINK1 表达似乎在纤维化肺组织中减少。与对照组相比，衰老小鼠肺和 IPF 患者活检组织中 PINK1 的表达也有所减少。此外，PINK1 缺陷会促进促纤维化环境。总的来说，这项研究表明，与年龄相关的自噬和线粒体自噬对肺损伤反应的下降可能有助于肺纤维化的促进和/或永久化。我们建议，促进自噬和线粒体质量控制可能会提供针对年龄相关纤维化疾病的干预措施。
Aging constitutes a significant risk factor for fibrosis, and idiopathic pulmonary fibrosis (IPF) is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to pulmonary fibrosis. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to lung injury in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to lung injury are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy (mitophagy). Fibroblast to myofibroblast differentiation (FMD) is an important feature of pulmonary fibrosis in which the profibrotic cytokine TGFβ1 plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts’ fate. On the contrary, FMD mediated by TGFβ1 is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a TGFβ1-adenoviral model of lung fibrosis. PINK1 expression is also reduced in the aging murine lung and biopsies from IPF patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to lung injury may contribute to the promotion and/or perpetuation of pulmonary fibrosis. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.