SIRT1 prevents cigarette smoking-induced lung fibroblasts activation by regulating mitochondrial oxidative stress and lipid metabolism.
SIRT1 prevents cigarette smoking-induced lung fibroblasts activation by regulating mitochondrial oxidative stress and lipid metabolism.
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SIRT1 通过调节线粒体氧化应激和脂质代谢来防止吸烟诱导的肺成纤维细胞活化
DOI：
10.1186/s12967-022-03408-5
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发表时间：
2022-05-14
影响因子：
7.4
通讯作者：
Meng, Ying
中科院分区：
文献类型：
--
作者：
Zhang, Yue;Li, Ting;Pan, Miaoxia;Wang, Wei;Huang, Wenhui;Yuan, Yafei;Xie, Zhanzhan;Chen, Yixin;Peng, Jun;Li, Xu;Meng, Ying
吸烟（CS）是特发性肺纤维化（IPF）的一个重要危险因素。它可以通过诱导氧化还原失衡激活肺成纤维细胞（LF）。我们以前表明，清除线粒体活性氧（mtROS）保护CS诱导的肺纤维化。然而，线粒体ROS在LF中的确切机制需要进一步研究。在这里，我们专注于线粒体ROS，以阐明它是如何调节的CS在LF和它如何有助于LF激活。我们用1%香烟烟雾提取物（CSE）处理细胞，并通过MitoSOX™指示剂检查mtROS水平。检测CSE对SIRT 1、SOD 2、线粒体NOX 4（mtNOX 4）、脂肪酸氧化相关蛋白PPARα、CPT 1a以及LF激活标志物Collagen I、α-SMA表达的影响。进行尼罗红染色以显示细胞脂质含量。然后，分别用Bodipy 493/503、LC 3和LAMP 1标记脂滴、自噬体和溶酶体。通过脂质滴与LC 3和LAMP 1的共定位来评价噬脂作用。探讨了自噬在脂质代谢和LF激活中的作用。此外，在体外和体内研究了靶向ROS清除剂mitoquinone和SIRT 1激活剂SRT 1720对线粒体氧化应激、自噬通量、脂质代谢和LF激活的影响。我们发现CS通过增加mtNOX 4和降低SOD 2来促进mtROS的产生。进一步证实了mtROS抑制了PPARα和CPT 1a的表达。它还减少了脂肪吞噬和上调细胞脂质含量，表明脂质代谢被CS干扰。此外，我们还发现，线粒体ROS导致的自噬通量受阻导致FAO不足和脂肪吞噬。此外，我们发现SIRT 1的减少是线粒体氧化还原失衡的原因。此外，我们还证明了SRT 1720和线粒体醌都可以抵消CS对体内NOX 4、SOD 2、PPARα和CPT 1a的影响。我们证明CS通过脂质代谢失调降低SIRT 1以激活LF，这是由于mtROS增加和自噬通量受损。这些事件可作为IPF患者的治疗靶点。在线版本包含补充材料，可通过10.1186/s12967-022-03408-5获得。
Cigarette smoking (CS) is a strong risk factor for idiopathic pulmonary fibrosis (IPF). It can activate lung fibroblasts (LF) by inducing redox imbalance. We previously showed that clearing mitochondrial reactive oxygen species (mtROS) protects against CS-induced pulmonary fibrosis. However, the precise mechanisms of mtROS in LF need further investigation. Here we focused on mtROS to elucidate how it was regulated by CS in LF and how it contributed to LF activation. We treated cells with 1% cigarette smoking extract (CSE) and examined mtROS level by MitoSOX™ indicator. And the effect of CSE on expression of SIRT1, SOD2, mitochondrial NOX4 (mtNOX4), fatty acid oxidation (FAO)-related protein PPARα and CPT1a and LF activation marker Collagen I and α-SMA were detected. Nile Red staining was performed to show cellular lipid content. Then, lipid droplets, autophagosome and lysosome were marked by Bodipy 493/503, LC3 and LAMP1, respectively. And lipophagy was evaluated by the colocalization of lipid droplets with LC3 and LAMP1. The role of autophagy on lipid metabolism and LF activation were explored. Additionally, the effect of mitochondria-targeted ROS scavenger mitoquinone and SIRT1 activator SRT1720 on mitochondrial oxidative stress, autophagy flux, lipid metabolism and LF activation were investigated in vitro and in vivo. We found that CS promoted mtROS production by increasing mtNOX4 and decreasing SOD2. Next, we proved mtROS inhibited the expression of PPARα and CPT1a. It also reduced lipophagy and upregulated cellular lipid content, suggesting lipid metabolism was disturbed by CS. In addition, we showed both insufficient FAO and lipophagy resulted from blocked autophagy flux caused by mtROS. Moreover, we uncovered decreased SIRT1 was responsible for mitochondrial redox imbalance. Furthermore, we proved that both SRT1720 and mitoquinone counteracted the effect of CS on NOX4, SOD2, PPARα and CPT1a in vivo. We demonstrated that CS decreased SIRT1 to activate LF through dysregulating lipid metabolism, which was due to increased mtROS and impaired autophagy flux. These events may serve as therapeutic targets for IPF patients. The online version contains supplementary material available at 10.1186/s12967-022-03408-5.
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影响因子：
6.9
作者：
Kim, Hak-Su;Yoo, Hyun Ju;Song, Jin Woo
通讯作者：
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影响因子：
4.8
作者：
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DOI：
10.1165/rcmb.2018-0324oc
发表时间：
2019-12-01
影响因子：
6.4
作者：
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通讯作者：
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作者：
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影响因子：
7.4
作者：
Huang, Long Shuang;Jiang, Peiyue;Natarajan, Viswanathan
通讯作者：
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