NOX4-Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK/Akt-Mediated TGF-β Signaling.
NOX4-Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK/Akt-Mediated TGF-β Signaling.
复制标题
NOX4 衍生的 ROS 通过激活非经典 p38MAPK/Akt 介导的 TGF-β 信号传导促进支气管平滑肌细胞中 I 型胶原蛋白沉积
DOI：
10.1155/2021/6668971
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发表时间：
2021
影响因子：
--
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Hao B;Sun R;Guo X;Zhang L;Cui J;Zhou Y;Hong W;Zhang Y;He J;Liu X;Li B;Ran P;Chen J
气道平滑肌(ASM)重构是慢性阻塞性肺疾病(COPD)的标志。NADPH氧化酶4(NOX4)介导的活性氧(ROS)的产生在ASM重塑的细胞分化和细胞外基质(ECM)合成中起着至关重要的作用。然而，其致病作用的确切机制仍不清楚。检测慢性阻塞性肺疾病患者和对照组肺组织中NOX4和转化生长因子-β-1的表达。建立香烟烟雾(CS)诱导的肺气肿小鼠模型，观察α-SMA、NOX4、β-1和I型胶原的变化。探讨细胞外基质标志物NOX4、转化生长因子-β/SmAD组分、MAPK/AKT信号转导通路的变化，探讨NOX4介导的ROS产生对人ASM细胞分化和重塑的影响机制。慢性阻塞性肺疾病患者肺上皮细胞和间质中NOX4和转化生长因子-β-1蛋白的表达明显高于对照组。此外，在CS诱导的肺气肿小鼠模型中，观察到NOX4和α-SMA的表达增加。转化生长因子-Akt1能够增加HBSMC的氧化负荷和I型胶原的产生，并增强β、p38MAPK和p-Akt473的磷酸化。这些作用可被ROS清除剂N-乙酰半胱氨酸、siRNA介导的Smad3和β4的下调以及药物抑制剂SB203580(p38MAPK抑制剂)和LY294002(Akt抑制剂)所抑制。NOX4介导的ROS的产生改变了转化生长因子-β1诱导的HBSMCs分化和I型胶原蛋白的合成，部分是通过Smad依赖的p38MAPK/Akt信号通路。
Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD). NADPH oxidase 4- (NOX4-) mediated reactive oxygen species (ROS) production plays a crucial role in cell differentiation and extracellular matrix (ECM) synthesis in ASM remodeling. However, the precise mechanisms underpinning its pathogenic roles remain elusive. The expression of NOX4 and TGF-β1 in the airway of the lung was measured in COPD patients and the control group. Cigarette smoke- (CS-) induced emphysema mice were generated, and the alteration of α-SMA, NOX4, TGF-β1, and collagen I was accessed. The changes of the expression of ECM markers, NOX4, components of TGF-β/Smad, and MAPK/Akt signaling in human bronchial smooth muscle cells (HBSMCs) were ascertained for delineating mechanisms of NOX4-mediated ROS production on cell differentiation and remodeling in human ASM cells. An increased abundance of NOX4 and TGF-β1 proteins in the epithelial cells and ASM of lung was observed in COPD patients compared with the control group. Additionally, an increased abundance expression of NOX4 and α-SMA was observed in the lungs of the CS-induced emphysema mouse model. TGF-β1 displayed abilities to increase the oxidative burden and collagen I production, along with enhanced phosphorylation of ERK, p38MAPK, and p-Akt473 in HBSMCs. These effects of TGF-β1 could be inhibited by the ROS scavenger N-acetylcysteine (NAC), siRNA-mediated knockdown of Smad3 and NOX4, and pharmacological inhibitors SB203580 (p38MAPK inhibitor) and LY294002 (Akt inhibitor). NOX4-mediated ROS production alters TGF-β1-induced cell differentiation and collagen I protein synthesis in HBSMCs in part through the p38MAPK/Akt signaling pathway in a Smad-dependent manner.