The β3/5 Integrin-MMP9 Axis Regulates Pulmonary Inflammatory Response and Endothelial Leakage in Acute Lung Injury

作者：Yao Tong, Chengrong Bao, Yi-Qiong Xu, Lei Tao, Yao Zhou, Lei Zhuang, Ying Meng, Hui Zhang, Jingjing Xue, Weijun Wang, Lele Zhang, Qingbo Pan, Zhenzhen Shao, Tianran Hu, Qian Guo, Qingsheng Xue, Lu Han, Yan Luo · 发表于：Journal of Inflammation Research · 年份：2021 · DOI：10.2147/jir.s331939 · 被引用次数：15 · 研究领域：Protease and Inhibitor Mechanisms、Cell Adhesion Molecules Research、Immune Response and Inflammation

BACKGROUND: Acute lung injury (ALI) is a severe respiratory disease with high rates of morbidity and mortality. Many mediators regarding endogenous or exogenous are involved in the pathophysiology of ALI. Here, we have uncovered the involvement of integrins and matrix metalloproteinases, as critical determinants of excessive inflammation and endothelial permeability, in the regulation of ALI. METHODS: Inflammatory cytokines were measured by quantitative real-time PCR for mRNA levels and ELISA for secretion levels. Endothelial permeability assay was detected by the passage of rhodamine B isothiocyanate-dextran. Mice lung permeability was assayed by Evans blue albumin (EBA). Western blot was used for protein level measurements. The intracellular reactive oxygen species (ROS) were evaluated using a cell-permeable probe, DCFH-DA. Intratracheal injection of lipopolysaccharide (LPS) into mice was conducted to establish the lung injury model. RESULTS: Exogenous MMP-9 significantly aggravated the inflammatory response and permeability in mouse pulmonary microvascular endothelial cells (PMVECs) treated by LPS, whereas knockdown of MMP-9 exhibited the opposite phenotypes. Knockdown of integrin β3 or β5 in LPS-treated PMVECs significantly downregulated MMP-9 expression and decreased inflammatory response and permeability in the presence or absence of exogenous MMP-9. Additionally, the interaction of MMP-9 and integrin β5 was impaired by a ROS scavenger, which further decreased the pro-i...