IL-33/ST2-ILC2-WISP1轴在机械通气促进ALI/ARDS相关肺纤维化中的作用与分子机制

机械通气是救治ARDS患者的关键措施之一，但其亦可诱发或加重ALI/ARDS相关肺纤维化。我们前期研究发现，即便是非损伤性机械通气，也能通过IL-33/ST2-WISP1信号通路加重脓毒症诱导的ALI。鉴于IL-33、ILC2和WISP1在纤维化中的重要作用，我们提出“机械通气通过IL- 33/ST2-ILC2-WISP1轴介导ALI/ARDS相关肺纤维化”的假说。本课题将选用WT、IL-33和ST2 KO小鼠并建立脓毒症和机械通气共同作用的“双打击”肺纤维化模型，明确机械通气能否促进iILC2经“肠-肺轴”募集入肺以及激活IL-33/ST2-ILC2-WISP1轴介导ALI/ARDS相关肺纤维化；其后在细胞分子水平用信号通路磷酸化蛋白芯片等技术阐明IL-33通过ST2诱导ILC2细胞产生WISP1的关键信号分子。本课题有助于寻找ALI/ARDS相关肺纤维化新的生物标志物。

Mechanical ventilation is one of the key measures to treat patients with ARDS, but it can also induce or aggravate ALI/ARDS-associated pulmonary fibrosis. Our previous study found that even noninjurious mechanical ventilation aggravated sepsis-induced ALI via IL-33/ST2-WISP1 signaling pathway. Because of the important role of IL-33, ILC2 and WISP1 in fibrosis, we propose the hypothesis that mechanical ventilation mediates ALI/ARDS-associated pulmonary fibrosis through the IL-33/ST2-ILC2-WISP1 axis. In this project, WT, IL-33 and ST2 KO mice will be used to establish a "Two-hit" pulmonary fibrosis model combined sepsis and mechanical ventilation, to determine whether mechanical ventilation promotes the recruitment of iILC2 into the lung via the "gut-lung axis" and activates the IL-33/ST2-ILC2-WISP1 axis to mediate ALI/ARDS-associated pulmonary fibrosis; subsequently, techniques such as signal pathway phosphorylated protein chip will be used to elucidate the key intracellular signaling molecules of WISP1 production in ILC2 induced by IL-33 via ST2 in the cellular and molecular level. This project is helpful to find new biomarkers or therapeutic targets for ALI/ARDS-associated pulmonary fibrosis.