急性呼吸窘迫综合征（ARDS）是临床常见的急危重症，脓毒症通过引起系统性炎症促进ARDS的发生与进展。受体相互作用蛋白1（RIP1）是诱导炎症和肺上皮细胞程序性坏死的节点分子，但机制未明。我们前期工作发现：炎症可诱导肺上皮细胞RIP1显著上调，增强中性粒细胞趋化因子CXCL1、2、3的表达，并导致细胞程序性坏死增加。推测RIP1下游信号轴参与了脓毒症相关ARDS肺损伤的进展。本项目拟检测患者肺泡灌洗液中的相关趋化因子和程序性坏死标志性分子，在细胞水平通过基因干扰、药理学抑制、ChIP、免疫共沉淀等明确RIP1诱导CXCL1、2、3表达的机制，并阐明炎症刺激通过RIP1介导坏死小体形成，导致肺上皮细胞程序性坏死的分子机制，最后ARDS大鼠模型验证RIP1在细胞实验中的作用。本试验将揭示RIP1是脓毒症相关ARDS肺损伤的关键分子，深化肺上皮细胞程序性坏死导致脓毒症相关ARDS肺损伤的机制。

Acute respiratory distress syndrome (ARDS) is a common and intractable problem in critical care medicine. Sepsis promotes the development and progression of ARDS by inducing systemic inflammatory response. Receptor interacting protein 1 (RIP1) is a nodal molecule which induces inflammation and necroptosis. Necroptosis is an important death mode of lung epithelial cells in inflammatory environment. However, their mechanism is still unclear. Our previous study found that inflammation could upregulate the expression of RIP1 and enhance the expression of chemokines CXCL1, CXCL2 and CXCL3 in chemotactic neutrophils. And it also increased the necroptosis of pulmonary epithelial cells. Thus, we hypothesize that multiple downstream signal axises of RIP1 may involve in the progression of sepsis-associated ARDS lung injury. In this study, we will test the chemokines and markers of necrosis in patient’s bronchoalveolar lavage fluid. We will elucidate mechanisms on how RIP1 induce the expression of CXCL1, CXCL2 and CXCL3 by using gene interference, pharmacological inhibition, ChIP, co-immunoprecipitation in vitro model. It also elucidate cellular and molecular mechanisms on how RIP1-mediated necrosome format and induce necroptosis of pulmonary epithelial cells. Finally, the critical role and mechanisms of all actions in vitro of RIP will be verified in rat models of ARDS. Our studies will reveal that RIP1 is the key molecule in the lung injury of sepsis-associated ARDS and it will deepen the mechanism of lung injury of sepsis-associated ARDS induced by necroptosis.