靶向抑制IL-36受体通过SIRT1/FOXO1介导巨噬细胞极性在体外循环心肌缺血再灌注损伤中的保护作机制研究

体外循环（CBP）是保障心脏手术顺利实施的重要手段，然而CBP后心肌缺血再灌注损伤（IRI）成为了临床面临的难题。CBP心肌IRI机制未明确，且缺乏特效防治手段。目前认为CBP心肌IRI与炎性损伤和氧化应激密切相关。本课题组前期研究表明，IL-36R–/–大鼠CBP后IRI心肌M1型巨噬细胞减少，M2型升高，MCP-1等趋化因子和IL-1β等炎症因子降低，SOD活性和MDA下降，中性粒细胞浸润减轻；抑制IL-36R后的巨噬细胞SIRT1、FOXO1蛋白水平升高。故而推测：抑制IL-36R可激活SIRT1/FOXO1，调控巨噬细胞极性，减轻炎症反应及氧化应激，从而改善CBP心肌IRI。为此，本课题组拟建立IL-36R–/–大鼠CBP心肌IRI模型，细胞缺氧-复氧模型，并采用基因导入、基因干扰等方法，阐明靶向抑制IL-36R改善CBP心肌IRI的分子机制，为防治CBP心肌IRI提供新干预靶点。

Cardiopulmonary bypass (CBP) is an important means to ensure the successful implementation of cardiac surgery. However, CBP-associated myocardial ischemia-reperfusion injury (IRI) has become an urgent clinical problem to be solved. The specific mechanism of CBP myocardial IRI is still unclear, and specific prevention and treatment methods are lacking. Most current views believe that CBP myocardial IRI is mainly caused by inflammatory injury and oxidative stress. The previous study of our research group showed that after knocking out IL-36R gene, CBP rats IRI myocardium M1 macrophage number, MCP-1 and other chemokines as well as IL-1β and other inflammatory factors are decreased, superoxide dismutase activity and malondialdehyde are also decreased, neutrophil infiltration is reduced and M2 macrophage number is increased; the protein levels of SIRT1 and FOXO1 in macrophages after IL-36R inhibition are increased. We speculate that the inhibition of IL-36R can activate SIRT1/FOXO1, regulate macrophage polarization, reduce inflammation and oxidative stress, and thus improve CBP myocardial IRI. For this reason, our research group plans to establish IL-36R–/–rat CBP myocardial IRI model, cell hypoxia-reoxygenation model, and use lentiviral vectors, gene introduction, gene interference etc. to clarify the molecular mechanism of targeted inhibition of IL-36R improve CBP myocardial IRI, and provide a new intervention target for the prevention and treatment of CBP myocardial IRI.