C5a单克隆抗体预处理联合术中肿瘤坏死因子α抗体灌注对体外循环肺损伤保护作用的新机制探讨

Lung injury is the most common complication associated with cardiopulmonary bypass(CPB). The molecular mechanism underlying the CPB-associated lung injury remians unclear. Understanding the mechanism could reveal potiential therapeituc targets to prevent the lung injury induced by CPB. Our previous studies have demonstrated that tumor necrosis factor-α (TNF-α) plays a critical role in CPB-induced lung injury and inhibition of TNF-α only partially relieve CPB-induced lung injury. Here, we hypothesize that pre-treatment with anti-C5a monoclonal antibody and intraoperative perfusion of anti-TNF-α antibody during CPB may intefere MAPK signaling pathway and thus attenuate CPB-induced lung injury. We propose to investigate the following four topics at molecular, cellular, and animal model levels: 1) protective effects of pre-treatment with anti-C5a monoclonal antibodies and intraoperative perfusion of anti-TNF-α antibodies during CPB on the lung; 2) effects of the pre-treatment and the intraoperative perfusion on the MAPK signaling pathway; 3) clarify the targetted molecules in the MAPK pathway by the pre-treatment and the intraoperative perfusion; 4) reveal the assocation between the MAPK singaling pathway and CPB-induced lung injury and mechanims underlying the protective effects of the pre-treatment and intraoperative perfusion.

肺损伤是CPB术后的常见并发症，其具体机制仍需深入探讨。明确CPB相关肺损伤发生的机 制可为其防治提供潜在靶点。前期研究中，我们已经明确TNF-α在CPB相关肺损伤中起关键作 用。但单纯阻断TNF-α只能起到削弱CPB相关肺损伤的作用，并不能完全实现肺保护。因此我 们提出“C5a单抗预处理联合术中TNF-α抗体灌注双重干预MAPK信号通路，减轻CPB相关肺损伤 ”的假说。本项目将从分子、细胞、组织以及动物水平等层面阐明：1）C5a单抗预处理联合TN F-α抗体灌注对CPB术后肺组织的保护作用；2）C5a单抗预处理联合TNF-α抗体灌注对MAPK信 号通路的作用机制；3）明确在C5a单抗预处理联合TNF-α抗体灌注作用下的MAPK信号通路相关 靶基因；4）揭示MAPK信号通路与CPB相关肺损伤的关系和C5a单抗预处理联合TNF-α抗体灌注 对CPB肺组织的保护机制为CPB肺保护提供全新靶点。

肺损伤是CPB术后的常见并发症，明确CPB相关肺损伤发生的机制可为其防治提供潜在靶点，是目前心脏外科亟待解决的瓶颈问题。前期我们已经明确TNF-α在CPB相关肺损伤中起关键作用。但单纯阻断TNF-α只能起到削弱CPB相关肺损伤的作用，并不能完全实现肺保护。因此我们提出：C5a单抗预处理联合术中TNF-α抗体灌注双重干预MAPK信号通路，减轻CPB相关肺损伤。本项目从分子、细胞、组织以及动物水平等层面阐明：C5a单抗预处理联合TNF-α抗体灌注对CPB术后肺组织的保护作用；C5a单抗预处理联合TNF-α抗体灌注对MAPK信号通路的作用机制；揭示MAPK信号通路与CPB相关肺损伤的关系和C5a单抗预处理联合TNF-α抗体灌注对CPB肺组织的保护机制,最终为CPB肺保护提供全新靶点。