细菌耐药性的快速攀升与抗菌药物研发滞缓的现状，驱使抗感染治疗进入活性抗菌与免疫调节双管齐下的新时代。多粘菌素E（Colistin）是治疗多药耐药革兰氏阴性杆菌所致严重感染的“最后防线”，课题组基于前期关于colistin通过p38/PMK-1信号转导通路激活低等模式生物C. elegans先天免疫提高抗感染能力的发现，从激活保护和过敏危害双向入手，首次提出“colistin免疫增强活性应用设想”以及“colistin肾毒性的炎性反应机制假说”，从分子、细胞和整体动物三个层面解析colistin对哺乳动物先天免疫系统作用机制，评价基于colistin免疫增强活性的抗菌药物联用方案的可行性，并通过炎性因子、组织病理以及p38抑制剂效果分析，验证colistin通过诱发炎症反应致肾损伤的假说，为开拓colistin除抗菌活性外的新用途、寻找降低colistin肾毒性的新策略奠定坚实的理论基础。

Rapid rise of antibiotic resistance and slowly development of antimicrobials has driven anti-infective research into a new era characterized by combination of antibacterial activity and immunomodulatory. Polymyxin E (Colistin) is the “last resort” of severe infections caused by multi-drug resistant Gram-negative pathogen. Our previous findings indicated that colistin can activate innate immunity via p38/PMK-1 signaling pathway and enhance the defense capability during the infection in a simple animal model C. elegans. Considering both of protective effects after immune activation and hypersensitivity caused by excessive activation, we propose the idea of antimicrobials combination regimen based on immune-enhancing activity of colistin and hypothesis of inflammatory response is one of the mechanisms of colistin nephrotoxicity. We designed experiments from the molecular, cellular and whole animal to analyze the mechanisms of colistin effect on the mammalian innate immune system and to evaluate the feasibility of antimicrobial combination regimen based on immunomodulatory activity of colistin. Hypothesis of colistin caused inflammation-induced renal injury through p38/MAPK pathway is verified by inflammatory cytokines analysis, histopathology observation and p38 inhibitors effect evaluation in a rat nephrotoxicity model. These series of studies will provide solid theoretical foundation for the new use of colistin besides antibacterial activity and reduce the risk of nephrotoxicity.