血浆高分子量激肽原在宿主应答革兰氏阴性细菌感染中的新功能与机制

革兰氏阴性细菌（G-）感染所致脓毒症死亡率极高，尚无有效的治疗。究其原因是对机体在G-细菌感染中反应失调的机制，尤其是天然免疫系统如何从免疫防御，转变为过度的系统性炎症反应的演变过程认识远远不足。最近我们报道血浆高分子量激肽原（HK）高亲和性结合脂多糖（LPS），作为LPS载体导致内毒素血症。进一步研究我们发现HK作为LPS的模式识别分子，在G-菌感染中起保护作用。因此我们提出假说：HK在G-菌感染和脓毒症发病中发挥双重调控作用（“双刃剑效应”）。本项目将运用HK基因敲除、人源化小鼠模型，质谱分析及siRNA药物干预等手段，系统研究HK在G-菌感染中的天然免疫效应，及感染失控时介导内毒素血症的转化机制，阐明HK作为天然免疫组份如何由防御作用转变为致病作用的演变过程，并探索HK抗体或靶向siRNA干预对G-菌脓毒症的治疗效应。以期为G-菌脓毒症发病新机理和治疗新方案提供依据。

Gram negative (G-) bacterial infection is the leading cause of sepsis. However, the mechanisms underlying the transition of the host response from immune defense to excessive systemic inflammatory state are still poorly understood. Very recently we have reported that high-molecular-weight kininogen (HK) binds LPS with high affinity and serves as a crucial LPS carrier in circulation supporting endotoxemia. In our preliminary studies, we further found that HK protects against a G- bacterial sepsis by functioning as a soluble PRM to sense and initiate inflammation response to the bacteria. Based on our new findings, we propose a hypothesis that HK plays a dual role in host response to G- bacteria infection or it’s comound LPS induced systemic inflammation. In this proposal, using mKng1 knock-out and kng1-humanized mouse models, we will determine the role of HK in the pathophysiological process of G- bacterial sepsis; characterize the underlying mechanism of HK in mediating the host response to G- bacteria and LPS proinflammatory activity as well as effector cells; and perform the experimental studies on the treatment of G- bacterial sepsis by targeting HK. The proposed studies will not only provide new insights into the pathogenesis of sepsis, but will also reveal HK may be a new potential therapeutic target for sepsis.