脓毒症急性肺损伤(ALI)早期，肺泡巨噬细胞(AM)过度M1极化是炎症反应失控的重要环节，其极化机制不明。申请者文章报道，疱疹病毒侵入介质(HVEM)及其配体BTLA信号均可加重ALI炎症反应。预实验发现，HVEM在ALI小鼠AM中表达显著上调，HVEM-siRNA干预后小鼠AM内M1型细胞因子与肺组织STAT1磷酸化水平同时降低、小鼠肺部炎症减轻。综上提出假说：ALI中HVEM可能通过STAT1途径促进AM向M1极化、影响ALI转归。本研究拟利用脓毒症ALI小鼠模型和原代巨噬细胞，通过siRNA干扰HVEM表达和配体重组蛋白激活HVEM，确定HVEM在ALI中促进AM向M1极化的作用;通过信号通路分子阻断剂和激动剂，探索HVEM下游信号通路；并在体验证干预HVEM调控AM极化对ALI转归的影响。旨在阐明脓毒症ALI中肺泡巨噬细胞极化的机制、为脓毒症ALI的治疗探索新的靶点。

In the early stage of sepsis-induced acute lung injury (ALI), excessive M1 polarization of alveolar macrophages is a key link in the uncontrolled inflammatory response, while its polarization regulation mechanism is unknown. The applicant reported that herpes simplex virus invading medium (HVEM) and its ligand BTLA signaling can aggravate ALI,. Preliminary experiments showed that HVEM expression in alveolar macrophages was significantly up-regulated the in ALI mice. After HVEM-siRNA intervention, M1 cytokine levels in alveolar macrophages and lung STAT1 phosphorylation levels decreased simultaneously, and the inflammation in mice lung was alleviated. We hypothesized that HVEM may promote alveolar macrophage towards M1 polarization through the STAT1 pathway and affect ALI outcome. This study intends to use a sepsis-induced ALI model and extracted primary macrophages, and intervene HVEM by siRNA and its ligand recombinant protein, to determine the role of HVEM in promoting alveolar macrophage towards M1 polarization during ALI. Pathway molecular agonist or antagonist would be used to explore the downstream signaling pathway of HVEM. Moreover, the effect of HVEM intervention on macrophage polarization on ALI prognosis was demonstrated. The aim of this study is to elucidate the polarization mechanism of alveolar macrophages in sepsis-induced ALI, as well as to explore new targets for ALI treatment.