急性呼吸窘迫综合征（ARDS）是一种多病因导致的临床危急重症，死亡率高。失控的炎症反应和促炎介质大量释放是ARDS的共同发病途径，但目前对其诱发机制尚不清楚。我们前期研究发现，一种新的炎症分子—细胞外组蛋白与ARDS的发生发展密切相关，并可能是激活异常免疫反应的关键介质，这为探索ARDS的发病机制和治疗靶点等开辟了新的视角。本项目拟制备感染性(脂多糖注射)和盐酸吸入性的小鼠ARDS模型，并结合临床病人资料，研究细胞外组蛋白的动态变化规律，探讨细胞外组蛋白对氧化应激、细胞凋亡、免疫细胞活化和炎症信号通路激活等事件的影响作用，从上游的早期损伤事件、中游的信号传导通路和下游的炎性因子等不同层面，阐释细胞外组蛋白在ARDS发病中的具体功能及分子机制，并通过给予特异性抗组蛋白中和抗体等干预措施验证假说。本研究有望在新的层面揭示ARDS发病的关键问题或核心关节，为临床早期预警和干预治疗等提供科学线索。

Acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. ARDS is physiologically characterized by enhanced alveolar-capillary permeability, hypoxemia, accumulation and activation of leukocytes within the lungs, and uncontrolled overwhelming inflammatory responses. It is noticeable that systemic inflammation is a common pathological feature shared by different etiologies-caused ARDS, as demonstrated by a rapid influx of leukocytes and releases of proinflammatory cytokines. However, the factors or mechanisms that trigger systemic inflammation in ARDS are largely unclear. Recently, extracellular histones have been identified as a new DAMP (Damage Associated Molecular Pattern) molecule and exhibited to be a major mediator of death in sepsis. In our pilot study, we found that extracellular histones were significantly released in the circulation of LPS-induced ARDS mice in a time-dependent manner, which likely contributed to the increase of inflammatory cytokines and the death of mice. Neutralization of histones by specific anti-histones antibodies strikingly improved the survival rate of ARDS mice. It thus indicated a dual role of extracellular histones either as a cell death marker for ARDS or as a new therapeutic target in the treatment of ARDS. In the present study, we aim to investigate the profile of extracellular histones levels following LPS-induced or acid aspiration-induced ARDS models as well as in clinical patients with ARDS. Moreover, the molecular pathways of extracellular histones involved in activation of innate immunity and inflammatory events will be examined. Most importantly, we will explore the protective effects and the potential therapeutic significance of specific anti-histones antibodies, which may serve as a new strategy in the treatment of ARDS. Our study will shed light on the pathogenesis of ARDS and provide valuable information for exploring its biomarker and therapeutic potential.