Role of lung WWOX deficiency in vascular leak during lung injury

项目摘要/摘要 急性呼吸窘迫综合征(ARDS)是一种严重的疾病，据估计 仅在美国每年就有20万名患者，导致大约7.5万人死亡，而且严重 对许多幸存者来说都是虚弱的。目前尚不存在特定的ARDS疗法，并努力 减少它的负担受到了对不同分子的不完全描述的限制 其发病机制。ARDS的主要致病特征是 肺血管屏障破坏所致的非心源性肺水肿 随之而来的是肺泡泛滥和呼吸衰竭。这些概念的基础是 事件包括肺内皮细胞(ECs)的细胞骨架收缩导致 细胞旁间隙的形成。新的策略，降低血管渗透性和 急性呼吸窘迫综合征的肺水肿是迫切需要的。这项建议的目标是确定 肿瘤抑制基因WWOX在肿瘤相关病理生物学过程中的作用 阿兹。WWOX位于人类第二活跃的常见染色体脆性部位 人类基因组，使其对所发生的遗传毒性应激高度敏感 在香烟烟雾和其他有毒呼吸道暴露期间。此应用程序中详细说明的数据 这表明1)暴露在香烟烟雾中的肺部会发生WWOX的丢失，而这 这一事件可能至少部分解释了吸烟者比吸烟者更容易患严重ARDS 在目前流行病学研究的新证据中观察到的非吸烟者，以及2) WWOX在体内和体外均具有强大的EC屏障保护作用 脂多糖(LPS)诱导的ARDS。本项目的目的是：1)确定 EC WWOX在小鼠ARDS中的表达，2)确定WWOX在ARDS中的分子机制 促进EC屏障保护和3)为基于WWOX的治疗建立概念基础 在香烟烟雾引发的脓毒症诱导的ARDS中。

Project Summary/Abstract Acute respiratory distress syndrome (ARDS) is a critical illness that afflicts an estimated 200,000 patients/year in the United States alone, kills approximately 75,000, and is seriously debilitating for many survivors. Specific ARDS therapies do not currently exist, and efforts to reduce its burden have been limited by an incomplete characterization of the diverse molecular mechanisms underlying its pathogenesis. The cardinal, morbidity-producing feature of ARDS is non-cardiogenic pulmonary edema resulting from pulmonary vascular barrier disruption with consequent alveolar flooding, and respiratory failure. The conceptual underpinning for these events consists of cytoskeletal contraction of pulmonary endothelial cells (ECs) leading to the formation of paracellular gaps. Novel strategies which reduce the vascular permeability and lung edema of ARDS are desperately needed. The objective of this proposal is to determine the contribution of the tumor suppressor WWOX to the pathobiological processes associated with ARDS. WWOX resides at the second most active common chromosomal fragile site in the human genome, making it highly susceptible to genotoxic stress such as that which occurs during cigarette smoke and other toxic respiratory exposures. Data detailed in this application suggests that 1) loss of WWOX occurs in the lung during cigarette smoke exposure, and this event may at least partly explain an increased susceptibility for severe ARDS in smokers versus nonsmokers observed in currently emerging evidence from epidemiologic studies, and 2) WWOX exerts potent EC barrier-protective effects during both in vivo and in vitro lipopolysaccharide (LPS)-induced ARDS. This project aims to 1) determine the significance of EC WWOX expression in murine ARDS, 2) define the molecular mechanisms by which WWOX promotes EC barrier protection and 3)Establish the conceptual basis for WWOX-based therapy in cigarette-smoke primed, sepsis-induced ARDS.