Role of lung WWOX deficiency in vascular leak during lung injury

项目总结/摘要 急性呼吸窘迫综合征（ARDS）是一种严重的疾病， 仅在美国，每年就有20万患者，造成约75，000人死亡， 对许多幸存者来说，目前不存在特定的ARDS疗法，并且努力 减少其负担受到不同分子的不完整表征的限制 其发病机制。ARDS的主要发病特征是 肺血管屏障破坏导致的非心源性肺水肿， 随之而来的肺泡灌洗和呼吸衰竭。这些的概念基础 事件由肺内皮细胞（EC）的细胞骨架收缩组成，导致 细胞间隙的形成。降低血管渗透性的新策略， 急性呼吸窘迫综合征的肺水肿是迫切需要的。本提案的目的是确定 肿瘤抑制因子WWOX对与肿瘤相关的病理生物学过程的贡献 ARDS。WWOX位于染色体中第二个最活跃的常见染色体脆性位点， 人类基因组，使其极易受到基因毒性压力，如发生 吸烟和其他有毒呼吸道暴露。本申请中的详细数据 提示：1）在香烟烟雾暴露期间，肺中发生WWOX损失， 事件至少可以部分解释吸烟者与非吸烟者相比， 在流行病学研究中观察到的不吸烟者，以及2） WWOX在体内和体外均发挥了有效的EC屏障保护作用 脂多糖（LPS）诱导的ARDS。本项目旨在：（1）确定 EC WWOX在小鼠ARDS中的表达，2）定义WWOX表达的分子机制， 促进EC屏障保护和3）建立基于WWOX的治疗的概念基础 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.