Microparticulate Caspase-1 mediated Lung Injury.

 描述（由申请方提供）：急性肺损伤（ALI）及其更严重的形式急性呼吸窘迫综合征（ARDS）是与严重脓毒症相关的最常见临床综合征，是美国发病率和死亡率的重要原因，死亡率为40%。虽然对ALI/ARDS中细胞损伤和死亡的发病机制了解很多，但我们的知识仍存在一些空白，因此目前没有有效的药物治疗。 在这种情况下，称为半胱天冬酶的酶是完成凋亡程序所必需的。吞噬细胞，特别是单核细胞/巨噬细胞，被认为是肺中炎症和免疫反应的主要组分，并且是胱天蛋白酶，特别是胱天蛋白酶-1的丰富储存库。caspase-1的功能已被认为超出了IL-10和IL-18的加工和激活，包括调节NF-κ B和诱导细胞凋亡。目前的项目旨在扩大我们最近的观察，微粒半胱天冬酶-1可以从单核吞噬细胞释放对靶细胞有远距离的影响。 本项目旨在研究一种新的假说，即凋亡酶，半胱天冬酶-1，封装在循环囊泡，肺细胞损伤和凋亡。中心假设是在靶特异性微粒中释放的单核细胞/巨噬细胞半胱天冬酶-1可以促进肺细胞凋亡，增强肺损伤。本项目为深入研究ARDS患者内皮细胞损伤和血管功能障碍的机制提供了一个非常必要的努力和框架，以提高我们对细胞损伤的分子机制的理解，并为阻止ALI/ARDS患者的细胞损伤提供新的治疗机会。因此，为了确定这种新途径的具体情况，我们提出了以下具体目标：1）发现单核细胞来源的细胞外caspase-1损伤肺血管内皮细胞的详细机制，2）表征危重患者血清中存在的循环caspase-1的形式，3）确定细胞外caspase-1如何被靶细胞摄取。该项目提供了一个机会，以检查在单核细胞/内皮细胞相互作用和细胞凋亡的复杂生物学的caspase-1的作用。这项工作的成功完成将揭示微粒和caspase-1介导的炎症体信号传导的关键组分，增强我们对细胞损伤的分子机制的理解，并提供新的治疗机会，以阻止脓毒症患者的肺损伤ALI/ARDS。

 DESCRIPTION (provided by applicant): Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are the most prevalent clinical syndromes associated with severe sepsis and are important causes of morbidity and mortality in United States with a mortality rate of 40%. Although much is known about the pathogenesis of cell injury and death in ALI/ARDS, there are several gaps in our knowledge; as a result of which there is currently no effective pharmacologic therapy. In this context, enzymes known as caspases are essential for completion of the apoptotic program. Phagocytes, in particular monocyte/macrophages, are recognized as major components of inflammatory and immunologic reactions in the lung and are rich reservoirs of caspases, especially caspase-1. The function of caspase-1 has recently been recognized to extend beyond the processing and activation of IL-1ß and IL-18 to include regulation of NF-kB and induction of apoptosis. The present project seeks to expand upon our recent observation that microparticulate caspase-1 can be released from mononuclear phagocytes to have distant effects on target cells. The present project seeks to investigate a novel hypothesis that links apoptotic enzyme, caspase-1, encapsulated in circulatory vesicles, to lung cell injury and apoptosis. The central hypothesis is that monocyte/macrophage caspase-1 released in target specific microparticles can promote lung cell apoptosis, enhancing lung injury. This project provides a much needed effort and framework to study the poorly understood mechanism of endothelial cell injury and vascular dysfunction in ARDS patients, to enhance our understanding of the molecular mechanisms underlying the cell injury and provide new therapeutic opportunities to halt the cell injury in ALI/ARDS patients. Therefore, to determine the specifics of this novel pathway, we propose the following specific aims: 1) To discover the detailed mechanisms by which monocyte derived extracellular caspase-1 injures lung vascular endothelial cells, 2) To characterize the forms of circulating caspase-1 present in the serum of critically ill patients and 3) To determine how extracellular caspase-1 is taken up by target cells. This project provides an opportunity to examine the role of caspase-1 in the complex biology of monocyte/endothelial cell interactions and apoptosis. Successful completion of this work will uncover critical components of microparticles and caspase-1 mediated inflammasome signaling, enhance our understanding of the molecular mechanisms underlying the cell injury and provide new therapeutic opportunities to halt the lung destruction in septic patients with ALI/ARDS.