ARDS: Injury from Microvesicular Caspase-1

描述(由申请人提供)：急性呼吸窘迫综合征(ARDS)是患有脓毒症、创伤和休克等严重情况的患者最常见的肺损伤原因。ARDS的特点是肺泡上皮细胞受损，从而导致非心源性肺水肿的发生。最近对ARDS介导的肺损伤的发展和形态的大量研究表明，程序性细胞死亡在疾病的各个阶段都是一个重要因素。然而，上皮细胞死亡的实际机制仍不清楚，旨在广泛抑制这一级联反应的策略未能改善患有ARDS的人类预后。为了开发更有效的治疗策略，有必要了解原发侮辱与炎症和远端器官损伤的全身表现之间的确切机制。吞噬细胞，特别是单核/巨噬细胞和中性粒细胞，被认为是肺部炎症和免疫反应的主要成分。半胱氨酸天冬氨酸氨基转移酶是细胞凋亡和分泌促炎细胞因子所必需的酶。在这种背景下，caspase-1的功能最近被认为超出了对IL-12和IL-18的处理和激活，包括对核因子-B的调节和诱导细胞凋亡。目前的提议试图扩展我们最近的观察，即有毒形式的caspase-1可以从单核吞噬细胞中释放出来，对靶细胞产生远距离的影响。中心假设是单核/巨噬细胞在特定的微泡中激活和释放caspase-1，从远处调节肺细胞的凋亡。特定的假设集中在caspase-1的能力，释放在微泡中，诱导肺上皮细胞凋亡，导致肺损伤。因此，为了确定这一新途径的特异性，我们提出了以下具体目标：1)确定微泡活性caspase-1在上皮细胞凋亡中的作用；2)阐明微泡活性caspase-1在ARDS介导的肺损伤中的作用。这一提议为研究caspase-1在单核细胞/上皮细胞相互作用的复杂生物学中的作用提供了一个机会。它有可能创造新的治疗机会来预防和治疗ARDS和其他炎症性疾病。 公共卫生相关性：急性呼吸窘迫综合征(ARDS)是一种急性肺衰竭，20%-50%的患者患有严重创伤、脓毒症或休克，其中超过40%的患者死亡。最近的科学研究表明，肺衬里细胞的死亡是液体泄漏到肺内的原因；因此，目前的研究提议提供了一个新的机会来了解特定的酶，caspase-1，可能如何发挥作用，导致这种损伤。我们的研究将确定在亚显微包装中释放的caspase-1是否可能与肺衬里细胞相互作用而诱导它们死亡，我们期待这一方法能够揭示ARDS介导的肺损伤的新见解，从而为预防和治疗ARDS创造新的治疗机会。

DESCRIPTION (provided by applicant): Acute respiratory distress syndrome (ARDS) is the most common cause of lung injury in patients suffering from severe conditions such as sepsis, trauma and shock. ARDS is characterized by damage to alveolar epithelial cells which allows the onset of noncardiogenic pulmonary edema. Numerous recent investigations on the development and morphology of ARDS mediated lung injury have shown programmed cell death to be an important factor throughout all stages of the disease. However, the actual mechanism of epithelial cell death remains unclear and strategies aimed at broad inhibition of this cascade have failed to improve outcome in human with ARDS. In order to develop more effective therapeutic strategies, it is necessary to understand the precise mechanism that links the primary insult with systemic manifestations of inflammation and distant organ injury. Phagocytes, in particular monocytes/ macrophages and polymorphonuclear neutrophils, are recognized as major components of inflammatory and immunologic reactions in the lung. Caspases are enzymes essential for apoptosis and secretion of pro-inflammatory cytokines. In this context, the function of caspase-1 has recently been recognized to extend beyond the processing and activation of IL-12 and IL-18 to include regulation of NF-(B and induction of apoptosis. The present proposal seeks to expand upon our recent observation that toxic forms of caspase-1 can be released from mononuclear phagocytes to have distant effects on target cells. The central hypothesis is that monocyte/macrophage caspase-1 activation and release in specific microvesicles act from a distance to regulate lung cell apoptosis. The specific hypothesis centers upon the ability of caspase-1, released within microvesicles, to induce apoptosis of lung epithelial cells, leading to lung injury. Therefore, to determine the specifics of this novel pathway, we propose the following specific aims: 1) to determine the role of microvesicular active caspase-1 in epithelial cell apoptosis and 2) to delineate the role of microvesicular active caspase-1 in ARDS mediated lung injury. This proposal provides an opportunity to examine the role of caspase-1 in the complex biology of monocyte /epithelial cell interactions. It has the potential to create new therapeutic opportunities to prevent and treat ARDS and other inflammatory diseases. PUBLIC HEALTH RELEVANCE: Acute respiratory distress syndrome (ARDS) is a type of acute lung failure that develops in 20-50% of patients suffering from major trauma, sepsis or shock and over 40% of these patients die. Recent scientific work suggests that death of lung lining cells is responsible for the leakage of fluid into the lung; hence the current research proposal provides a new opportunity to understand how a particular enzyme, caspase-1, may function to cause this injury. Our study will determine if caspase-1 released in submicroscopic packages may interact with lung lining cells to induce their death and we expect this approach to uncover novel insights into ARDS mediated lung injury and thus create new therapeutic opportunities to prevent and treat ARDS.