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、创伤和休克等严重疾病的患者肺损伤的最常见原因。急性呼吸窘迫综合征的特点是肺泡上皮细胞受损，可引起非心源性肺水肿。最近许多关于ARDS介导的肺损伤的发展和形态学的研究表明，程序性细胞死亡是贯穿该疾病所有阶段的一个重要因素。然而，上皮细胞死亡的实际机制尚不清楚，旨在广泛抑制这一级联反应的策略未能改善ARDS患者的预后。为了制定更有效的治疗策略，有必要了解将原发性损伤与炎症和远端器官损伤的系统性表现联系起来的确切机制。吞噬细胞，特别是单核/巨噬细胞和多形核中性粒细胞，被认为是肺部炎症和免疫反应的主要组成部分。半胱天冬酶是细胞凋亡和促炎细胞因子分泌所必需的酶。在这种情况下，caspase-1的功能最近已经被认识到不仅仅是加工和激活IL-12和IL-18，还包括调节NF- B和诱导细胞凋亡。目前的建议旨在扩大我们最近的观察，毒性形式的caspase-1可以从单核吞噬细胞中释放出来，对靶细胞有遥远的影响。核心假设是单核细胞/巨噬细胞caspase-1在特定微泡中的激活和释放从远处调控肺细胞凋亡。具体的假设集中在微泡内释放的caspase-1诱导肺上皮细胞凋亡，导致肺损伤的能力上。因此，为了确定这一新途径的具体情况，我们提出以下具体目标：1)确定微泡活性caspase-1在上皮细胞凋亡中的作用；2)描述微泡活性caspase-1在ARDS介导的肺损伤中的作用。这一提议提供了一个机会来检查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。它有可能为预防和治疗急性呼吸窘迫综合征和其他炎症性疾病创造新的治疗机会。

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.