ARDS: Injury from Microvesicular Caspase-1

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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.