ADAM15 is a member of the ADAM family (proteinases with a disintegrin and a metalloproteinase domain). It is expressed by inflammatory cells, but little is known about its roles in the lung. Our studies of ADAM15-/- mice in a murine model of acute lung injury show that ADAM15 promotes PMN accumulation in the lung, and promotes alveolar capillary barrier injury. ADAM15 delays PMN apoptosis in the lung, and reduces macrophage uptake of apoptotic targets in vitro. ADAM15 is stored in PMN, and rapidly translocates to the PMN surface when cells are activated. ADAM15 degrades a lung extracellular matrix protein. We will investigate the mechanisms by which ADAM15 increases the lung PMN burden during All, and the cell biology and enzyme biochemistry of ADAM15 in PMN. We propose to pursue the following Specific Aims:
Specific Aim 1. Investigate the mechanism by which ADAM15 promotes PMN survival in the lung:
Aim 1 A: We will test our hypothesis that ADAM15 increases the lung PMN burden by delaying PMN apoptosis by shedding of TNF receptor family members that regulate apoptosis.
Aim 1 B: We will test our hypothesis that ADAM15 also increases the lung PMN burden by inhibiting uptake of apoptotic PMN by lung macrophages.
Specific Aim 2. Investigate the cell biology of ADAM15 in PMN.
Aim 2 A. We will test our hypothesis that ADAM15 is stored as a preformed proteinase within PMN cytoplasmic storage sites, and rapidly translocates to the cell surface when PMN are activated to degranulate. We will identify the storage sites for ADAM15 in PMN.
Aim 2 B. We will test our hypothesis that ADAM15 is subsequently internalized from the surface of activated PMN by a clathrin-dependent mechanism.
Specific Aim 3. We will test our hypothesis that ADAM15 expressed on the surface of PMN is a TIMP- resistant proteinase that cleaves matrix and non-matrix proteins to promote lung inflammation and injury. We hope that our studies will provide novel insights into the mechanisms by which ADAM15 promotes neutrophilic lung inflammation and lung injury during ALI, and that in the long term, this will facilitate the design of new treatment strategies for ALI in man.
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