Acute lung injury (ALI) is characterized by an exudative phase of alveolar-capillary leak and leukocyte extravasation followed by pulmonary vasoconstruction and intrapulmonary shunting in response to hypoxia. Although alterations in vasoreactivity contribute to the morbidity of ALI, the signal-transducing mechanism underlying the sequential changes in vascular permeability is incompletely defined. Our studies suggest that urokinase plasminogen activator (uPA) and a-defensins secreted by activated neutrophils exert opposing effects on vascular tone through low-density lipoprotein-related receptor (LRP) and the integrin alpha-v-beta3, and that system is regulated by oxygen tension. Based on these findings, we will explore the hypothesis that uPA regulates vascular contractility and influences downstream permeability by forming a signal-transducing complex with LRP and alpha-v-beta3 that is dysregulated by hypoxia and disrupted by a-defensin.
In Specific Aim 1 we will study the molecular determinants required to form ternary complexes between uPA, Ovfo and LRP, its role in pulmonary vascular contraction, and the effect of defensin. In Specific expression and signal transduction will be elucidated.
In Specific Aim 3 the role of LRP/alpha-v-beta3 in the development of ALI will be examined in wildtype, uPA -/- and defensin-transgenic mice. Proteolytic and the non-proteolytic effects of uPA on the vasculature will be distinguished through a novel uPA and d-kringle uPA transgenic mouse delivery system using platelet-specific promoters. Taken together these studies will provide insight into the regulation of vascular tone and permeability by uPA in ALI and identify novel agonists (uPA and defensin) and a novel signal-transducing pathway (LRP/ alpha-v-beta3) as potential sites to ameliorate disease severity.
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