Urokinase, Defensin and Acute Lung Injury

急性肺损伤（ALI）的特征是肺泡毛细血管渗漏和白细胞外渗的渗出期，随后是肺血管建设和肺内分流，以应对缺氧。尽管血管反应性的改变有助于ALI的发病，但血管通透性序列变化的信号转导机制尚不完全明确。我们的研究表明，尿激酶纤溶酶原激活剂（uPA）和活化的中性粒细胞分泌的a-防御素通过低密度脂蛋白相关受体（LRP）和整合素α -v- β 3对血管张力起相反的作用，该系统受氧张力调节。基于这些发现，我们将探索uPA通过与LRP和α -v- β 3形成信号转导复合物来调节血管收缩性并影响下游通透性的假设，该信号转导复合物因缺氧而失调，并被a-防御素破坏。在具体目标1中，我们将研究分子决定因素

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.