Acute lung injury (ALl) is frequently associated with sepsis. Activation of procoagulant and fibrinolytic cascades occurs in ALl, and includes increased expression of urokinase plasminogen activator (uPA) and its inhibitors, such as plasminogen activator inhibitor (PAl-1), in the lungs. ALl is also characterized by the accumulation of large numbers of activated neutrophils in the lungs. Our preliminary data demonstrate a novel pro-inflammatory role for uPA. These results show that uPA contributes to acute lung injury produced by endotoxemia and also potentiates LPS and PGN induced neutrophil activation. Determination of the molecular mechanisms and receptors through which uPA enhances neutrophil activation and contributes to the development of ALl is the major goal of the proposed experiments. Our hypothesis is that processes involving the balance between uPA and its inhibitors contribute to neutrophil activation and pulmonary inflammation in sepsis induced ALl.
The specific aims of this project are: 1) To elucidate the effects of uPA and the kringle domain of uPA on neutrophil activation, the receptors involved in uPA induced potentiation of neutrophil activation, and the role of uPA in contributing to the development of LPS and P. aeruginosa induced ALl; 2) To determine the importance of uPA generated plasmin in contributing to neutrophil activation and to the development of ALl; and 3) To examine how interactions between uPA and PAl modulate neutrophil activation and development of ALl. Our goal is to characterize mechanisms involved in neutrophil activation that are modulated by exposure to uPA, plasmin, and PAl-1, and that contribute to the development and severity of ALl. Delineation of such uPA dependent pro-inflammatory mechanisms, that may not involve proteolytic properties of uPA, will provide novel insights into interactions between fibrinolytic cascades and neutrophil activation, particularly in the setting of neutrophil dependent inflammatory responses, such as ALl. The proposed experiments are likely to suggest new therapeutic approaches to improve outcome from important clinical conditions, such as sepsis induced acute lung injury in which both fibrinolytic and neutrophil dependent pathways play major roles.
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