Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality. The pathogenesis of TRALI is poorly understood and suffers from the lack of a clinically relevant in vivo animal model. We propose in this application to develop mouse models of TRALI by transfusing (1) monoclonal antibodies to mice with corresponding MHC I and II antigens, (2) polyclonal antibodies from alloimmunized mice to mismatched strains, and (3) older blood products with neutrophil priming activity to genetically identical mice. Also, we will use clinically relevant priming mechanisms (LPS, positive pressure ventilation) to potentially augment the response to the mouse models of TRALI. The versatility of three mouse models, and also the potential combination of individual models, will allow dissection of the pathogenic mechanisms responsible for acute lung injury. We postulate that the neutrophil will be a key cellular mediator of mouse TRALI and will test the role of neutrophil and endothelial adhesion molecules, immune complex receptors, and activated complement receptors using transgenic mice and cell depletion/reconstitution experiments. We also hypothesize that the alveolar macrophage may play an important role in mouse TRALI and we will test this hypothesis with alveolar macrophage depletion and repletion experiments. Using alveolar macrophage depletion/reconstitution experiments, the role of immune complex and activated complement receptors will also be tested. Finally, we postulate that the alveolar epithelium will contribute to the pathogenesis and resolution of experimental TRALI. The capacity of the alveolar epithelium to remove alveolar edema will be studied in the mouse models of TRALI and the ability of cAMP agonists to accelerate the resolution of pulmonary edema, and thereby provide a potential treatment for experimental TRALI, will be determined. By developing a relevant animal model of TRALI and carefully determining its pathogenic mechanisms, we will generate new insights into this serious compliction of transfusion therapy.
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