Patients with sepsis are highly susceptible to the development of nosocomial infection, particularly bacterial infection of the lung. While the exact mechanism(s) that contribute to sepsis-mediated immunosuppression remains unclear, dysregulation of monocyte/macrophage function is believed to play an important role in these phenomena. Recently, peroxisome proliferator-activated receptor-gamma (PPARy), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, has been shown to inhibit the expression of inflammatory mediators from monocytes/macrophages and other leukocyte populations. The hypothesis of this proposal is that sepsis induced immunosuppression is mediated, in part, by PPARy. Furthermore, we postulate that inhibition of this ligand dependent transcription factor will reverse sepsis-induced changes in alveolar macrophage function, resulting in augmented lung antibacterial host defense. A murine model of cecal ligation and puncture (resulting in an abdominal sepsis syndrome) will be utilized to assess the following Specific Aims: I) to determine the time course and magnitude of PPARy expression in lung during the evolution of murine abdominal sepsis; II) to determine the functional significance of PPARy activation on effector cell functions of primary murine alveolar macrophages or murine alveolar macrophage cell lines; III) to identify the endogenous signals that regulate PPARy expression during the evolution of murine abdominal sepsis; and IV) to determine the effect of inhibition of PPARy on sepsis- induced alterations in alveolar macrophage function ex-vivo and susceptibility to Pseudomonas pneumonia in-vivo. Performance of the studies outlined will help define the role of PPARy as a mediator of sepsis-induced alveolar macrophage dysfunction, and may lead to the development of novel therapies to be employed in the treatment of patients with sepsis.
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