RESPIRATORY FAILURE IN A MODEL OF P. CARINII PNEUMONIA

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DESCRIPTION (from applicant's abstract): It is hypothesized that infection with P. carinii renders the alveolar epithelium more susceptible to secondary insults, particularly hyperoxia, leading to respiratory failure in patients with PCP. To evaluate this hypothesis, the investigators will utilize a well-established CD4 depleted mouse model of P. carinii pneumonia, which is subsequently exposed to hyperoxia as a prototypical stress for alveolar wall injury. They propose that P. carinii infected mice will develop more severe lung injury following exposure to hyperoxia. They also postulate that GM-CSF, a potent cytokine generated by alveolar epithelial cells and macrophages, is critical in ameliorating this response. GM-CSF expression induced in response to P. carinii infection exerts a protective effect to limit lung injury. They postulate that inhibition of lung GM-CSF expression as a result of hyperoxia is a critical event promoting lung injury and respiratory failure. Four specific aims will be undertaken. Initially they will characterize the response of P. carinii infected mice to hyperoxia. Next, they will determine the expression of GM-CSF in this animal infection model and in mice that genetically lack GM-CSF following exposure to PCP and hyperoxic conditions. They will further determine whether direct interaction of P. carinii and alveolar epithelial cells through integrins induces GM-CSF expression. Finally, they will evaluate the protective effect of GM-CSF in P. carinii pneumonia and in subsequent progression of lung injury following hyperoxia.