Pneumocystis carinii produces a life-threatening pneumonia in patients who are immunocompromised. It is especially prevalent among patients with AIDS. While the hallmark of P. carinii pneumonia (PCP) is hypoxia, the type and extent of lung injury produced by P. carinii has never been defined or characterized. The goal of this proposal is to define and begin to characterize the pulmonary insult resulting from PCP. This will be accomplished by completing the following specific aims: 1) to determine the extent and means by which P. carinii directly contributes to injury and altered lung function in the absence of a host immune response, i.e., in a SCID mouse; 2) to determine the extent and mechanism by which the host inflammatory response contributes to the pathophysiological changes that occur in PCP; and 3) to determine whether manipulation of the host inflammatory response can ameliorate the pathophysiological sequelae of PCP. Preliminary experiments show that the host inflammatory response itself contributes significantly to the overall pulmonary injury in a SCID mouse model of PCP. Using the most modem molecular/cellular and physiologic techniques, including assessment of lung compliance in a ventilated living mouse, this proposal will test the hypothesis that the pathogenesis of PCP is the result of both the direct effect of P. carinii on the lung and the effect of the P. carinii-driven host inflammatory response. This will be done by carefully manipulating various aspects of the inflammatory response to determine the effect on lung injury. If this hypothesis is proven correct, the information gained from the proposed studies can be utilized to develop new therapeutic modalities to improve the morbidity and mortality resulting from PCP.
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