Lung Damage from P. carinii: pathogenesis and prevention

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DESCRIPTION (provided by applicant): Pneumocystis carinii pneumonia (PcP) is a significant cause of morbidity and mortality in patients with a compromised immune system such as those with AIDS or those receiving immunosuppressive therapy for malignancy, organ transplantation or other underlying medical conditions. The central hypothesis for this proposed program project grant (PPG) is: lung injury during PcP is largely the result of the immune-mediated inflammatory response to P. carinii and that specific and effective control of this response will improve the morbidity and mortality associated with PcP. To test our hypothesis in mouse models of PcP we have set the following goals for this proposed PPG: 1) To elucidate the mechanisms by which lymphocytes, phagocytic cells and relevant soluble mediators interact to damage alveolar epithelial cells, perturb the surfactant system and interfere with normal lung function. 2) to utilize the knowledge gained through the completion of goal 1 to identify and test potential new adjunctive therapies for PcP based on control of specific injurious inflammatory pathways. To accomplish our goals we have assembled a multi-disciplinary group of investigators who bring expertise in microbiology, immunology, molecular biology, surfactant biochemistry and biophysics and respiratory cell and molecular biology to this project. This group of investigators will be able to examine the pathogenesis of PcP from the initial interaction between P. carinii and specific cells of the immune system through the development of a P. carinii-specific immune response then on to the effects of alveolar epithelial cells and surfactant with resultant end stage pulmonary dysfunction. This investigative effort will identify potential sites for therapeutic intervention to reduce the morbidity and mortality associated with PcP. I