THE PROBLEM: The Acquired Immunodeficiency Syndrome (AIDS) is an urgent world-wide clinical problem. Pneumocystis carinii pneumonia (PCP) is a major cause of morbidity and mortality in these patients. Inhaled pentamidine isethionate has been used both for treatment of and prophylaxis against Pneumocystis carinii pneumonia. However, the mechanism of action of pentamidine against Pneumocystis carinii remains unknown. HYPOTHESIS: Pulmonary alveolar macrophages are the primary resident host defense cell in the lung and are capable of releasing several inflammatory mediators including toxic oxygen radicals. We hypothesize that pentamidine activates alveolar macrophage function, specifically enhancing the release of toxic oxygen radicals in response to stimulation.
The specific aims are to determine if inhaled pentamidine stimulates alveolar macrophages to release oxygen radicals in vivo and to evaluate the effects of these oxygen radicals on P. carinii. During the past year we have developed a rat model of inhaled pentamidine to evaluate the above hypothesis. Alveolar macrophages from rats treated with pentamidine will be tested for their quantitative ability to release toxic oxygen radicals and the specific effects of these oxidants on viability and growth of P. carinii will be evaluated. SIGNIFICANCE: Inhaled pentamidine as prophylactic treatment against Pneumocystis carinii pneumonia is an attempt to target drug therapy in an organ specific, non-toxic manner. The development of a rat model that closely mimics the human situation allows us to evaluate the mechanism of action of pentamidine and define its effects on lung cells both in the short and long term. Determination of the mechanism of action of inhaled pentamidine may improve clinical management of immunosuppressed patients with Pneumocystis carinii pneumonia.
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