Immune-mediated inflammation directly impairs pulmonary function, contributing to the pathogenesis of Pneumocystis carinii pneumonia

The clinical severity of Pneumocystis carinii pneumonia (PCP) correlates cl osely with the appearance of pulmonary markers of inflammation. Therefore, a model system was developed whereby physiological studies could be perform ed on Live mice to determine the extent to which pulmonary inflammation con tributes to respiratory impairment during PCP. P. carinii-infected severe c ombined immunodeficient mice displayed little evidence of pulmonary inflamm ation and exhibited normal oxygenation and dynamic lung compliance. When co mparably infected littermates were immunologically reconstituted, however, an intense immune-mediated inflammatory response was observed that resulted in significant decreases in both lung compliance and oxygenation. As the p neumonia resolved, pulmonary function returned toward normal. To begin to d efine the cell populations contributing to inflammation-associated respirat ory impairment during PCP, similar studies were performed in CD4(+) T cell- depleted mice. Mice depleted of both CD4(+) and CD8(+) cells developed infe ction, but they demonstrated neither abnormal lung compliance nor increased respiratory rate and displayed no markers of lung injury. In contrast, mic e depleted of only CD4(+) T cells exhibited severe pulmonary inflammation a nd injury, decreased oxygenation and lung compliance, and increased respira tions. Respiratory compromise was associated with the presence of activated CD8(+) cells and neutrophils in broncho-alveolar lavage fluid. These obser vations provide direct experimental evidence that the host's response to P. carinii directly impairs pulmonary function and contributes to the pathoge nesis of PCP. Furthermore, CD8(+) T cells Likely contribute to the respirat ory compromise observed during PCP.