The overall objective of this project is to define mechanisms for the regulation of alveolar macrophage function. The current study will investigate how immunosuppression influences the functions of alveolar macrophages and what effect this may have on host defense against opportunistic pulmonary infection. It is our hypothesis that immunosuppression decreases alveolar macrophage function and that this decreased function is important in the pathogenesis of opportunistic infection. The present proposal will test this hypothesis in the rat, using glucocorticoid treatment as a model of immunosuppression and Pneumocystis carinii pneumonia as a model of opportunistic infection.
Specific Aim 1. To characterize the effects of experimentally- induced immunosuppression on alveolar macrophage function. Alveolar macrophages will be recovered from glucocorticoid- treated rats at serial intervals and examined for functions relevant to host defense against infection: cytotoxic function, expression of Ia determinants, elaboration of interleukin-1, and release of arachidonic acid metabolites. Glucocorticoid-treated rats will also be monitored for infection with Pneumocystis carinii, so that changes in the functions of alveolar macrophages can be correlated with the development of infection.
Specific Aim 2. To examine whether functions of alveolar macrophages which are decreased during immunosuppression can be increased in vitro. Alveolar macrophages from glucocorticoid- treated rats will be cultured in vitro with recombinant interferon gamma and tumor necrosis factor alpha to see if specific functions can be increased in response to these cytokines.
Specific Aim 3. To examine whether functions of alveolar macrophages which are decreased during immunosuppression can be increased in vivo. Based upon the results of experiments performed for Specific Aims 1 and 2, glucocorticoid-treated rats will be exposed to aerosolized cytokines at selected time points. The functions of lavaged alveolar macrophages will then be assayed to see if aerosolized cytokines can increase the function of these cells in vivo.
Specific Aim 4. To examine whether increasing alveolar macrophage function in vivo can prevent or ameliorate opportunistic infection of the lungs. Based upon the results of experiments performed for Specific Aim 3, glucocorticoid-treated rats will be exposed to aerosolized cytokine(s) and monitored for infection with Pneumocystis carinii, to see if increasing alveolar macrophage function in vivo will influence the natural history of this infection. The results of these experiments will provide new information as to how immunosuppression affects specific alveolar macrophage functions and how this influences host defense against Pneumocystis carinii. The ability to increase alveolar macrophage function by aerosol delivery of cytokines may warrant extension of this work to the study of humans with immunosuppression and opportunistic pulmonary infections.
