DESCRIPTION (provided by applicant): Pneumocystis carinii pneumonia remains a significant cause of mortality and morbidity in immune compromised patients, particularly those with AIDS, malignancy, and organ transplantation. Our investigations demonstrate that respiratory impairment during PC pneumonia is more closely related to exuberant pulmonary inflammation than to toxic effects of the organism. Adjunctive anti-inflammatory corticosteroid therapy (given in addition to antibiotics) improves outcome in this infection. Our studies demonstrate that cell wall beta-glucans of Pneumocystis (PCBG) specifically interact with alveolar macrophages to trigger inflammatory activation through NF-kappaB translocation, stimulating release of TNF-alpha and chemokines that promote neutrophil recruitment in the lungs. Additional investigations demonstrate that alveolar epithelial cells also interact with PC beta-glucans and are potently activated to release chemokines including MIP-2, which further promote lung inflammation. Epithelial responses are robust and of magnitude comparable or greater than those elicited by macrophages. The mechanisms of activation of alveolar macrophages and epithelial cells by PCBG involve multiple distinct receptor systems. In the current proposal, we hypothesize that alveolar macrophages and epithelial cells are activated by PCBG through distinct receptor systems involving CD11b/CD18 in macrophages and lactosylceramide in epithelial cells resulting in NF-kappaB-based activation. These concepts will be addressed through four independent but interrelated specific aims. In Aim 1, we will assess the roles of CD11b/CD18 integrins and TLR-2 (toll like) co-receptors in initiating NF-kappaB mediated inflammatory responses in macrophages. In Aim 2, the mechanisms through which lactosylceramide initiates inflammatory activation of epithelial cells will be determined. Aim 3 will evaluate the mechanisms of PCBG internalization in macrophage and epithelial cell inflammatory activation. Finally, Aim 4 will utilize mice deficient in CD11b or TLR2, and inhibitors of lactosylceramide, to study the roles of these lung responses during development of PC pneumonia in the intact host. Organisms burden and associated measures of lung inflammation will be studied during the course of PC pneumonia in these animals. Better understanding of the interactions of PC beta-glucans with host alveolar macrophages and epithelial cells will assist in the development of novel adjuvant anti-inflammatory.
|Effective start/end date||7/10/93 → 6/30/18|