The macrophage mannose receptor plays an important role in both host defense and in regulation of inflammation. Physiologic ligands for this receptor are both particulate and soluble, and include pathogens such as Pseudomonas, Candida, and Pneumocystis; and, proteins such as neutrophil- derived myeloperoxidase and extracellular lysosomal hydrolases. The receptor binds these ligands and delivers them tot he phagolysosomal compartment for degradation, thus removing agents for the extracellular space that might contribute to injury or continuing inflammation. The mannose receptor is exquisitely regulated by modulating agents that are produced at or travel to the site of injury. The receptor is inactivated or down-regulated by proteases, oxidants, endotoxin, and interferon- gamma. Alternatively, the mannose receptor is dramatically up-regulated by anti-inflammatory agents such as dexamethasone. The receptor is not present on circulating monocytes, but appears during in vitro differentiation induced by M-CSF. The overall goal of this project is to study potential mechanisms of regulation of the mannose receptor in in vivo lung injury models.
The specific aims of this project are 1) to characterize the regulation of the macrophage mannose receptor in the endotoxin-treated rat and sheep models of acute lung injury, and in human alveolar macrophages isolated from patients with ARDS; 2) to determine the potential role of xanthine oxidase-derived oxidants and macrophage-derived nitric oxide in the down- regulation of the mannose receptor; and, 3) to study the effect of immunosuppressive or antiinflammatory agents on the regulation of the mannose receptor, xanthine oxidase, and nitric oxide synthase in in vitro and in vivo models.
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