Defensins, a family of lysosomal antimicrobial peptides, are among the principal constituents of human and other mammalian phagocytes. Their varied biological activities suggest important roles in host defense, proinflammatory, and cytotoxic events. In the rabbit, two defensins, macrophage cationic peptides MCP-1 and 2, are actively synthesized in alveolar but not other macrophages, undergo complex processing, and are targeted to lysosomes by a novel mechanism. During the first few weeks of postnatal life, the MCP content of alveolar macrophages increases at least seven-fold, and it rises three-fold after immune stimulation. To understand the factors which control the synthesis of these peptides, we will: 1. Study the processing and targeting of defensins (macrophage cationic proteins MCP-1 and 2) in rabbit alveolar macrophages 2. Identify the pathways of tissue-specific, developmental and immune regulation of defensin synthesis in rabbit alveolar macrophages 3. Correlate the transcriptional activity of defensin genes with their state of methylation and their interaction with nuclear DNA-binding proteins in rabbit alveolar and peritoneal macrophages, monocytes and other cell types. The study of MCP synthesis and processing will reveal how pulmonary macrophages synthesize and package potentially cytotoxic proteins without incurring autocytoxicity. Investigations of the regulation of MCP synthesis will shed light on macrophage differentiation in response to their tissue environment-a little understood process which makes alveolar macrophages phenotypically distinct from other macrophages. Pulmonary infections are major causes of illness and death. Although the ability of the lung to defend itself against microbial pathogens arises from a network of cellular, humoral and structural elements, the antimicrobial activities of its alveolar macrophages are central determinants of Post defense. In the long-term future, the results of these studies may facilitate the design of immunotherapeutic peptide genes whose product can be specifically targeted to alveolar macrophage lysosomes.
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