Wednesday, May 8, 2024
5/8/2024
DESCRIPTION (provided by applicant): The purpose of this study is to gain a better understanding of the source, function, and cause of the elevated levels of Endothelin-1 (ET-1) observed during infection and inflammation. Initially described as a potent vascular smooth muscle constrictor released from the endothelium by ischemia, injury, or inflammation, ET-1 is now known to be produced by a variety of cells and tissues under normal and pathological conditions. Elevated levels of ET-1 are observed during and may contribute to the pathology of a number of localized and systemic inflammatory conditions including atherosclerosis, asthma, and sepsis. While the importance of ET-1 for normal cardiovascular development during embryogenesis and cardiovascular function in the adult is widely accepted, the importance of ET-1 during these inflammatory conditions is only beginning to emerge. Clinical and experimental studies have identified macrophages as a potential source of ET-1 during infection and inflammation. Studies outlined in this proposal are designed to characterize the production of endothelin- 1 (ET-1) by macrophages in response to microbial challenge. We propose to identify receptor-ligand interactions, cell signaling events, and cis- and trans-acting factors which regulate the production of ET-1 by macrophages. We hypothesize that ET-1 production is part of the characteristic macrophage response to microbial challenge and that macrophages are a key source of ET-1 during infection and inflammation. Macrophage derived ET-1 has the potential to affect tissue perfusion, angiogenesis, atherogenesis, leukocyte extravasation, and immune cell function. An understanding of how ET-1 production is regulated during pathological states, and how this differs from its normal physiological production, may allow for the design of specific therapeutic interventions which can harness its aberrant production without disrupting its normal physiological activities.
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