This study will focus on the interactions of the inflammatory peptide neurotensin (NT), with mast cells and leukocytes. Earlier experiments from our laboratories and those of others have shown NT to promote the release of histamine (H) from peritoneal, pleural, heart, skeletal and recently, cutaneous mast cells in vitro and in vivo and elevate blood H, LTC4 and LTB4 levels when given IV. Within minutes of NT's injection intense hypotension, hyperglycemia and cyanosis develop, the latter involving a blood stasis with hemotocrits of 60%. NT is the most potent substance known to increase vascular permeability and its dramatic effects far exceed those of H, LTC4 and PGE2. While evidence strongly indicates that the source of H is the tissue mast cell, the sources of LTC4, LTB4 and PGE2 released by NT is unclear. Experiments are proposed to answer this question. Recently we discovered that blood and all tissues contain precursors to NT-related peptides which yield micro-M concentration of immunoreactive NT when treated with acid proteases. These NT-related peptides also have biological activity as they stimulate H release from the isolated mast cell. We hypothesize that these NT-related peptides are generated at inflammatory sites by the action of acid proteases from activated leukocytes and that they mediate the second phase of inflammation. We propose experiments aimed towards testing this hypothesis and gaining an understanding of how NT activates mast cells and possibly other cells and how it stimulates LTC4, LTB4 and PGE2 production. One possibility to be tested is that NT activates leukocytes to release mast cell- degranulating peptides. The biologic and chemical properties of these peptides will also be compared to those of NT. Finally, we will determine directly if NT or NT-like peptides are generated during various inflammatory reactions and if antisera against NT or NT antagonists will alter the inflammatory response.
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