TRANSCELLULAR LEUKOTRIENE BIOSYNTHESIS AND INFLAMMATION

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Leukotrienes (LT) are biologically active lipids derived from cellular oxidative metabolism of arachidonic acid. These substances are prominent among the autocoid mediators that initiate, aggravate, or sustain inflammatory disorders. The sulfidopeptide leukotrienes, typified by LTC4 and its metabolites, have been attributed a significant role in respiratory anaphylaxis because of their potent bronchoconstrictive actions. Leukotriene B4 (5S,12R)-5,12-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid) has multiple actions relevant to inflammation including a chemotactic effect, a myotropic effect, and an hyperalgesic effect. Recent investigations indicate that enzymatic and cellular cooperation between erythrocytes and neutrophils is a novel mechanism for leukotriene B4 formation. Three features characterize this transcellular biosynthetic process. First, neutrophils produce and secrete LTA4, the pivotal, intermediate in leukotriene biosynthesis. Second, erythrocytes assimilate and convert that LTA4 into LTB4 via the action of their LTA4 epoxide hydrolase. Third, suicide inactivation of LTA4 hydrolase by its reactive substrate accompanies LTB4 formation. We propose to investigate the regulation, modulating and consequences of LTB4 formation by erythrocyte-neutrophil interactions. We aim to: I. Characterize factors that influence erythrocyte-neutrophil interactions and formation of leukotriene B4 by transcellular biosynthesis. II. Characterize the suicide inactivation of leukotriene A4 hydrolase, the enzyme that catalyzes leukotriene B4 formation. III. Develop antibodies against suicide inactivated and native leukotriene A4 epoxide hydrolase as immunochemical probes for transcellular biosynthesis. This is the initial stage in a new research proposal based on the hypothesis that: i) transcellular biosynthesis of leukotriene B4 via erythrocyte-neutrophil interactions is a physiologically and pathologically relevant process; and ii) this process can be detected and monitored via the status of LTA4 epoxide hydrolase within erythrocytes. If successful, a direct application to human disease will be investigated.