The leukotrienes (LTs) constitute a family of 5-lipoxygenase products of arachidonic acid metabolism which have been shown to effect peripheral airway smooth muscle constriction, increased vascular permeability, and granulocyte chemotaxis at nanomolar concentrations, such that their potencies for these pro-inflammatory effects are, in general, two to three orders of magnitude greater than those of other known mediators. Depending upon the organ system in which they are generated, these compounds are thus of potential relevance to a wide spectrum of inflammatory events including asthma, various forms of arthritis, and pathological vascular events involving inflammation in either an initiating or a potentiating capacity. We intend to explore a number of aspects of the biology of these compounds including cellular origins; the mechanisms of cell activation to generate LTs; isolation and characterization of specific enzymes in the LT biosynthesis pathway; biological effects on contractile, vascular and chemotactic assay systems; and isolation and identification of their receptors, with characterization of the chemical basis for interaction of LT and receptor. Additionally, we intend to pursue the discovery of inhibitors of both the biosynthetic enzymes and of the functional response to the LTs. The accomplishment of this project depends upon the unique capabilities of each contributing group: development of anti-leukotriene radioimmunoassays, including production of monoclonal antibodies, enzyme purification, receptor identification and characterization, and functional evaluation of inhibitors and antagonists at Harvard Medical School; cell culture and immunopharmacology of cell activation with product identification by radioimmunoassays at Brandeis University; and the entire chemical initiative, including synthesis of natural leukotrienes, design and synthesis of LT analog compounds at LT-carrier protein immunogens, development of affinity reagents, and the design and synthesis of enzyme inhibitors and functional antagonists at the Department of Chemistry, Harvard University.
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