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The leukotrienes (LTs) were discovered in 1979 as a group of acute inflammatory mediators derived from arachidonic acid in leukocytes. Their biosynthesis was shown to proceed via the 5-lipoxygenase (5-LO) pathway. LT biosynthesis has subsequently been demonstrated in other bone marrow-derived cells expressing 5-LO including eosinophils, mast cells, and macrophages. 5-LO converts arachidonic acid into LTA4 with 5(S)-HpETE as an intermediate. The conjugation of glutathione to LTA4 results in the formation LTC4. LTC4 is rapidly metabolized to LTD4 and LTE4. This metabolism is essentially complete within 10 minutes in the human lung. LTC4, LTD4, and LTE4 are collectively referred to as cysteinyl-leukotrienes (cys-LTs). LTC4 and LTD4 are potent mediators of asthma and hypersensitivity. They induce bronchoconstriction, increase microvascular permeability, and are vasoconstrictors of coronary arteries. Cys-LTs can accumulate to relatively high concentrations in the effusion fluids associated with inflammation (e.g., ascities fluid, synovial fluid, pleural effusion, pericardial or cerebral aspirates). Since LT metabolism is incomplete in these circumstances, substantial amounts of LTC4, LTD4, and LTE4 may be present (e.g., bronchalveolar lavage fluid from asthmatic subjects may contain 700-1,000 pg/ml of cys-LTs comprised mainly of LTC4 and LTD4). Cys-LTs are excreted in urine as intact LTE4 (~9-12%) and LTE4 metabolites. Since LTC4 and LTD4 and virtually absent from urine, the cys-LT measurement in urine is often best accomplished by measuring LTE4 (LTE4 EIA Kit, Catalog No. 520411). Cultured cells synthesizing LTC4 will generally release it into the medium where it will accumulate without further metabolism. |