Mediation of leukocyte components of inflammatory reactions by lipoxygenase products of arachidonic acid.

The leukocyte lipoxygenase products LTB4 and 5-HETE elicit human neutrophil and eosinophil chemotactic responses in vitro and in vivo (Fig. 4), and are present at elevated concentrations in the lesions of some human inflammatory diseases, such as rheumatoid arthritis and the spondyloarthritides. The chemotactic potency of LTB4 is similar to that of the minor fragment of the fifth component of human complement, termed C5a, and is 30- to 300-fold greater than that of 5-HETE and of other natural DHETE isomers. Human neutrophils possess distinct subsets of chemotactic factor receptors that are specific for LTB4 and for 5-HETE, as demonstrated by the selective competitive inhibition of the chemotactic responses to the parent stimuli by acetyl LTB4 and 5-HETE methyl ester, respectively, and by the failure of the lipid chemotactic factors to bind to isolated membrane protein constituents of the human neutrophil receptors for chemotactic formyl-methionyl peptides. LTB4 and 5-HETE also elicit human neutrophil and eosinophil chemokinesis, stimulate the uptake of calcium and D-glucose, and enhance the expression of C3b receptors on the leukocytes; however, they exert only a minimal effect on superoxide generation and lysosomal enzyme release. LTB4, but not 5-HETE, stimulates the release of calcium from previously unexchangeable intraneutrophil pools, as has been described for potent peptide chemotactic factors. Although far less potent than LTC4 and LTD4, LTB4 constricts peripheral airways, enhances mucous secretion in the airways of the lung, and dilates and enhances the permeability of the microvasculature in skin and other organs (Fig. 4). A variety of leukocyte functions, including chemotaxis, D-glucose uptake, and lysosomal enzyme release, are impaired in association with the depletion of endogenous lipoxygenase products. Exogenous 5-HETE reverses some of the functional deficits of HETE-depleted leukocytes. Inhibition of leukocyte lipoxygenase activity also suppresses the intracellular content of hydroperoxyeicosatetraenoic acids and of novel polar metabolites of arachidonic acid that may be critical to the activation of human neutrophils and eosinophils. Thus LTB4 and the less potent 5-HETE are active extracellular mediators of the leukocytic components of hypersensitivity and inflammation and may also serve an important role as intracellular mediators of leukocyte function.