The Role of Arachidonic Acid Metabolites in Local and Systemic Inflammatory Processes

Summary

Leukotrienes are synthesised from arachidonic acid via the 5-lipoxygenase pathway in neutrophils, eosinophils, monocytes/macrophages, basophils and certain mast cell populations. Their synthesis is closely regulated by several known factors and the cells which contain 5-lipoxygenase do not all possess the capability to synthesise all of the leukotrienes. Neutrophils produce leukotriene B₄, which attracts other neutrophils, whereas the leukotriene C₄, produced by eosinophils, increases the contractile activity of smooth muscle. Monocytes/macrophages are able to produce both of these leukotrienes. Receptor sites for leukotriene B₄ have been identified on monocytes and neutrophils and receptors for leukotriene D₄, a cleavage product of leukotriene C₄, have been defined in pulmonary tissue.

In animals, sulphidopeptide leukotrienes have been shown to cause potent vasoconstriction resulting in increased blood pressure and increased vascular permeability leading to hypovolaemia. These leukotrienes also depress renal (in animals) and pulmonary (in animals and humans) function, the latter probably as a result of effects on peripheral rather than central airways. In patients with mild asthma, however, there is no differential activity of this type. The sulphidopeptide leukotrienes caused wheal and flare when administered intradermally in healthy volunteers, which was of considerably longer duration than that induced by prostaglandin D₂. Conversely, leukotriene B₄ caused accumulation of neutrophils in the absence of wheal and flare.

Studies into the effects of dietary fish oil showed that 2 constituents, docosahexanoic acid and eicosapentaenoic acid (EPA), inhibit the conversion of arachidonic acid by cyclo-oxygenase, but not by 5-lipoxygenase. Furthermore, 5-lipoxygenase converts EPA to a pentene series of leukotrienes and the sulphidopeptide derivatives possess similar activity to their tetrameric counterparts. Conversely, the pentene leukotriene B₅ has attenuated activity. In healthy volunteers, it was shown that the 5-lipoxygenase pathway was markedly attenuated in activated white blood cells after 6 weeks of dietary supplementation with fish oil capsules. In addition, the neutrophils had lost their ability to adhere to endothelial cell monolayers and demonstrated a reduced capacity to engage in a chemotactic response.

The leukotrienes, therefore, are important factors in mediating inflammation and the potential for moderating their activity by dietary means deserves a full clinical examination.