Leukotrienes and Other Eicosanoids as Mediators of Airway Obstruction

Prostaglandins and related compounds comprise an ubiquitous biological system which utilizes arachidonic acid (5,8,11,14-eicosatetraenoic acid) as a common cellular precursor to synthesize a great number of substances with a broad range of activities, including participation in the cellular and humoral events of inflammation and allergy. Briefly, prostaglandins and thromboxanes (TX) are formed in reactions initiated by the aspirin-sensitive fatty acid cyclooxygenase, whereas leukotrienes (LT) and several other compounds are generated by different lipoxygenases present in human tissues. In the field of asthma, the mast cell-derived PGD2α, as well as PGF2α and TXA2 are known as reasonably potent bronchoconstrictors, and asthmatics are remarkably hyper-reactive to inhalation of PGF2α. However, the therapeutic failure of aspirin and related cyclooxygenase inhibitors in the treatment of asthma suggests that these compounds are less likely to be primary mediators. On the other hand, several lines of evidence indicate that three closely related leukotrienes, LTC4, LTD4 and LTE4, previously known as slow-reacting substance of anaphylaxis (SRS-A), have the potential to be major mediators of the airway perturbations characteristic of bronchial asthma. Thus, as documented both in experimental animals and in man, these leukotrienes are exquisitely potent in causing bronchial smooth muscle contraction, mucosal edema, and secretion of mucus into the lumen. In particular, LTC4, LTD4 and LTE4 have been linked to allergic asthma because allergen challenge is a potent stimulus for their release from, e.g., lung tissue of asthmatics. In fact, it has been documented that inhibition of leukotriene formation can block allergen-induced contractions of isolated human bronchi. There is also compelling evidence that non-immunological activation may evoke LT release from mast cells, alveolar macrophages and neutrophils. In addition, LTB4, which also is formed in the lung, stimulates leukocyte activation including infiltration into the tissue. Considered together, it is apparent that leukotrienes may serve as one set of final common mediators of airway inflammation. The presentation will give an overview of leukotriene mechanisms that are considered of relevance to airway function, with particular reference to interactions between leukotrienes and secondarily released cyclooxygenase products. Since the major eicosanoid product in the human lung is 15-monohydroxy-eicosatetraenoic acid, it is of considerable interest that a novel group of eicosanoid mediators, the lipoxins, also are formed by lipoxygenation of arachidonic acid at C-15. Finally, experimental work analyzing the effect of lipoxygenase inhibitors and anti-inflammatory steroids on the airway responses to allergen challenge will be mentioned.