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 PGD2 alpha, as well as PGF2 alpha and TXA2 are known as reasonably potent bronchoconstrictors, and asthmatics are remarkably hyperreactive to inhalation of PGF2 alpha. 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.(ABSTRACT TRUNCATED AT 250 WORDS)