Lipoxygenase pathway and hydroperoxy acids: possible relevance to aspirin-induced asthma and hyperirritability of airways in asthmatics

Abstract

The precise mechanisms(s) responsible for airway hyperreactivity to spasmogenic agents (for example, cholinergic stimulants, alpha-adrenergic agonists, histamine, PGF2 alpha and several other nonspecific stimuli) in asthmatics is not known. Substantial evidence exists fo the mediator, as well as modulatory, roles of the products of arachidonic acid metabolism operating via the cyclo-oxygenase pathway in the pathophysiology of lung diseases. Aspirin and other inhibitors of cyclo-oxygenase induce severe bronchospasm and asthmatic attacks in a significant population of asthmatic patients. This adverse effect of aspirin is often attributed to inhibition of the synthesis and release of defensive "modulatory" endogenous prostaglandins (PGD and PGI2?) in the lungs. Thus, removal of their "negative feedback" mechanism on the allergic release of chemical mediators (e.g., histamine and SRS-A: leukotriene C and D) from lung mast cells could lead to an enhancement of the release of mediators and severity of asthmatic attacks. In addition to these mechanisms, recent work suggests the diversion of arachidonic acid (AA) metabolism via the lipoxygenase pathway (especially after cyclo-oxygenase inhibition by aspirin and indomethacin), thereby leading to the formation of a new class of biologically active lipids: hydroperoxy acids (HPETE and HETE), leukotrienes (LTA, B, C, D, E) and SRS or SRS-A (LTC, LTD). The inherent or drug (aspirin)-induced deficiency or blockade of cyclo-oxygenases(s) and/or peroxidases in the lungs (and/or other body tissues, including leukocytes) leading to diversion of AA into the formation and accumulation of SRS (leukotrienes), especially in sensitive individuals, could explain the mechanism of aspirin-induced asthma, and probably the generalized syndrome of aspirin-tolerance. Furthermore, the hydroperoxy acids, leukotrienes, (SRS) may also sensitize receptors for other mediators and common nonspecific irritants, and/or induce airway contractions directly. Collectively, these mechanisms could account for airway hyperreactivity in asthma.