Modulation of arachidonic acid metabolites as potential therapy of asthma

Abstract

Bronchial asthma is a multifactorial disease characterized by reversible bronchoconstriction, airway hyperreactivity, oedema and excessive mucus production. Present therapy directed against specific mediators has not been overwhelmingly successful. Even though there exists a multiplicity of purported mediators, perhaps the key to better therapy is a vigorous understanding of the arachidonic acid cascade and investigations to modulate specific products of these pathways. Within the cyclooxygenase pathway an interesting scenario might be to effectively antagonize the potent bronchoconstrictive effects of prostaglandin (PG)D2 and its recently identified predominant metabolite, an 11-hydroxyl epimer, 9 alpha,11 beta-PGF2. PGD2 is the major cyclooxygenase product released from sensitized human lung and bronchoalveolar lavage (BAL) mast cells; it possesses a myriad of biological actions relevant to the pathogenesis of asthma. While no specific antagonists of PGD2 or 9 alpha,11 beta-PGF2 have been identified, some preliminary studies have suggested that, perhaps, PGD2 may be interacting, at least in part, with thromboxane receptors. In addition, peroxidation of arachidonic acid catalyzed by 5-lipoxygenase produces the leukotrienes, which are extremely potent bronchoconstrictors as well as oedema and mucus secretagogues. Leukotrienes are primary mast cell mediators which may be the vital link to both early (acute) and late (chronic) asthmatic attacks. Research seeking leukotriene antagonists has been intensive. Leading clinical candidates have emerged from Smith Kline and French, Lilly, Merck-Frosst, ICI-Stuart and other groups. However, we must await the outcome of ongoing clinical trials in asthmatics to determine just how important the leukotrienes really are in the pathogenesis of asthma, allergy and inflammation. Thus, modulation of the effects of products of arachidonic acid metabolism may provide a new and more specific treatment for bronchial asthma.