SELECTED ARTICLES FROM THE RECENT LITERATURE 2003

12/23/03

Role of leukotrienes on airways disease

Summary
Recent alterations of the paradigm for the effects of chronic airways inflammation in asthma were reviewed by Holgate et al. Overall, there is an exaggerated inflammatory reaction and subsequent remodeling in the airway tissues as a consequence of abnormal injury and repair responses arising from a subjects' susceptibility to inhaled environmental components. An epithelial-mesenchymal trophic unit becomes activated resulting in epithelial remodeling and airway smooth muscle (ASM) proliferation, conditioned by a complex interaction of cytokine effects. Histamine, prostanoids and cysteinyl leukotrienes (Cys LT) are potent agonists of ASM contraction. The Cys LT appear to play a central role in the ASM contraction and hypertrophy seen in chronic asthma. On the other hand, prostaglandin E2 (PGE2), the predominant prostanoid in the airway epithelium, is a potent inhibitor of these pro-inflammatory events and thereby inhibits the airway remodeling process. The capacity of the epithelium to synthesize Cyst LT is inversely related to its capacity to make PGE2. The ASM can also express receptors for Cys LT, up-regulated by cytokine effects. Therefore, Cys LT likely play an important role in the airway remodeling seen in persistent asthma including increased goblet cells, mucus production, vascularity, ASM proliferation and fibrosis. These pathologic events are inhibited by Cys LT receptor antagonists in a mouse model of asthma.

Reference
J Allergy Clin Immunology 2003; (1 Suppl): S18-34

Editor's Comments
It is now recognized that both inflammatory responses and ASM changes play pathogenic roles in chronic persistent asthma. This excellent review describes evidence to explain the recent concept that chronic asthma is not always a fully reversible disease. Rather there are alterations that eventually lead to irreversible airway changes (remodeling). A cell type called the myofibroblastic is key to this development. The authors postulate that Cys LT play a central role in airway remodeling. However, it that is the case, it is surprising that clinically employed Cys LT receptor antagonists such as montelukast are not more effective than shown in the treatment of chronic asthma. One can argue that orally administered agents such as montelukast do not get to key loci in the airways in sufficient concentrations to block Cys LT effects. However, previous studies have shown that these agents do block very well the effects of inhaled exogenous Cys LT. More investigation is needed.

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