Exploring new approaches to the treatment of asthma: potential roles for lipoxins and aspirin-triggered lipid mediators

Abstract

The prevalence of asthma continues to increase and its optimal treatment remains a challenge. During asthma, leukotrienes and prostaglandins are generated in human airways, leading to bronchoconstriction and airway inflammation. Several pharmaceutical agents are currently available to inhibit the formation or action of these lipid mediators, but asthmatic individuals have heterogeneous and often incomplete therapeutic responses. Lipoxins are a class of eicosanoids distinct from leukotrienes and prostaglandins. Temporal analyses in experimental models of acute inflammation reveal early coordinate appearance of leukotrienes and prostaglandins followed by delayed lipoxin biosynthesis concurrent with resolution of the inflammatory response. Of interest, lipoxins display unique antiinflammatory actions and, in an experimental model of asthma, administration of a stable analog of 15-epi-lipoxin A(4) markedly decreased both airway hyperresponsiveness and inflammation. In addition, overexpression of human lipoxin A(4) (LXA(4)) receptors in murine leukocytes also protected animals from the development of airway inflammation. Inhibition of airway hyperresponsiveness and allergic airway inflammation with a LXA(4) stable analog highlights a unique counterregulatory profile for LXA(4) and its leukocyte receptor in airway responses and suggests that lipoxins and related pathways present novel multipronged therapeutic approaches for consideration in airway inflammation and human asthma.