Specifically targeting PGE2 synthase by inhibition of microsomal prostaglandin E synthase-1 (mPGES-1) has emerged as a potential therapeutic target. Deletion of mPGES-1 has demonstrated cardioprotective effects potentially through substrate diversion augmenting formation of cardioprotective prostanoids. The risk of substrate diversion to produce bronchoconstrictor prostanoids during airway hyper-reactivity was investigated by Wang et al. using mPGES-1 knockout mice. Using the ozone-induced airway hyper-reactivity model, reduction in bronchoalveolar lavage prostaglandin E2 (PGE2), with concomitant increase in 6-keto-PGF1α, PGD2, and PGF2α, was observed after methacholine challenge in knockout mice. However, there was no change in lung resistance, carbachol-induced narrowing of the airways, or cell trafficking in mPGES-1 knockout versus wild-type mice. Despite substrate diversion to other prostanoids, suppression of PGE2 by deletion (or inhibition) of mPGES-1 provided no evidence suggestive of enhanced airway dysfunction and no reason to suggest that selective targeting of mPGES-1 may predispose patients at risk to airway dysfunction.
See article at J Pharmacol Exp Ther 2010, 334:63–68.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics