Abstract
Nonsteroidal anti-inflammatory drugs ameliorate pain and fever by inhibiting cyclooxygenase (COX) and suppressing prostanoid formation. Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes formation of PGE2 from the COX product PGH2 and has emerged as a therapeutic target. Inhibition of mPGES-1, however, renders the PGH2 substrate available for diversion to other PG synthases. To address the possibility that substrate diversion augments formation of PGs that might modulate bronchial tone, we assessed the impact of mPGES-1 deletion in a mouse model of ozone-induced airway hyper-responsiveness. Ozone exposure increased total lung resistance to inhaled methacholine in wild-type mice. Deletion of mPGES-1 had little effect on total lung resistance in either naive or ozone-exposed animals. The carbachol-induced narrowing of luminal diameter in intrapulmonary airways of lung slices from acute ozone-exposed mice was also unaltered by mPGES-1 deletion. Likewise, although concentrations of PGE2 were reduced in bronchoalveolar lavage fluid, whereas 6-keto-PGF1α, PGD2, and PGF2α, all were increased, deletion of mPGES-1 failed to influence cell trafficking into the airways of either naive or ozone-exposed animals. Despite biochemical evidence of PGH2 substrate diversion to potential bronchomodulator PGs, deletion of mPGES-1 had little effect on ozone-induced airway inflammation or airway hyper-responsiveness. Pharmacologically targeting mPGES-1 may not predispose patients at risk to airway dysfunction.
Footnotes
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL083799 (to G.A.F.) and HL080676 (to R.A.P.)]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES013508] (to R.A.P.); and the American Heart Association [Grant 0735397N] (to M.W.).
Disclosure: G.A.F. is the McNeil Professor of Translational Medicine and Therapeutics. He has consulted in the past year for AstraZeneca, Logical Therapeutics, and Nicox on NSAIDs and related compounds.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.166678.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- COX
- cyclooxygenase
- NSAID
- nonsteroidal anti-inflammatory drug
- tNSAID
- traditional NSAID
- PG
- prostaglandin
- mPGES-1
- microsomal PGE synthase-1
- PGI2
- prostacyclin
- BAL
- bronchoalveolar lavage
- PCLS
- precision-cut lung slices
- WT
- wild type
- KO
- knockout
- ANOVA
- analysis of variance
- MO
- methoxime
- FA
- forced air
- Tx
- thromboxane.
- Received January 28, 2010.
- Accepted April 2, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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