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Articles in PresS, published online ahead of print December 13, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00324.2002
Submitted on September 26, 2002
Accepted on December 4, 2002
1 Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, N.C., USA
2 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, N.C., USA
3 Genetic Technologies, Pfizer global research and development, Groton, C.T., USA
4 Department of Medicine, Thomas Jefferson University, Chapel Hill, N.C., USA
5 Department of Medicine, University of Pennsylvania, Chapel Hill, N.C., USA
6 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, N.C., USA; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, N.C., USA
* To whom correspondence should be addressed. E-mail: treawouns{at}aol.com.
Prostaglandin E2 (PGE2) has complex effects on airway tone and the existence of four PGE2 (EP) receptors, each with distinct signaling characteristics, has provided a possible explanation for the seemingly contradictory actions of this lipid mediator. To identify the receptors mediating the actions of PGE2 on bronchomotor tone, we examined its effects on the airways of wild type and EP receptor deficient mice. In conscious mice the administration of PGE2 increased airway responsiveness primarily through the EP1 receptor, although on certain genetic backgrounds a contribution of the EP3 receptor was detected. These effects of PGE2 were eliminated by pre-treatment with either atropine or bupivacaine, and were undetectable in anesthetized mice or in dennervated tracheal rings, where only EP2-mediated relaxation of airway smooth muscle was observed. Taken together, our findings are consistent with a model in which PGE2 modulates airway tone by activating multiple receptors expressed on various cell populations and in which the relative contribution of these receptors might depend on the expression of modifier alleles. PGE2/EP1/EP3-induced airway constriction occurs indirectly through activation of neural pathways, while PGE2-induced bronchodilation results from direct activation of EP2 receptors on airway smooth muscle. This segregation of EP receptor function within the airway suggests that PGE2 analogues that selectively activate the EP2 receptor without activating the EP1/EP3 receptors might prove useful in the treatment of asthma.
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