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1 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 Deoartment of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
3 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
4 Department of Pharmacology, Merck Frosst Canada, Kirkland, Quebec, Canada
5 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Deoartment of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: treawouns{at}aol.com.
Prostaglandin E2 (PGE2), similar to 
-adrenergic receptor agonists, can protect airways from bronchoconstriction and resulting increase in airway resistance induced by a number of agents including cholinergic receptor agonists and antigen. Here we examine the impact of sustained alterations in PGE2 pathways on changes in airway resistance. Genetic methods were utilized to alter PGE2 metabolism and signal transduction in the murine lung. PGE2 levels were elevated by generating mice lacking 15-hydroxyprostaglandin (HPGD), the major catabolic enzyme of PGE2 and by generating a transgenic line, in which mouse PGE2 synthase (Ptges) expression is driven by a lung specific promoter, hSP-C. Conversely, to determine the impact of loss of PGE2 on airway reactivity, we examine mice lacking this synthase (Ptges-/-) and receptors which mediate the actions of PGE2, particularly the PGE2 EP2 receptor (Ptger2). Diminished capacity to produce and respond to PGE2 does not alter the response of mice to cholinergic stimuli. In contrast, the responsiveness to cholinergic stimulation is dramatically altered in animals with elevated PGE2 levels. The Hpgd-/- and hSP-C-Ptges transgenic lines both show attenuated airway responsiveness to methacholine as measured by lung resistance. Thus, while compromise of the Ptges/ PGE2/Ptger2 pathway does not alter airway responsiveness, genetic modulation that elevates PGE2 levels in the lung attenuates airway responsiveness.
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