Prostaglandin E2protects lower airways against bronchoconstriction

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Abstract
Prostaglandin E2(PGE2), similar to β-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. We examined the impact of sustained alterations in PGE2pathways on changes in airway resistance. Genetic methods were utilized to alter PGE2metabolism and signal transduction in the murine lung. PGE2levels were elevated by generating mice lacking 15-hydroxyprostaglandin ( Hpgd−/−), the major catabolic enzyme of PGE2, and by generating a transgenic line in which mouse PGE2synthase ( Ptges) expression is driven by a human lung-specific promoter, hSP-C. Conversely, to determine the impact of loss of PGE2on airway reactivity, we examined mice lacking this synthase ( Ptges−/−) and receptors that mediate the actions of PGE2, particularly the PGE2EP2receptor ( Ptger2). Diminished capacity to produce and respond to PGE2did not alter the response of mice to cholinergic stimuli. In contrast, the responsiveness to cholinergic stimulation was dramatically altered in animals with elevated PGE2levels. The Hpgd−/−and hSP- C- Ptges transgenic lines both showed attenuated airway responsiveness to methacholine as measured by lung resistance. Thus, whereas compromise of the Ptges/PGE2/ Ptger2 pathway does not alter airway responsiveness, genetic modulation that elevates PGE2levels in the lung attenuates airway responsiveness.

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