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Prostaglandin E₂ protects lower airways against bronchoconstriction

¹Curriculum in Genetics and Molecular Biology, ²Department of Genetics, and ³Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina, Chapel Hill, North Carolina; and ⁴Department of Pharmacology, Merck Frosst Canada, Kirkland, Quebec, Canada

Submitted 19 May 2005 ; accepted in final form 5 August 2005

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. We examined 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 human lung-specific promoter, hSP-C. Conversely, to determine the impact of loss of PGE₂ on airway reactivity, we examined mice lacking this synthase (Ptges^–/–) and receptors that mediate the actions of PGE₂, particularly the PGE₂ EP₂ receptor (Ptger2). Diminished capacity to produce and respond to PGE₂ did not alter the response of mice to cholinergic stimuli. In contrast, the responsiveness to cholinergic stimulation was dramatically altered in animals with elevated PGE₂ levels. 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 PGE₂ levels in the lung attenuates airway responsiveness.

lung mechanics; bronchoprotection; prostaglandins; asthma; Ptges; Ptger2; 15-hydroxyprostaglandin

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