Prostaglandin E2 elicits greater bronchodilation than salbutamol in mouse intrapulmonary airways in lung slices

Abstract Background Current asthma therapy may not adequately target contraction of smaller intrapulmonary airways, which are a major site of airway obstruction and inflammation. The aim of this study was to characterise responses of mouse intrapulmonary airways to prostaglandin E 2 (PGE 2 ) and compare its dilator efficacy with the β 2 -adrenoceptor agonist salbutamol in situ , using lung slices. Methods Lung slices (150 μm) were prepared from male Balb/C mice. Changes in intrapulmonary airway lumen area were recorded and analysed by phase-contrast microscopy. Relaxation to PGE 2 and salbutamol were assessed following various levels of pre-contraction with methacholine, serotonin or endothelin-1, as well as following overnight incubation with PGE 2 or salbutamol. The mechanism of PGE 2 -mediated relaxation was explored using selective EP antagonists (EP 1/2 AH6809; EP 4 L-161982) and Ca 2+ -permeabilized slices, where airway responses are due to regulation of Ca 2+ -sensitivity alone. Results PGE 2 elicited EP 1/2 -mediated relaxation of intrapulmonary airways. PGE 2 was more potent than salbutamol in opposing submaximal pre-contraction to all constrictors tested, and only PGE 2 opposed maximal pre-contraction with endothelin-1. Relaxation to PGE 2 was maintained when contraction to methacholine was mediated via increased Ca 2+ -sensitivity alone. PGE 2 was less sensitive to homologous or heterologous desensitization of its receptors than salbutamol. Conclusion The greater efficacy and potency of PGE 2 compared to salbutamol in mouse intrapulmonary airways supports further investigation of the mechanisms underlying this improved dilator responsiveness for the treatment of severe asthma.