The role of the ß2‐adrenoceptor Gs pathway in the development of the asthma phenotype in murine models

Abstract

Asthma is a chronic inflammatory disease of the airways. We have shown the requirement of the β2AR in the development of three main features of asthma in murine models. β2AR signal through various pathways including the canonical Gs and the β‐arrestin pathway. The objective of this study was to determine if formoterol and salmeterol, documented to have different relative intrinsic efficacies at the Gs pathway resulted in different asthma phenotypes. We used wild type (WT) and phenylethanolamine‐N‐methyltransferase null mice (PNMT−/−) mice. PNMT is responsible for converting norepinephrine into epinephrine and null mice have no detectable levels of epinephrine, the endogenous ligand for ß2AR. PNMT−/− mice were treated with formoterol and salmeterol 10μg/kg/day and 3μg/kg/day respectively, intraperitoneally twice daily at four treatment durations. Mice were phenotyped in an ovalbumin sensitized and challenged (Ova S/C) model. WT, but not PNMT−/− mice, had significant increases in inflammatory cells, mucus hyper‐secretion and airway hyper‐responsiveness. Ova S/C PNMT−/− mice, treated with formoterol and salmeterol significantly restored the asthma phenotype to the level seen in WT mice. Thus drugs with differing efficacies at the Gs pathway are equal at restoring the asthma phenotype, and suggest this pathway is not responsible for the requirement of ß2AR activation in development of the asthma phenotype.