We sought to understand the functions of Regulator of G Protein Signaling 4 (RGS4), a cytoplasmic protein expressed in airway smooth muscle (ASM) and bronchial epithelium that regulates activity of GPCRs, in asthma.
We examined RGS4 expression in human lung biopsies by immunohistochemistry. We assessed airways hyper-responsiveness (AHR) and lung inflammation in germline and ASM-specific Rgs4-/- mice and in mice treated with an RGS4 antagonist following challenge with Aspergillus fumigatus. We examined the role of RGS4 in NSAID-associated bronchoconstriction by challenging AERD-like (ptges1-/-) mice with aspirin.
RGS4 expression in respiratory epithelium is increased in subjects with severe asthma. Allergen-induced AHR was unexpectedly diminished in Rgs4-/- mice, a finding associated with increased airway PGE2 levels. RGS4 modulated allergen-induced PGE2 secretion in human bronchial epithelial cells and prostanoid-dependent bronchodilation. The RGS4 antagonist CCG203769 attenuated AHR induced by allergen or aspirin challenge of wild type (WT) or ptges1-/- mice, respectively, in association with increased airway PGE2 levels.
RGS4 may contribute to the development of AHR by reducing airway PGE2 biosynthesis in allergen- and aspirin-induced asthma.
Copyright © 2020. Published by Elsevier Inc.