Abstract

Prostaglandin D2 (PGD2) signals via the DP1 and DP2 receptors. In Phase II trials, DP2 antagonism decreased airway inflammation and airway smooth muscle (ASM) area in moderate-to-severe asthma patients. However, in Phase III, DP2 antagonism failed to lower the rate of exacerbations, and DP2 as a target was shelved. Here, using a preclinical model of chronic experimental asthma, we demonstrate that rhinovirus-induced exacerbations increase PGD2 release, mucus production, transforming growth factor (TGF)-ß1 and type-2 inflammation. DP2 antagonism or DP1 agonism ablates these phenotypes, increases epithelial EGF expression and decreases ASM area via increased IFN-?. In contrast, dual DP1-DP2 antagonism or dual corticosteroid/DP2 antagonism, which attenuates endogenous PGD2, prevented ASM resolution. We demonstrate that DP2 antagonism resolves ASM remodelling via PGD2/DP1-mediated upregulation of IFN-? expression, and that dual DP2 antagonism/corticosteroid therapy, as often occurred in th...

Authors	Ullah, MA; Rittchen, S; Li, J; Curren, BF; Namubiru, P; Ahmed, T; Howard, DR; Rahman, MM; Sikder, MAA; Rashid, RB; Collinson, N; Lor, M; Smythe, ML; Phipps, S
Journal	Nature Communications
Pages	10253
Volume	15
Date	26/12/2024
Grant ID	FWF, W1241 | Department of Health | National Health and Medical Research Council (NHMRC); 8109 | European Molecular Biology Organization (EMBO)
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41467-024-54670-8