Medizinische Universität Graz - Research portal
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SHR Neuro Cancer Cardio Lipid Metab Microb
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.
Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma.
Nat Commun. 2024; 15(1):10253
Doi: 10.1038/s41467-024-54670-8
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- Co-authors Med Uni Graz
- Rittchen Sonja
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- 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)-β1 and type-2 inflammation. DP2 antagonism or DP1 agonism ablates these phenotypes, increases epithelial EGF expression and decreases ASM area via increased IFN-γ. 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-γ expression, and that dual DP2 antagonism/corticosteroid therapy, as often occurred in the human trials, impairs the efficacy of DP2 antagonism by suppressing endogenous PGD2 and IFN-γ production.
- Find related publications in this database (using NLM MeSH Indexing)
- Asthma - drug therapy, metabolism
- Animals - administration & dosage
- Prostaglandin D2 - metabolism
- Receptors, Prostaglandin - antagonists & inhibitors, metabolism
- Adrenal Cortex Hormones - pharmacology, therapeutic use
- Receptors, Immunologic - metabolism, antagonists & inhibitors
- Interferon-gamma - metabolism
- Mice - administration & dosage
- Disease Models, Animal - administration & dosage
- Humans - administration & dosage
- Airway Remodeling - drug effects
- Male - administration & dosage
- Female - administration & dosage
- Transforming Growth Factor beta1 - metabolism
- Muscle, Smooth - drug effects, metabolism
- Drug Therapy, Combination - administration & dosage
- Picornaviridae Infections - drug therapy, virology
- Inflammation - drug therapy