Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma
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Le résumé fourni par la source
ABSTRACT Background 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 patients with moderate-to-severe asthma, but in the Phase III clinical trials, DP2 antagonism failed to significantly lower the rate of exacerbations. Here, we hypothesised that DP2 antagonism resolves established ASM remodeling via endogenous PGD2/DP1 activation and that this beneficial effect is ablated by dual corticosteroid therapy. Methods Neonatal mice were co-exposed to pneumonia virus of mice (PVM) and cockroach extract in early life to induce severe bronchiolitis, then re-infected with PVM and challenged to cockroach extract in adulthood to progress disease to chronic experimental asthma (CEA). The efficacy of DP2 antagonism monotherapy or various dual therapies was assessed in the setting of a rhinovirus (RV)-induced exacerbation. Results RV inoculation increased PGD2 release, mucus production, collagen deposition, transforming growth factor (TGF)-β1 expression and type-2 inflammation. Treatment with a DP2 antagonist or DP1 agonist ablated the aforementioned phenotypes, increased type-1 immunity, and decreased ASM area. Dual DP1-DP2 antagonism or dual corticosteroid/DP2 antagonism, which attenuated endogenous PGD2 levels, prevented the resolution of ASM area induced by DP2 antagonism alone. The resolution of ASM remodelling following DP2 antagonism was mediated by IFN-γ and associated with decreased TGF-β1 expression. Conclusion DP2 antagonism resolved ASM remodelling via PGD2/DP1-mediated upregulation of interferon-γ expression. Dual DP2 antagonism/corticosteroid therapy, as occurred in many of the human trials, suppressed PGD2 and IFN-γ production, impairing the efficacy of DP2 antagonism.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma
- Date Crossref
- 15/11/2023
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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QIMR Berghofer Medical Research Institute pays non établi dans la noticeStructure de recherche
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Medical University of Graz Otto Loewi Research Center for Vascular Biology pays non établi dans la noticeUniversité ou école supérieure
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Shanghai Jiao Tong University Department of Laboratory Medicine pays non établi dans la noticeUniversité ou école supérieure
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Shanghai First People's Hospital pays non établi dans la noticeÉtablissement de santé
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The University of Queensland Institute for Molecular Bioscience pays non établi dans la noticeUniversité ou école supérieure
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Respiratory Immunology Laboratory pays non établi dans la noticeStructure de recherche
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School of Biomedical Sciences pays non établi dans la noticeUniversité ou école supérieure
QIMR Berghofer Medical Research Institute, Otto Loewi Research Center for Vascular Biology — Medical University of Graz et Department of Laboratory Medicine — Shanghai Jiao Tong University, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.