Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma

Abstract

BackgroundProstaglandin 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.MethodsNeonatal 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.ResultsRV 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.ConclusionDP2 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.