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

Md Ashik Ullah, Sonja Rittchen, Jia Li, Bodie F. Curren, Patricia Namubiru, Tufael Ahmed, Daniel R. Howard, Muhammed Mahfuzur Rahman, Md Al Amin Sikder, Ridwan B. Rashid, Natasha Collinson, Mary Lor, Mark L. Smythe and Simon Phipps ()
Additional contact information
Md Ashik Ullah: QIMR Berghofer Medical Research Institute
Sonja Rittchen: QIMR Berghofer Medical Research Institute
Jia Li: QIMR Berghofer Medical Research Institute
Bodie F. Curren: QIMR Berghofer Medical Research Institute
Patricia Namubiru: QIMR Berghofer Medical Research Institute
Tufael Ahmed: QIMR Berghofer Medical Research Institute
Daniel R. Howard: QIMR Berghofer Medical Research Institute
Muhammed Mahfuzur Rahman: QIMR Berghofer Medical Research Institute
Md Al Amin Sikder: QIMR Berghofer Medical Research Institute
Ridwan B. Rashid: QIMR Berghofer Medical Research Institute
Natasha Collinson: QIMR Berghofer Medical Research Institute
Mary Lor: QIMR Berghofer Medical Research Institute
Mark L. Smythe: University of Queensland
Simon Phipps: QIMR Berghofer Medical Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54670-8

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