Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma
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.
Authors
- Md Ashik Ullah (ORCID: https://orcid.org/0000-0002-0025-1796)
- Md Al Amin Sikder (ORCID: https://orcid.org/0000-0003-0663-2415)
- Sonja Rittchen
- Natasha Collinson (ORCID: https://orcid.org/0000-0002-3805-0017)
- Patricia Namubiru (ORCID: https://orcid.org/0000-0003-0320-874X)
- Daniel R. Howard (ORCID: https://orcid.org/0000-0002-2121-8362)
- Muhammed Mahfuzur Rahman (ORCID: https://orcid.org/0000-0002-2077-7189)
- Mark L. Smythe (ORCID: https://orcid.org/0000-0001-7840-1021)
- Bodie F. Curren (ORCID: https://orcid.org/0000-0002-1165-6406)
- Mary Lor (ORCID: https://orcid.org/0009-0000-8886-402X)
- Simon Phipps (ORCID: https://orcid.org/0000-0002-7388-3612)
- Tufael Ahmed (ORCID: https://orcid.org/0000-0002-0378-6542)
- Ridwan Bin Rashid (ORCID: https://orcid.org/0000-0001-5095-8848)
- Jia Li (ORCID: https://orcid.org/0000-0002-5931-3058)
Institutions
- Queensland University of Technology (AU)
- The University of Queensland (AU)
- Shanghai Jiao Tong University (CN)
- Medical University of Graz (AT)
- QIMR Berghofer Medical Research Institute (AU)
- Shanghai First People's Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1038/s41467-024-54670-8
- Citations
- 3
- Primary Topic
- Asthma and respiratory diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.98
Funders
- European Molecular Biology Organization
- QIMR Berghofer Medical Research Institute
- Austrian Science Fund
- Medical Research Council
- National Health and Medical Research Council
- Institute for Molecular Bioscience, University Of Queensland