Respiratory Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, 8010, Austria.
Nat Commun. 2024 Nov 26;15(1):10253. doi: 10.1038/s41467-024-54670-8.
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.
前列腺素 D2（PGD2）通过 DP1 和 DP2 受体发出信号。在 II 期试验中，DP2 拮抗剂可减少中重度哮喘患者的气道炎症和气道平滑肌（ASM）面积。然而，在 III 期，DP2 拮抗剂未能降低恶化率，DP2 作为靶点被搁置。在这里，我们使用慢性实验性哮喘的临床前模型证明，鼻病毒引起的恶化会增加 PGD2 的释放、粘液产生、转化生长因子（TGF）-β1 和 2 型炎症。DP2 拮抗剂或 DP1 激动剂消除了这些表型，通过增加 IFN-γ 增加上皮 EGF 表达并减少 ASM 面积。相比之下，双重 DP1-DP2 拮抗剂或双重皮质类固醇/DP2 拮抗剂会减弱内源性 PGD2，从而阻止 ASM 消退。我们证明 DP2 拮抗剂通过 PGD2/DP1 介导的 IFN-γ 表达上调来解决 ASM 重塑，而在人类试验中经常发生的双重 DP2 拮抗剂/皮质类固醇治疗通过抑制内源性 PGD2 和 IFN-γ 产生来损害 DP2 拮抗剂的疗效。
