Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon-λ (IFN-λ) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN-λ production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.

前列腺素D2（PGD2）通过PGD2受体2（DP2，也称为CRTH2）在2型效应细胞上发出信号，从而促进哮喘的发病。然而，人们对其在呼吸道合胞病毒（RSV）细支气管炎（哮喘发展的主要危险因素）中的作用了解甚少。我们显示，RSV感染上调了培养的人原代气道上皮细胞（AECs）的造血前列腺素D合酶的表达，并增加了PGD2的释放。此外，与健康对照组相比，在因RSV细支气管炎住院的婴儿的鼻咽样品中，PGD2的产量增加。在严重病毒性毛细支气管炎的新生小鼠模型中，DP2拮抗作用降低了病毒载量，免疫病理学和发病率，并消除了以后生活中随后哮喘发作的易感性。这种保护性反应在双重DP1 / DP2拮抗作用下被取消，并与特定的DP1激动剂复制。DP2阻断或DP1激动的有益作用不是通过2型炎症介导，而是与干扰素λ（IFN-λ）[白介素28A / B（IL-28A / B）]表达增加相关，并在治疗后消失IL-28A中和。在受RSV感染的AEC培养物中，DP1激活上调了IFN-λ的产生，继而增加了IFN刺激的基因表达，从而加速了病毒清除。我们的发现表明，DP2拮抗剂或DP1激动剂可能是用于治疗病毒性细支气管炎的有用抗病毒药，并且可能作为哮喘的主要预防剂。DP2阻断或DP1激动的有益作用与干扰素λ（IFN-λ）[白介素28A / B（IL-28A / B）]表达增加有关，并在IL-28A中和后消失。在受RSV感染的AEC培养物中，DP1激活上调了IFN-λ的产生，继而增加了IFN刺激的基因表达，从而加速了病毒清除。我们的发现表明，DP2拮抗剂或DP1激动剂可能是用于治疗病毒性细支气管炎的有用抗病毒药，并且可能作为哮喘的主要预防剂。DP2阻断或DP1激动的有益作用与干扰素λ（IFN-λ）[白介素28A / B（IL-28A / B）]表达增加有关，并在IL-28A中和后消失。在受RSV感染的AEC培养物中，DP1激活上调了IFN-λ的产生，继而增加了IFN刺激的基因表达，从而加速了病毒清除。我们的发现表明，DP2拮抗剂或DP1激动剂可能是用于治疗病毒性细支气管炎的有用抗病毒药，并且可能作为哮喘的主要预防剂。