Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
Front Immunol. 2021 Aug 19;12:704427. doi: 10.3389/fimmu.2021.704427. eCollection 2021.
Viral pneumonias are a major cause of morbidity and mortality, owing in part to dysregulated excessive lung inflammation, and therapies to modulate host responses to viral lung injury are urgently needed. Protectin conjugates in tissue regeneration 1 (PCTR1) and protectin D1 (PD1) are specialized pro-resolving mediators (SPMs) whose roles in viral pneumonia are of interest. In a mouse model of Respiratory Syncytial Virus (RSV) pneumonia, intranasal PCTR1 and PD1 each decreased RSV genomic viral load in lung tissue when given after RSV infection. Concurrent with enhanced viral clearance, PCTR1 administration post-infection, decreased eosinophils, neutrophils, and NK cells, including NKG2D activated NK cells, in the lung. Intranasal PD1 administration post-infection decreased lung eosinophils and expression. PCTR1 increased lung expression of cathelicidin anti-microbial peptide and decreased interferon-gamma production by lung CD4 T cells. PCTR1 and PD1 each increased interferon-lambda expression in human bronchial epithelial cells and attenuated RSV-induced suppression of interferon-lambda in mouse lung . Liquid chromatography coupled with tandem mass spectrometry of RSV-infected and untreated mouse lungs demonstrated endogenous PCTR1 and PD1 that decreased early in the time course while cysteinyl-leukotrienes (cys-LTs) increased during early infection. As RSV infection resolved, PCTR1 and PD1 increased and cys-LTs decreased to pre-infection levels. Together, these results indicate that PCTR1 and PD1 are each regulated during RSV pneumonia, with overlapping and distinct mechanisms for PCTR1 and PD1 during the resolution of viral infection and its associated inflammation.
病毒性肺炎是发病率和死亡率的主要原因，部分原因是肺炎症失调过度，因此迫切需要调节宿主对病毒性肺损伤反应的治疗方法。组织再生 1（PCTR1）和保护素 D1（PD1）是专门的促解决介质（SPM），其在病毒性肺炎中的作用受到关注。在呼吸道合胞病毒（RSV）肺炎的小鼠模型中，在 RSV 感染后给予鼻内 PCTR1 和 PD1 均可降低肺组织中的 RSV 基因组病毒载量。伴随病毒清除增强，感染后给予 PCTR1 可减少肺中的嗜酸性粒细胞、中性粒细胞和 NK 细胞，包括 NKG2D 激活的 NK 细胞。感染后给予鼻内 PD1 可减少肺中的嗜酸性粒细胞和 表达。PCTR1 增加肺中抗菌肽 cathelicidin 的表达，并减少肺 CD4 T 细胞产生干扰素-γ。PCTR1 和 PD1 均增加人支气管上皮细胞中的干扰素-λ表达，并减弱 RSV 诱导的小鼠肺中干扰素-λ的抑制作用。RSV 感染和未处理的小鼠肺的液相色谱串联质谱分析显示，内源性 PCTR1 和 PD1 在早期时间过程中减少，而半胱氨酰白三烯（cys-LTs）在早期感染期间增加。随着 RSV 感染的消退，PCTR1 和 PD1 增加，cys-LTs 减少至感染前水平。总之，这些结果表明，PCTR1 和 PD1 在 RSV 肺炎期间均受到调节，PCTR1 和 PD1 在病毒感染及其相关炎症的消退过程中具有重叠和独特的机制。
