Arguinchona Lauren M, Zagona-Prizio Caterina, Joyce Megan E, Chan Edward D, Maloney James P
School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Front Cardiovasc Med. 2023 Jan 6;9:1054690. doi: 10.3389/fcvm.2022.1054690. eCollection 2022.
As 2023 approaches, the COVID-19 pandemic has killed millions. While vaccines have been a crucial intervention, only a few effective medications exist for prevention and treatment of COVID-19 in breakthrough cases or in unvaccinated or immunocompromised patients. SARS-CoV-2 displays early and unusual features of micro-thrombosis and immune dysregulation that target endothelial beds of the lungs, skin, and other organs. Notably, anticoagulation improves outcomes in some COVID-19 patients. The protein transforming growth factor-beta (TGF-β1) has constitutive roles in maintaining a healthy microvasculature through its roles in regulating inflammation, clotting, and wound healing. However, after infection (including viral infection) TGF-β1 activation may augment coagulation, cause immune dysregulation, and direct a path toward tissue fibrosis. Dysregulation of TGF-β signaling in immune cells and its localization in areas of microvascular injury are now well-described in COVID-19, and such events may contribute to the acute respiratory distress syndrome and skin micro-thrombosis outcomes frequently seen in severe COVID-19. The high concentration of TGF-β in platelets and in other cells within microvascular thrombi, its ability to activate the clotting cascade and dysregulate immune pathways, and its pro-fibrotic properties all contribute to a unique milieu in the COVID-19 microvasculature. This unique environment allows for propagation of microvascular clotting and immune dysregulation. In this review we summarize the physiological functions of TGF-β and detail the evidence for its effects on the microvasculature in COVID-19. In addition, we explore the potential role of existing TGF-β inhibitors for the prevention and treatment of COVID-19 associated microvascular thrombosis and immune dysregulation.
随着2023年的临近，新冠疫情已导致数百万人死亡。尽管疫苗是一项关键干预措施，但在突破性病例或未接种疫苗或免疫功能低下的患者中，用于预防和治疗新冠的有效药物却寥寥无几。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）表现出微血栓形成和免疫失调的早期异常特征，这些特征靶向肺部、皮肤和其他器官的内皮床。值得注意的是，抗凝治疗可改善一些新冠患者的预后。转化生长因子-β1（TGF-β1）蛋白通过调节炎症、凝血和伤口愈合，在维持健康的微血管系统中发挥着重要作用。然而，感染（包括病毒感染）后，TGF-β1的激活可能会增强凝血、导致免疫失调，并引发组织纤维化。免疫细胞中TGF-β信号的失调及其在微血管损伤区域的定位，在新冠疫情中已有详细描述，这些事件可能导致严重新冠患者常见的急性呼吸窘迫综合征和皮肤微血栓形成。血小板和微血管血栓中其他细胞内的高浓度TGF-β，其激活凝血级联反应和失调免疫途径的能力，以及其促纤维化特性，都导致了新冠微血管系统中独特的环境。这种独特的环境使得微血管凝血和免疫失调得以扩散。在这篇综述中，我们总结了TGF-β的生理功能，并详细阐述了其在新冠疫情中对微血管系统影响的证据。此外，我们还探讨了现有TGF-β抑制剂在预防和治疗新冠相关微血管血栓形成和免疫失调方面的潜在作用。
