Hollenberg Morley D, Epstein Murray
Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Kidney Int Suppl (2011). 2022 Apr;12(1):48-62. doi: 10.1016/j.kisu.2021.12.001. Epub 2022 Mar 18.
The coronavirus disease 2019 (COVID-19) pandemic, causing considerable mortality and morbidity worldwide, has fully engaged the biomedical community in attempts to elucidate the pathophysiology of COVID-19 and develop robust therapeutic strategies. To this end, the predominant research focus has been on the adaptive immune response to COVID-19 infections stimulated by mRNA and protein vaccines and on the duration and persistence of immune protection. In contrast, the role of the innate immune response to the viral challenge has been underrepresented. This overview focuses on the innate immune response to COVID-19 infection, with an emphasis on the roles of extracellular proteases in the tissue microenvironment. Proteinase-mediated signaling caused by enzymes in the extracellular microenvironment occurs upstream of the increased production of inflammatory cytokines that mediate COVID-19 pathology. These enzymes include the coagulation cascade, kinin-generating plasma kallikrein, and the complement system, as well as angiotensin-generating proteinases of the renin-angiotensin system. Furthermore, in the context of several articles in this Supplement elucidating and detailing the trajectory of diverse profibrotic pathways, we extrapolate these insights to explore how fibrosis and profibrotic pathways participate importantly in the pathogenesis of COVID-19. We propose that the lessons garnered from understanding the roles of microenvironment proteinases in triggering the innate immune response to COVID-19 pathology will identify potential therapeutic targets and inform approaches to the clinical management of COVID-19. Furthermore, the information may also provide a template for understanding the determinants of COVID-19-induced tissue fibrosis that may follow resolution of acute infection (so-called "long COVID"), which represents a major new challenge to our healthcare systems.
2019年冠状病毒病（COVID-19）大流行在全球范围内造成了相当高的死亡率和发病率，促使生物医学界全力阐明COVID-19的病理生理学并制定有效的治疗策略。为此，主要的研究重点一直是mRNA和蛋白质疫苗刺激的针对COVID-19感染的适应性免疫反应，以及免疫保护的持续时间和持久性。相比之下，针对病毒挑战的先天免疫反应的作用却未得到充分体现。本综述聚焦于对COVID-19感染的先天免疫反应，重点关注细胞外蛋白酶在组织微环境中的作用。由细胞外微环境中的酶介导的蛋白酶信号传导发生在介导COVID-19病理的炎性细胞因子产生增加之前。这些酶包括凝血级联反应、激肽生成性血浆激肽释放酶、补体系统，以及肾素-血管紧张素系统中生成血管紧张素的蛋白酶。此外，在本增刊中几篇阐明并详细描述多种促纤维化途径轨迹的文章的背景下，我们推断这些见解，以探讨纤维化和促纤维化途径如何在COVID-19发病机制中发挥重要作用。我们认为，从理解微环境蛋白酶在触发针对COVID-19病理的先天免疫反应中的作用中汲取的经验教训，将确定潜在的治疗靶点，并为COVID-19的临床管理方法提供参考。此外，这些信息还可能为理解急性感染消退后可能出现的COVID-19诱导的组织纤维化（所谓的“长新冠”）的决定因素提供一个模板，这对我们的医疗系统构成了一项重大的新挑战。
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