{"title":"先天免疫反应、微环境蛋白酶与COVID-19大流行:病理生理机制和新出现的治疗靶点","authors":"Morley D. Hollenberg , Murray Epstein","doi":"10.1016/j.kisu.2021.12.001","DOIUrl":null,"url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":48895,"journal":{"name":"Kidney International Supplements","volume":null,"pages":null},"PeriodicalIF":19.3000,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931295/pdf/","citationCount":"10","resultStr":"{\"title\":\"The innate immune response, microenvironment proteinases, and the COVID-19 pandemic: pathophysiologic mechanisms and emerging therapeutic targets\",\"authors\":\"Morley D. Hollenberg , Murray Epstein\",\"doi\":\"10.1016/j.kisu.2021.12.001\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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.</p></div>\",\"PeriodicalId\":48895,\"journal\":{\"name\":\"Kidney International Supplements\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":19.3000,\"publicationDate\":\"2022-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931295/pdf/\",\"citationCount\":\"10\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Kidney International Supplements\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2157171621000630\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Kidney International Supplements","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2157171621000630","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
The innate immune response, microenvironment proteinases, and the COVID-19 pandemic: pathophysiologic mechanisms and emerging therapeutic targets
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.
期刊介绍:
Kidney International Supplements is published on behalf of the International Society of Nephrology (ISN) and comes complimentary as part of a subscription to Kidney International. Kidney International Supplements is a peer-reviewed journal whose focus is sponsored, topical content of interest to the nephrology community.