Targeting of neutrophil activation in the early phase of the disease for prevention of Coronavirus disease‐19 severity

Sendo, Fujiro; Yoshitake, Hiroshi; Araki, Yoshihiko

doi:10.1111/1348-0421.12978

Cited by 5 publications

(6 citation statements)

References 119 publications

(231 reference statements)

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“…It follows that major research efforts are being directed to better understand the molecules that effect neutrophil priming, activation and release. Among others, these include the C5a/C5aR axis and neutrophil chemokines such as CXCL8, neutrophil elastase and CXCR2 (78)(79)(80), some of which are being explored as therapeutic targets.…”

Section: Complement and Coagulation And The Seamless Web Neutrophils ...mentioning

confidence: 99%

Coagulation and complement: Key innate defense participants in a seamless web

2022

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In 1969, Dr. Oscar Ratnoff, a pioneer in delineating the mechanisms by which coagulation is activated and complement is regulated, wrote, “In the study of biological processes, the accumulation of information is often accelerated by a narrow point of view. The fastest way to investigate the body’s defenses against injury is to look individually at such isolated questions as how the blood clots or how complement works. We must constantly remind ourselves that such distinctions are man-made. In life, as in the legal cliché, the devices through which the body protects itself form a seamless web, unwrinkled by our artificialities.” Our aim in this review, is to highlight the critical molecular and cellular interactions between coagulation and complement, and how these two major component proteolytic pathways contribute to the seamless web of innate mechanisms that the body uses to protect itself from injury, invading pathogens and foreign surfaces.

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Section: Complement and Coagulation And The Seamless Web Neutrophils ...mentioning

confidence: 99%

Coagulation and complement: Key innate defense participants in a seamless web

2022

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“…Thus, a myriad of thromboinflammatory cellular events, shown here and more, is triggered by SARS-CoV-2 as a consequence of complement activation that impacts on the vascular endothelium. [43,44]. Efforts are underway to identify key steps in neutrophil priming, activation, migration and release that might be targeted to prevent downstream adverse effects.…”

Section: Neutrophils Neutrophil Extracellular Traps Complement and Co...mentioning

confidence: 99%

“…Many of these enzymes activate coagulation and platelets yielding platelet-neutrophil aggregates that adhere to activated endothelial cells, amplifying the thromboinflammatory process. They also inactivate anticomplement/anticoagulant endothelial factors tissue factor pathway inhibitor (TFPI) and thrombomodulin, and cleave C5 to generate more C5a [43,44]. Efforts are underway to identify key steps in neutrophil priming, activation, migration and release that might be targeted to prevent downstream adverse effects.…”

Section: Neutrophils Neutrophil Extracellular Traps Complement and Co...mentioning

confidence: 99%

“…Efforts are underway to identify key steps in neutrophil priming, activation, migration and release that might be targeted to prevent downstream adverse effects. These include using C5a/ C5aR inhibitors, alone or in combination with blockers of other neutrophil chemokines/effectors such as CXCL8 (IL-8), CXCR2 or neutrophil elastase [43,45].…”

Section: Neutrophils Neutrophil Extracellular Traps Complement and Co...mentioning

confidence: 99%

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Complement contributions to COVID-19

Conway

Pryzdial

2022

Current Opinion in Hematology

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Purpose of review COVID-19 remains a major source of concern, particularly as new variants emerge and with recognition that patients may suffer long-term effects. Mechanisms underlying SARS-CoV-2 mediated organ damage and the associated vascular endotheliopathy remain poorly understood, hindering new drug development.Here, we highlight selected key concepts of how the complement system, a major component of innate immunity that is dysregulated in COVID-19, participates in the thromboinflammatory response and drives the vascular endotheliopathy. Recent findingsRecent studies have revealed mechanisms by which complement is activated directly by SARS-CoV-2, and how the system interfaces with other innate thromboinflammatory cellular and proteolytic pathways involving platelets, neutrophils, neutrophil extracellular traps and the coagulation and kallikrein-kinin systems. With this new information, multiple potential sites for therapeutic intervention are being uncovered and evaluated in the clinic.

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“…Neutrophilia, or the remarkable increase in the number of neutrophils in the bloodstream, is reported in up to 70% of COVID-19 patients and is associated with more severe symptoms [1]. The pathology of COVID-19 is also associated with systemic priming and delayed apoptosis/clearance of neutrophils from the lungs [2]. Neutrophils activation is a double-edged sword during the immune response to infections as they act as effector cells that are fundamental components of innate immunity but are also profoundly histotoxic [3,4].…”

Section: Introductionmentioning

confidence: 99%

Evidence associating neutrophilia, lung damage, hyperlactatemia, blood acidosis, impaired oxygen transport, and mortality in critically ill COVID-19 patients

Yasseen,

Elkhodiry,

El-sayed

et al. 2023

Preprint

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Background: COVID-19 severity and high in-hospital mortality are often associated with severe hypoxemia, hyperlactatemia, and acidosis. Since neutrophil numbers in severe COVID-19 can exceed 80% of the total circulating leukocytes and that they are massively recruited to infected lungs, we investigated whether metabolic acidosis mediated by the glycolytic neutrophils is associated with lung damage and impaired oxygen delivery in critically ill patients. Methods: Based on prospective mortality outcome, 102 critically ill-hospitalized COVID-19 patients were divided into two groups: ICU-Survivors (ICU-S, n=36) and ICU-Non-survivors (ICU-NS, n=66). Blood samples were collected from patients and control subjects to explore correlations between neutrophil counts, lung damage, glycolysis, blood lactate, blood pH, hemoglobin oxygen saturation, and mortality outcome. We also interrogated isolated neutrophils for glycolytic activities and for apoptosis using high-throughput fluorescence imaging complemented with transcriptomic analyses. Stratified survival analyses were conducted to estimate mortality risk associated with higher lactate among predefined subgroups. Results: Neutrophil counts were consistently higher in critically ill patients while exhibiting remarkably lower apoptosis. Transcriptomic analysis revealed miRNAs associated with downregulation of genes involved in neutrophils apoptosis. Both CT lung damage scores and neutrophil counts predicted mortality. Severinghaus fitting of hemoglobin oxygen saturation curve revealed a right-shift indicating lower oxygen capacity in non-survivors, which is consistent with lower blood-pH observed in the same group. Levels of blood lactate were increased in patients but significantly more in the ICU-NS relative to the control group. ROC analysis followed by Kaplan-Meyer survival analysis stratified to the obtained cut-off values showed that CT damage scores, neutrophil counts, and lactate levels are predictors of mortality within 15 days following blood collection. Conclusion: The current results implicate neutrophilia as a potential player in metabolic acidosis and deranged oxygen delivery associating SARS-CoV-2 infection thus contributing to mortality outcome.

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Targeting of neutrophil activation in the early phase of the disease for prevention of Coronavirus disease‐19 severity

Cited by 5 publications

References 119 publications

Coagulation and complement: Key innate defense participants in a seamless web

Coagulation and complement: Key innate defense participants in a seamless web

Complement contributions to COVID-19

Evidence associating neutrophilia, lung damage, hyperlactatemia, blood acidosis, impaired oxygen transport, and mortality in critically ill COVID-19 patients

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