Patients with COVID-19: in the dark-NETs of neutrophils

Cell Death and Differentiation, Journal Year: 2021, Volume and Issue: 28(11), P. 3125 - 3139

Published: May 24, 2021

SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed curb pandemic, it is paramount define mechanisms develop protective therapies prevent organ dysfunction in patients with COVID-19. Individuals that severe manifestations have signs of dysregulated innate adaptive immune responses. Emerging evidence implicates neutrophils disbalance between neutrophil extracellular trap (NET) formation degradation plays central role pathophysiology inflammation, coagulopathy, damage, immunothrombosis characterize cases Here, we discuss supporting for NETs COVID-19 present putative mechanisms, by which promote tissue injury immunothrombosis. We therapeutic strategies, been successful treatment immunο-inflammatory disorders target NET or degradation, as potential approaches may benefit

Language: Английский

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Neutrophil extracellular traps regulate ischemic stroke brain injury

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(10)

Published: March 31, 2022

Ischemic stroke prompts a strong inflammatory response, which is associated with exacerbated outcomes. In this study, we investigated mechanistic regulators of neutrophil extracellular trap (NET) formation in and whether they contribute to NET-forming neutrophils were found throughout brain tissue ischemic patients, elevated plasma NET biomarkers correlated worse Additionally, observed increased platelet surface-expressed high-mobility group box 1 (HMGB1) patients. Mechanistically, platelets identified as the critical source HMGB1 that caused NETs acute phase stroke. Depletion or platelet-specific knockout significantly reduced levels after stroke, greatly improved We subsequently therapeutic potential neonatal NET-inhibitory factor (nNIF) Mice treated nNIF had smaller infarcts, long-term neurological motor function, enhanced survival specifically blocked without affecting recruitment Importantly, also outcomes diabetic aged mice was still effective when given hour onset. These results support pathological role for warrant further investigation therapy.

Language: Английский

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Sepsis: network pathophysiology and implications for early diagnosis

AJP Regulatory Integrative and Comparative Physiology, Journal Year: 2023, Volume and Issue: 324(5), P. R613 - R624

Published: March 7, 2023

Sepsis, a medical emergency, is the overwhelming host response to infection leading organ failure. The pathophysiology of this heterogeneous disease includes an inflammatory that stimulates complex interaction between endothelial and complements with associated coagulation abnormalities. Despite more comprehensive understanding sepsis pathophysiology, there exists translational gap improve diagnosis clinically. Many proposed biomarkers diagnose lack sufficient specificity sensitivity be used in routine clinical practice. There has also been progress diagnostic tools due focus on pathway. Inflammation are known linked innate immune response. Early immunothrombotic changes could result early switch from aid diagnosis. This review integrates both preclinical studies highlight providing framework for how development immunothrombosis as starting point investigate

Language: Английский

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Role of Platelets in Detection and Regulation of Infection

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2020, Volume and Issue: 41(1), P. 70 - 78

Published: Oct. 29, 2020

Platelets are classically known as essential mediators of hemostasis and thrombosis. However, in recent years, platelets have gained recognition for their inflammatory functions, which modulate the immune response during infectious diseases. contain various immunoreceptors that enable them to act sentinels recognize intravascular pathogens. Upon activation, directly limit pathogen growth through release AMPs (antimicrobial proteins) ensure clearance activation cells. aberrant platelet can lead inflammation thrombotic events.

Language: Английский

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Intracellular communication and immunothrombosis in sepsis

Journal of Thrombosis and Haemostasis, Journal Year: 2022, Volume and Issue: 20(11), P. 2475 - 2484

Published: Aug. 18, 2022

Abstract

Inflammation and coagulation are the critical responses to infection that include leukocytes, platelets, vascular endothelial cells responding in concert eradicate invading pathogen. In sepsis, a variety of cell surface receptors, including toll‐like Fcγ‐receptors, G‐protein‐coupled adhesion detect pathogens elicit thromboinflammatory responses. Concurrently, molecular patterns released from host damaged accelerate immune through binding same pattern recognition receptors. Cytokines, chemokines, extracellular vesicles important mediators for amplifying distant as part systemic response infections. At time, communicate with each other via direct contact, molecules, paracrine mediators, tunneling nanotubes, which regulating inflammation thrombus formation. Despite increasing attention immunothrombosis these close communication systems less understood but play role defense mechanisms. this review, cellular activation intercellular sepsis focus on will be considered.

Language: Английский

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Sepsis – it is all about the platelets

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 7, 2023

Sepsis is accompanied by thrombocytopenia and the severity of associated with mortality. This characteristic disseminated intravascular coagulation (DIC), sepsis-associated coagulopathy. Many pathogens, both bacterial viral, that cause sepsis also directly activate platelets, which suggests pathogen-induced platelet activation leads to systemic thrombosis drives multi-organ failure DIC. In this paper we review mechanisms pathogens evidence for a role anti-platelet agents in management sepsis.

Language: Английский

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Managing Cardiovascular and Cancer Risk Associated with JAK Inhibitors

Drug Safety, Journal Year: 2023, Volume and Issue: 46(11), P. 1049 - 1071

Published: July 25, 2023

Janus kinase inhibitors (JAKi) have enormous appeal as immune-modulating therapies across many chronic inflammatory diseases, but recently this promise has been overshadowed by questions regarding associated cardiovascular and cancer risk emerging from the ORAL Surveillance phase 3b/4 post-marketing requirement randomized controlled trial. In that study of patients with rheumatoid arthritis existing risk, tofacitinib, first JAKi registered for disease, failed to meet non-inferiority thresholds when compared tumor necrosis factor both incident major adverse events cancer. While result was unexpected many, subsequently published observational data also supported finding. Notably, however, such a largely not yet demonstrated in outside specific clinical situation examined trial, even face studies examining this. Nevertheless, signal practically re-aligned approaches tofacitinib other varying extents, patient populations contexts: within arthritis, psoriatic axial spondyloarthritis, bowel atopic dermatitis, beyond. Application individual can be more challenging remains important harness substantive potential maximum extent safely possible. This review only explores evolution regulatory response signal, its informing data, biological plausibility, impact on guidelines, factors clinicians must consider navigating their considering therapy.

Language: Английский

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Neutrophil extracellular traps mediate deep vein thrombosis: from mechanism to therapy

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 23, 2023

Deep venous thrombosis (DVT) is a part of thromboembolism (VTE) that clinically manifests as swelling and pain in the lower limbs. The most serious clinical complication DVT pulmonary embolism (PE), which has high mortality rate. To date, its underlying mechanisms are not fully understood, patients usually present with symptoms only after formation thrombus. Thus, it essential to understand deep vein for an early diagnosis treatment DVT. In recent years, many studies have concluded Neutrophil Extracellular Traps (NETs) closely associated These released by neutrophils and, addition trapping pathogens, can mediate thrombi, thereby blocking blood vessels leading development disease. Therefore, this paper describes occurrence NETs discusses mechanism action on thrombosis. It aims provide direction improved near future.

Language: Английский

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Thromboembolic Adverse Drug Reactions in Janus Kinase (JAK) Inhibitors: Does the Inhibitor Specificity Play a Role?

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(5), P. 2449 - 2449

Published: Feb. 28, 2021

Recent advances in immunology enabled the characterization of several signal transmitting pathways responsible for proper cytokine and chemokine signaling. Among them, Janus kinases (JAKs) are essential components receptor activation systems. The discovery JAK synthesis kinase inhibitors (JAKi or Jakinibs), which have proven to be efficacious treatment hematologic malignancies rheumatological disorders continue investigated many clinical indications. Blocking multiple cytokines belonging families with a single small molecule may, however, create potential risk patients. Recently, higher thromboembolic complications, namely, deep vein thrombosis pulmonary embolism, has been recognized as main concern during Jakinibs. At present, it is not entirely clear whether this increased related direct blockade, presence concomitant diseases treated patients other unknown circumstances that work together increase side effect. In review, we discuss data on effects, special emphasis mechanism may risk. Many indirect indicate specificity inhibitor action, such preferentially blocking one signaling pathway upsets balance between pro anti-thrombotic activities.

Language: Английский

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The roles of platelets in COVID-19-associated coagulopathy and vaccine-induced immune thrombotic thrombocytopenia

Trends in Cardiovascular Medicine, Journal Year: 2021, Volume and Issue: 32(1), P. 1 - 9

Published: Aug. 27, 2021

In coronavirus disease 2019 (COVID-19), multiple thromboinflammatory events contribute to the pathophysiology, including coagulation system activation, suppressed fibrinolysis, vascular endothelial cell injury, and prothrombotic alterations in immune cells such as macrophages neutrophils. Although thrombocytopenia is not an initial presentation infectious coagulopathy, recent studies have demonstrated vital role of platelets COVID-19-associated coagulopathy SARS-CoV-2 its spike protein been known directly or indirectly promote release inflammatory mediators that lead coagulopathy. clinical features vaccine-induced thrombotic include uncommon locations thrombosis, cerebral venous sinus, we speculate spike-protein-initiated pathways are involved pathogenesis thrombocytopenia, current evidence suggests promotor other cofactors perturbed response reaction enhance production anti-platelet factor 4 antibody.

Language: Английский

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