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1.
Bull Exp Biol Med ; 174(6): 806-809, 2023 Apr.
Article in English | MEDLINE | ID: covidwho-2315974

ABSTRACT

We studied the neutrophils and monocytes obtained from 37 patients with various inflammatory diseases such as psoriasis, acute infectious process in the abdominal cavity (acute appendicitis/abscess of the abdominal cavity, and acute cholecystitis), acute pancreatitis, and post-COVID syndrome after mild COVID infection. The number and the morphological structure of neutrophil extracellular traps (NET) as well as the effect of IgG on NET were examined. NET were visualized and counted by fluorescence microscopy with fluorescent dye SYBR Green. All the studied types of inflammation were accompanied by spontaneous formation of NET. After application of IgG, the number of NET doubled, their size increased, and transformation of net-like traps into the cloud forms was observed. The clouds form structure of the network is not capable of capturing pathogens with subsequent retraction, the products of its enzymatic degradation can be the factors of secondary alteration. The study results demonstrate a previously unknown mechanism of infection resistance.


Subject(s)
COVID-19 , Extracellular Traps , Pancreatitis , Humans , Extracellular Traps/metabolism , Acute Disease , Pancreatitis/metabolism , COVID-19/metabolism , Neutrophils/metabolism , Immunoglobulin G/metabolism
2.
Int J Mol Sci ; 24(7)2023 Mar 28.
Article in English | MEDLINE | ID: covidwho-2306813

ABSTRACT

Neutrophils-polymorphonuclear cells (PMNs) are the cells of the initial immune response and make up the majority of leukocytes in the peripheral blood. After activation, these cells modify their functional status to meet the needs at the site of action or according to the agent causing injury. They receive signals from their surroundings and "plan" the course of the response in both temporal and spatial contexts. PMNs dispose of intracellular signaling pathways that allow them to perform a wide range of functions associated with the development of inflammatory processes. In addition to these cells, some protein complexes, known as inflammasomes, also have a special role in the development and maintenance of inflammation. These complexes participate in the proteolytic activation of key pro-inflammatory cytokines, such as IL-1ß and IL-18. In recent years, there has been significant progress in the understanding of the structure and molecular mechanisms behind the activation of inflammasomes and their participation in the pathogenesis of numerous diseases. The available reports focus primarily on macrophages and dendritic cells. According to the literature, the activation of inflammasomes in neutrophils and the associated death type-pyroptosis-is regulated in a different manner than in other cells. The present work is a review of the latest reports concerning the course of inflammasome activation and inflammatory cytokine secretion in response to pathogens in neutrophils, as well as the role of these mechanisms in the pathogenesis of selected diseases.


Subject(s)
Inflammasomes , Neutrophils , Humans , Inflammasomes/metabolism , Neutrophils/metabolism , Inflammation/metabolism , Macrophages/metabolism , Cytokines/metabolism , Interleukin-1beta/metabolism , Carrier Proteins/metabolism , Pyroptosis , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
3.
Chin Clin Oncol ; 12(2): 18, 2023 Apr.
Article in English | MEDLINE | ID: covidwho-2299870

ABSTRACT

A vital constituent of innate immunity, neutrophils had previously been considered functionally rigid with a fixed, defined role in host pathogen response, in part due to their fleeting lifespan. However, that consensus opinion has changed with evidence of functional neutrophil plasticity in a range of diseases including cancer. Typically difficult to sequence due to their low level of transcriptomic activity, advances in single cell RNA sequencing has allowed for closer examination of the neutrophil transcriptome in humans and mouse models and their interaction with other immune system constituents, both in health and disease, allowing for description of neutrophil phenotypes beyond previous descriptions reliant upon microscopic appearance, surface marker expression, and function. Transcriptomic analysis shows that neutrophils develop and mature along a fixed trajectory, but their transcriptome varies based on maturity, the insult that has provoked release from the bone marrow, and the tissue to which they are recruited. Thus neutrophil heterogeneity increases with maturity, with immature neutrophils being more transcriptomically rigid. Here, we review work done in neutrophil single cell RNA sequencing in mice and humans in health and a range of disease states including coronavirus disease 2019 (COVID-19) infection, and solid cancers to provide a template for understanding neutrophil biology in context.


Subject(s)
COVID-19 , Neoplasms , Humans , Animals , Mice , Neutrophils/metabolism , Immunity, Innate , Neoplasms/genetics , Phenotype
4.
Int J Mol Sci ; 24(5)2023 Mar 03.
Article in English | MEDLINE | ID: covidwho-2256874

ABSTRACT

Although many studies have been exploring the mechanisms driving NETs formation, much less attention has been paid to the degradation and elimination of these structures. The NETs clearance and the effective removal of extracellular DNA, enzymatic proteins (neutrophil elastase, proteinase 3, myeloperoxidase) or histones are necessary to maintain tissue homeostasis, to prevent inflammation and to avoid the presentation of self-antigens. The persistence and overabundance of DNA fibers in the circulation and tissues may have dramatic consequences for a host leading to the development of various systemic and local damage. NETs are cleaved by a concerted action of extracellular and secreted deoxyribonucleases (DNases) followed by intracellular degradation by macrophages. NETs accumulation depends on the ability of DNase I and DNAse II to hydrolyze DNA. Furthermore, the macrophages actively engulf NETs and this event is facilitated by the preprocessing of NETs by DNase I. The purpose of this review is to present and discuss the current knowledge about the mechanisms of NETs degradation and its role in the pathogenesis of thrombosis, autoimmune diseases, cancer and severe infections, as well as to discuss the possibilities for potential therapeutic interventions. Several anti-NETs approaches had therapeutic effects in animal models of cancer and autoimmune diseases; nevertheless, the development of new drugs for patients needs further study for an effective development of clinical compounds that are able to target NETs.


Subject(s)
Autoimmune Diseases , Extracellular Traps , Animals , Extracellular Traps/metabolism , Neutrophils/metabolism , Deoxyribonuclease I/metabolism , Autoimmune Diseases/metabolism , DNA/metabolism
5.
Front Immunol ; 14: 1130288, 2023.
Article in English | MEDLINE | ID: covidwho-2259138

ABSTRACT

Introduction: Thromboinflammatory complications are well described sequalae of Coronavirus Disease 2019 (COVID-19), and there is evidence of both hyperreactive platelet and inflammatory neutrophil biology that contributes to the thromoinflammatory milieu. It has been demonstrated in other thromboinflammatory diseases that the circulating environment may affect cellular behavior, but what role this environment exerts on platelets and neutrophils in COVID-19 remains unknown. We tested the hypotheses that 1) plasma from COVID-19 patients can induce a prothrombotic platelet functional phenotype, and 2) contents released from platelets (platelet releasate) from COVID-19 patients can induce a proinflammatory neutrophil phenotype. Methods: We treated platelets with COVID-19 patient and disease control plasma, and measured their aggregation response to collagen and adhesion in a microfluidic parallel plate flow chamber coated with collagen and thromboplastin. We exposed healthy neutrophils to platelet releasate from COVID-19 patients and disease controls and measured neutrophil extracellular trap formation and performed RNA sequencing. Results: We found that COVID-19 patient plasma promoted auto-aggregation, thereby reducing response to further stimulation ex-vivo. Neither disease condition increased the number of platelets adhered to a collagen and thromboplastin coated parallel plate flow chamber, but both markedly reduced platelet size. COVID-19 patient platelet releasate increased myeloperoxidasedeoxyribonucleic acid complexes and induced changes to neutrophil gene expression. Discussion: Together these results suggest aspects of the soluble environment circulating platelets, and that the contents released from those neutrophil behavior independent of direct cellular contact.


Subject(s)
Blood Platelets , COVID-19 , Humans , Blood Platelets/metabolism , Neutrophils/metabolism , COVID-19/metabolism , Thromboplastin/metabolism , Collagen/metabolism
6.
Int J Mol Sci ; 24(6)2023 Mar 07.
Article in English | MEDLINE | ID: covidwho-2288759

ABSTRACT

Acute respiratory distress syndrome (ARDS) threatens the survival of critically ill patients, the mechanisms of which are still unclear. Neutrophil extracellular traps (NETs) released by activated neutrophils play a critical role in inflammatory injury. We investigated the role of NETs and the underlying mechanism involved in acute lung injury (ALI). We found a higher expression of NETs and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) in the airways, which was reduced by Deoxyribonuclease I (DNase I) in ALI. The administration of the STING inhibitor H-151 also significantly relieved inflammatory lung injury, but failed to affect the high expression of NETs in ALI. We isolated murine neutrophils from bone marrow and acquired human neutrophils by inducing HL-60 to differentiate. After the PMA interventions, exogenous NETs were obtained from such extracted neutrophils. Exogenous NETs intervention in vitro and in vivo resulted in airway injury, and such inflammatory lung injury was reversed upon degrading NETs with or inhibiting cGAS-STING with H-151 as well as siRNA STING. In conclusion, cGAS-STING participates in regulating NETs-mediated inflammatory pulmonary injury, which is expected to be a new therapeutic target for ARDS/ALI.


Subject(s)
Acute Lung Injury , Extracellular Traps , Respiratory Distress Syndrome , Humans , Mice , Animals , Extracellular Traps/metabolism , Acute Lung Injury/metabolism , Neutrophils/metabolism , Respiratory Distress Syndrome/metabolism , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism
7.
Arterioscler Thromb Vasc Biol ; 42(9): 1103-1112, 2022 09.
Article in English | MEDLINE | ID: covidwho-2285811

ABSTRACT

The activating interplay of thrombosis and inflammation (thromboinflammation) has been established as a major underlying pathway, driving not only cardiovascular disease but also autoimmune disease and most recently, COVID-19. Throughout the years, innate immune cells have emerged as important modulators of this process. As the most abundant white blood cell in humans, neutrophils are well-positioned to propel thromboinflammation. This includes their ability to trigger an organized cell death pathway with the release of decondensed chromatin structures called neutrophil extracellular traps. Decorated with histones and cytoplasmic and granular proteins, neutrophil extracellular traps exert cytotoxic, immunogenic, and prothrombotic effects accelerating disease progression. Distinct steps leading to extracellular DNA release (NETosis) require the activities of PAD4 (protein arginine deiminase 4) catalyzing citrullination of histones and are supported by neutrophil inflammasome. By linking the immunologic function of neutrophils with the procoagulant and proinflammatory activities of monocytes and platelets, PAD4 activity holds important implications for understanding the processes that fuel thromboinflammation. We will also discuss mechanisms whereby vascular occlusion in thromboinflammation depends on the interaction of neutrophil extracellular traps with ultra-large VWF (von Willebrand Factor) and speculate on the importance of PAD4 in neutrophil inflammasome assembly and neutrophil extracellular traps in thromboinflammatory diseases including atherosclerosis and COVID-19.


Subject(s)
Atherosclerosis , COVID-19 , Extracellular Traps , Thrombosis , Atherosclerosis/metabolism , Extracellular Traps/metabolism , Histones/metabolism , Humans , Inflammasomes/metabolism , Inflammation/metabolism , Neutrophils/metabolism , Thromboinflammation , Thrombosis/etiology , Thrombosis/metabolism , von Willebrand Factor/metabolism
8.
Expert Rev Hematol ; 15(8): 727-745, 2022 08.
Article in English | MEDLINE | ID: covidwho-2258639

ABSTRACT

INTRODUCTION: COVID-19 is associated to an increased risk of thrombosis, as a result of a complex process that involves the activation of vascular and circulating cells, the release of soluble inflammatory and thrombotic mediators and blood clotting activation. AREAS COVERED: This article reviews the pathophysiological role of platelets, neutrophils, and the endothelium, and of their interactions, in the thrombotic complications of COVID-19 patients, and the current and future therapeutic approaches targeting these cell types. EXPERT OPINION: Virus-induced platelet, neutrophil, and endothelial cell changes are crucial triggers of the thrombotic complications and of the adverse evolution of COVID-19. Both the direct interaction with the virus and the associated cytokine storm concur to trigger cell activation in a classical thromboinflammatory vicious circle. Although heparin has proven to be an effective prophylactic and therapeutic weapon for the prevention and treatment of COVID-19-associated thrombosis, it acts downstream of the cascade of events triggered by SARS-CoV-2. The identification of specific molecular targets interrupting the thromboinflammatory cascade upstream, and more specifically acting either on the interaction of SARS-CoV-2 with blood and vascular cells or on the specific signaling mechanisms associated with their COVID-19-associated activation, might theoretically offer greater protection with potentially lesser side effects.


Subject(s)
COVID-19 , Thrombosis , Blood Platelets/metabolism , COVID-19/complications , Endothelium/metabolism , Humans , Neutrophils/metabolism , SARS-CoV-2 , Thrombosis/etiology , Thrombosis/metabolism
9.
Int J Mol Sci ; 24(1)2022 Dec 22.
Article in English | MEDLINE | ID: covidwho-2242287

ABSTRACT

In this paper, we present a literature review of the role of CXC motif chemokine ligand 1 (CXCL1) in physiology, and in selected major non-cancer diseases of the cardiovascular system, respiratory system and skin. CXCL1, a cytokine belonging to the CXC sub-family of chemokines with CXC motif chemokine receptor 2 (CXCR2) as its main receptor, causes the migration and infiltration of neutrophils to the sites of high expression. This implicates CXCL1 in many adverse conditions associated with inflammation and the accumulation of neutrophils. The aim of this study was to describe the significance of CXCL1 in selected diseases of the cardiovascular system (atherosclerosis, atrial fibrillation, chronic ischemic heart disease, hypertension, sepsis including sepsis-associated encephalopathy and sepsis-associated acute kidney injury), the respiratory system (asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, coronavirus disease 2019 (COVID-19), influenza, lung transplantation and ischemic-reperfusion injury and tuberculosis) and the skin (wound healing, psoriasis, sunburn and xeroderma pigmentosum). Additionally, the significance of CXCL1 is described in vascular physiology, such as the effects of CXCL1 on angiogenesis and arteriogenesis.


Subject(s)
Cardiovascular Diseases , Chemokine CXCL1 , Respiratory Tract Diseases , Skin Diseases , Humans , Cardiovascular System/metabolism , Chemokine CXCL1/metabolism , Chemokine CXCL2/metabolism , Chemokines/metabolism , Lung/metabolism , Neutrophil Infiltration , Neutrophils/metabolism , Receptors, Interleukin-8B/metabolism , Respiratory System , Skin
10.
Physiol Rep ; 11(3): e15556, 2023 02.
Article in English | MEDLINE | ID: covidwho-2228884

ABSTRACT

The COVID-19 pandemic restricted the regular training and competition program of athletes. Vaccines against COVID-19 are known to be beneficial for the disease; however, the unknown side effects of vaccines and postvaccination reactions have made some athletes hesitant to get vaccinated. We investigated the changes in inflammatory responses and menstrual cycles of female athletes before and after vaccination. Twenty female athletes were enrolled in this study. Blood was collected from each subject before the first COVID-19 vaccination and after the first and second vaccinations. Laboratory data, including white blood cell, neutrophil, lymphocyte, and platelet counts, and inflammatory markers, including NLR (neutrophil-to-lymphocyte ratio), PLR (platelet lymphocyte ratio), RPR (red cell distribution width to platelet ratio), SII (systemic immune-inflammation index), and NeuPla (neutrophil-platelet ratio), were analyzed statistically. The menstrual changes before and after vaccination and the side effects were collected by questionnaires. No significant changes in the laboratory data were found after the first and second shots when compared to those at prevaccination: white blood cell, neutrophil, lymphocyte, platelet, NLR, PLR, SII, RPR, and NeuPla (p > 0.05). In addition, there were no significant changes in the menstruation cycle or days of the menstrual period (p > 0.05). All side effects after vaccination were mild and subsided in 2 days. The blood cell counts, inflammatory markers, and menstruation of female athletes were not affected by COVID-19 vaccines.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , Female , COVID-19 Vaccines/metabolism , Menstruation , Pandemics , COVID-19/metabolism , Blood Cell Count , Lymphocytes/metabolism , Inflammation/metabolism , Neutrophils/metabolism , Retrospective Studies
11.
Medicina (Kaunas) ; 59(1)2022 Dec 23.
Article in English | MEDLINE | ID: covidwho-2228279

ABSTRACT

Background and objectives: The prognoses of patients experiencing a prolonged stay in the intensive care unit (ICU) are often significantly altered by hospital-acquired infections (HAIs), the early detection of which might be cumbersome. The aim of this study was to investigate the roles of the neutrophil-to-lymphocyte (NLR), derived-NRL (d-NLR), platelet-to-lymphocyte (PLR), and lymphocyte-to-C-reactive protein (LCR) ratios in predicting the progression to septic shock and death. Materials and Methods: A retrospective analysis of a consecutive series of ninety COVID-19 patients with prolonged hospitalization (exceeding 15 days) admitted to the ICU was conducted. The prevalence of culture-proven HAIs throughout their hospital stays was documented. NLR, dNLR, PLR, and LCR were recorded on admission, day 7, and day 14 to assess their discriminative prowess for detecting further progression to septic shock or death. Results: The prevalence of HAIs was 76.6%, 50% of patients met the criteria for septic shock, and 50% died. The median time to the first positive culture was 13.5 days and 20.5 days for developing septic shock. Mechanical ventilation was a key contributing factor to HAI, septic shock, and mortality. On admission and day 7 NLR, dNLR, PLR, and LCR values had no prognostic relevance for events occurring late during hospitalization. However, day-14 NLR, dNLR, and PLR were independent predictors for progression to septic shock and mortality and have shown good discriminative capabilities. The AUCs for septic shock were 0.762, 0.764, and 0.716, while the values for predicting in-hospital death were 0.782, 0.778, and 0.758, respectively. Conclusions: NLR, dNLR, and PLR are quick, easy-to-use, cheap, effective biomarkers for the detection of a more severe disease course, of the late development of HAIs, and of the risk of death in critically ill patients requiring a prolonged ICU stay.


Subject(s)
COVID-19 , Shock, Septic , Humans , Neutrophils/metabolism , Shock, Septic/epidemiology , Retrospective Studies , Hospital Mortality , COVID-19/epidemiology , COVID-19/metabolism , Lymphocytes , Prognosis , Intensive Care Units
12.
Eur J Med Chem ; 250: 115175, 2023 Mar 15.
Article in English | MEDLINE | ID: covidwho-2237130

ABSTRACT

C-X-C motif chemokine receptor 2 (CXCR2) is G protein-coupled receptor (GPCR) and plays important roles in various inflammatory diseases and cancers, including chronic obstructive pulmonary disease (COPD), atherosclerosis, asthma, and pancreatic cancer. Upregulation of CXCR2 is closely associated with the migration of neutrophils and monocytes. To date, many small-molecule CXCR2 antagonists have entered clinical trials, showing favorable safety and therapeutic effects. Hence, we provide an overview containing the discovery history, protein structure, signaling pathways, biological functions, structure-activity relationships and clinical significance of CXCR2 antagonists in inflammatory diseases and cancers. According to the latest development and recent clinical progress of CXCR2 small molecule antagonists, we speculated that CXCR2 can be used as a biomarker and a new target for diabetes and that CXCR2 antagonists may also attenuate lung injury in coronavirus disease 2019 (COVID-19).


Subject(s)
Asthma , COVID-19 , Pancreatic Neoplasms , Pulmonary Disease, Chronic Obstructive , Humans , Pulmonary Disease, Chronic Obstructive/drug therapy , Neutrophils/metabolism , Asthma/metabolism , Receptors, Interleukin-8B , Pancreatic Neoplasms/metabolism
13.
Int J Mol Sci ; 24(3)2023 Jan 31.
Article in English | MEDLINE | ID: covidwho-2225329

ABSTRACT

Neutrophil extracellular traps (NETs) and oxidative stress are considered to be beneficial in the innate immune defense against pathogens. However, defective clearance of NETs in the lung of acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients could lead to severe respiratory syndrome infection, the so-called coronavirus disease 2019 (COVID-19). To elucidate the pathways that are related to NETs within the pathophysiology of COVID-19, we utilized RNA sequencing (RNA-seq) as well as immunofluorescence and immunohistochemistry methods. RNA-seq analysis provided evidence for increased oxidative stress and the activation of viral-related signaling pathways in post-mortem lungs of COVID-19 patients compared to control donors. Moreover, an excess of neutrophil infiltration and NET formation were detected in the patients' lungs, where the extracellular DNA was oxidized and co-localized with neutrophil granule protein myeloperoxidase (MPO). Interestingly, staining of the lipid peroxidation marker 4-hydroxynonenal (4-HNE) depicted high colocalization with NETs and was correlated with the neutrophil infiltration of the lung tissues, suggesting that it could serve as a suitable marker for the identification of NETs and the severity of the disease. Moreover, local inhalation therapy to reduce the excess lipid oxidation and NETs in the lungs of severely infected patients might be useful to ameliorate their clinical conditions.


Subject(s)
COVID-19 , Extracellular Traps , Humans , COVID-19/metabolism , Extracellular Traps/metabolism , SARS-CoV-2 , Lung , Oxidative Stress , Neutrophils/metabolism
14.
Blood Coagul Fibrinolysis ; 34(2): 87-92, 2023 Mar 01.
Article in English | MEDLINE | ID: covidwho-2222897

ABSTRACT

Coronavirus disease 2019 (COVID-19), which is caused by novel coronavirus-2019 (nCoV-2019), is a highly contagious disease with high mortality and morbidity risk. Infected people may suffer from respiratory infections, which may be more progressive in patients with a defective immune system and underlying medical problems. In this regard, the cells involved in the innate immune system, play a decisive role in disease progression and complication development. Pathogen entrapment is the critical role of neutrophil extracellular traps (NETosis). This process involves the widespread release of fibrous structures by the stimulant-activated neutrophils. These fibrous structures are composed of cytosolic proteins and granular contents brought together by a network of released chromatins. This network can inhibit the spread of pathogens by their entrapment. Moreover, NETosis damage the host by producing toxic agents and triggering thrombosis. Therefore, this phenomenon may act as a double-edged sword. Regarding the rapid expansion of COVID-19, it is crucial to examine the involvement of NETosis in infected patients. This study aims to discuss NETosis participation to show its probable association with increased risk of thrombogenicity and help develop new therapeutic approaches in the battle against this viral disease.


Subject(s)
COVID-19 , Extracellular Traps , Thrombosis , Humans , Extracellular Traps/metabolism , Neutrophils/metabolism , Thrombosis/metabolism , SARS-CoV-2
15.
Wiad Lek ; 75(12): 2926-2932, 2022.
Article in English | MEDLINE | ID: covidwho-2226744

ABSTRACT

OBJECTIVE: The aim: The study conducted to have a better understanding on the role of neutrophil-lymphocyte ratio in the determination of the prognosis of COVID-19 and to assist in predicting disease severity. PATIENTS AND METHODS: Materials and methods: A total of 96 patients within age group 18-80 years who were verified positive for the COVID-19 by PCR, and admitted to (Al-Sader Medical City) in Al-Najaf City between (July to October 2020) were enrolled in a cohort retrospective study, Neutrophil to lymphocyte ratio was calculated via taking the absolute neutrophil count divided by the absolute lymphocyte count. Other parameters like (renal function tests, D-dimer, C-reactive protein, serum ferritin) also has been studied in relation to outcome of patients with COVID-19. RESULTS: Results: The Neutrophil-lymphocyte ratio was significantly associated with low oxygen saturation and poor outcome. A significant difference was found between two clusters in CRP, serum ferritin, and D-dimer level. In addition, age and obstructive airway disease were important clinical predictors for poor outcome. CONCLUSION: Conclusions: The study was a useful prognostic marker linked with poor outcome in patients admitted for COVID-19 pneumonia. Other inflammatory markers, such as ferritin, CRP, and D-dimer were also associated with critical illness and increased mortality from COVID-19 disease.


Subject(s)
COVID-19 , Humans , Adolescent , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and over , Neutrophils/metabolism , Retrospective Studies , SARS-CoV-2 , ROC Curve , Lymphocytes/metabolism , Prognosis
16.
Medicina (Kaunas) ; 59(1)2022 Dec 28.
Article in English | MEDLINE | ID: covidwho-2208633

ABSTRACT

Immune organ failure is frequent in critical illness independent of its cause and has been acknowledged for a long time. Most patients admitted to the ICU, whether featuring infection, trauma, or other tissue injury, have high levels of alarmins expression in tissues or systemically which then activate innate and adaptive responses. Although necessary, this response is frequently maladaptive and leads to organ dysfunction. In addition, the counter-response aiming to restore homeostasis and repair injury can also be detrimental and contribute to persistent chronic illness. Despite intensive research on this topic in the last 40 years, the immune system is not routinely monitored in critical care units. In this narrative review we will first discuss the inflammatory response after acute illness and the players of maladaptive response, focusing on neutrophils, monocytes, and T cells. We will then go through commonly used biomarkers, like C-reactive protein, procalcitonin and pancreatic stone protein (PSP) and what they monitor. Next, we will discuss the strengths and limitations of flow cytometry and related techniques as an essential tool for more in-depth immune monitoring and end with a presentation of the most promising cell associated markers, namely HLA-DR expression on monocytes, neutrophil expression of CD64 and PD-1 expression on T cells. In sum, immune monitoring critically ill patients is a forgotten and missing piece in the monitoring capacity of intensive care units. New technology, including bed-side equipment and in deep cell phenotyping using emerging multiplexing techniques will likely allow the definition of endotypes and a more personalized care in the future.


Subject(s)
Critical Illness , HLA-DR Antigens , Humans , HLA-DR Antigens/metabolism , Intensive Care Units , Monocytes , Neutrophils/metabolism , Biomarkers/metabolism
17.
Front Immunol ; 13: 1078891, 2022.
Article in English | MEDLINE | ID: covidwho-2198917

ABSTRACT

Introduction: The intravascular formation of neutrophil extracellular traps (NETs) is a trigger for coagulation and blood vessel occlusion. NETs are released from neutrophils as a response to strong inflammatory signals in the course of different diseases such as COVID-19, cancer or antiphospholipid syndrome. NETs are composed of large, chromosomal DNA fibers decorated with a variety of proteins such as histones. Previous research suggested a close mechanistic crosstalk between NETs and the coagulation system involving the coagulation factor XII (FXII), von Willebrand factor (VWF) and tissue factor. However, the direct impact of NET-related DNA fibers on blood flow and blood aggregation independent of the coagulation cascade has remained elusive. Methods: In the present study, we used different microfluidic setups in combination with fluorescence microscopy to investigate the influence of neutrophil-derived extracellular DNA fibers on blood rheology, intravascular occlusion and activation of the complement system. Results: We found that extended DNA fiber networks decelerate blood flow and promote intravascular occlusion of blood vessels independent of the plasmatic coagulation. Associated with the DNA dependent occlusion of the flow channel was the strong activation of the complement system characterized by the production of complement component 5a (C5a). Vice versa, we detected that the local activation of the complement system at the vascular wall was a trigger for NET release. Discussion: In conclusion, we found that DNA fibers as the principal component of NETs are sufficient to induce blood aggregation even in the absence of the coagulation system. Moreover, we discovered that complement activation at the endothelial surface promoted NET formation. Our data envisions DNA degradation and complement inhibition as potential therapeutic strategies in NET-induced coagulopathies.


Subject(s)
COVID-19 , Extracellular Traps , Humans , Extracellular Traps/metabolism , COVID-19/metabolism , Neutrophils/metabolism , DNA/metabolism , Complement Activation
18.
Nature ; 614(7948): 530-538, 2023 02.
Article in English | MEDLINE | ID: covidwho-2185938

ABSTRACT

Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.


Subject(s)
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid , Cell Self Renewal , Macrophages, Alveolar , Neutrophils , Animals , Mice , 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/metabolism , Acute Lung Injury , Animals, Newborn , Arachidonate 12-Lipoxygenase/deficiency , Arachidonate 15-Lipoxygenase/deficiency , COVID-19 , Influenza A virus , Lipopolysaccharides , Lung/cytology , Lung/virology , Macrophages, Alveolar/cytology , Macrophages, Alveolar/metabolism , Neutrophils/metabolism , Orthomyxoviridae Infections , Prostaglandins E , SARS-CoV-2 , Disease Susceptibility
19.
Redox Biol ; 59: 102557, 2023 02.
Article in English | MEDLINE | ID: covidwho-2150474

ABSTRACT

Neutrophil and airway epithelial cell interactions are critical in the inflammatory response to viral infections including respiratory syncytial virus, Sendai virus, and SARS-CoV-2. Airway epithelial cell dysfunction during viral infections is likely mediated by the interaction of virus and recruited neutrophils at the airway epithelial barrier. Neutrophils are key early responders to viral infection. Neutrophil myeloperoxidase catalyzes the conversion of hydrogen peroxide to hypochlorous acid (HOCl). Previous studies have shown HOCl targets host neutrophil and endothelial cell plasmalogen lipids, resulting in the production of the chlorinated lipid, 2-chlorofatty aldehyde (2-ClFALD). We have previously shown that the oxidation product of 2-ClFALD, 2-chlorofatty acid (2-ClFA) is present in bronchoalveolar lavage fluid of Sendai virus-infected mice, which likely results from the attack of the epithelial plasmalogen by neutrophil-derived HOCl. Herein, we demonstrate small airway epithelial cells contain plasmalogens enriched with oleic acid at the sn-2 position unlike endothelial cells which contain arachidonic acid enrichment at the sn-2 position of plasmalogen. We also show neutrophil-derived HOCl targets epithelial cell plasmalogens to produce 2-ClFALD. Further, proteomics and over-representation analysis using the ω-alkyne analog of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDyA) showed cell adhesion molecule binding and cell-cell junction enriched categories similar to that observed previously in endothelial cells. However, in contrast to endothelial cells, proteins in distinct metabolic pathways were enriched with 2-ClFALD modification, particularly pyruvate metabolism was enriched in epithelial cells and mitochondrial pyruvate respiration was reduced. Collectively, these studies demonstrate, for the first time, a novel plasmalogen molecular species distribution in airway epithelial cells that are targeted by myeloperoxidase-derived hypochlorous acid resulting in electrophilic 2-ClFALD, which potentially modifies epithelial physiology by modifying proteins.


Subject(s)
COVID-19 , Plasmalogens , Humans , Animals , Mice , Plasmalogens/chemistry , Plasmalogens/metabolism , Peroxidase/metabolism , Hypochlorous Acid/metabolism , Endothelial Cells/metabolism , COVID-19/metabolism , SARS-CoV-2/metabolism , Proteins/metabolism , Neutrophils/metabolism , Aldehydes/metabolism
20.
Int J Mol Sci ; 23(24)2022 Dec 08.
Article in English | MEDLINE | ID: covidwho-2155131

ABSTRACT

Some physicians use dapsone as part of the standard treatment of severe COVID-19 patients entering the ICU, though some do not. To obtain an indication of whether dapsone is helping or not, we undertook a retrospective chart review of 29 consecutive ICU COVID-19 patients receiving dapsone and 30 not receiving dapsone. As we previously reported, of those given dapsone, 9/29 (30%) died, while of those not given dapsone, 18/30 (60%) died. We looked back on that data set to determine if there might be basic laboratory findings in these patients that might give an indication of a mechanism by which dapsone was acting. We found that the neutrophil-to-lymphocyte ratio decreased in 48% of those given dapsone and in 30% of those not given dapsone. We concluded that dapsone might be lowering that ratio. We then reviewed collected data on neutrophil related inflammation pathways on which dapsone might act as presented here. As this was not a controlled study, many variables prevent drawing any conclusions from this work; a formal, randomized controlled study of dapsone in severe COVID-19 is warranted.


Subject(s)
COVID-19 , Humans , COVID-19/metabolism , Neutrophils/metabolism , Dapsone/therapeutic use , Retrospective Studies , Intensive Care Units , Lymphocytes
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