scholarly journals PAD Inhibitors as a Potential Treatment for SARS-CoV-2 Immunothrombosis

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1867
Author(s):  
Willie Elliott ◽  
Maheedhara R. Guda ◽  
Swapna Asuthkar ◽  
Narasaraju Teluguakula ◽  
Durbaka V. R. Prasad ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Inflammatory Diseases ◽  
Linear Connection ◽  
Neutrophil Extracellular Traps ◽  
Review Article ◽  
Potential Treatment ◽  
Extracellular Traps ◽  
Mutant Strains ◽  
Arginine Residues ◽  
Thrombotic Complications

Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the virus’s dynamicity has resulted in the evolution of various variants, including the delta variant and the more novel mu variant. With a multitude of mutant strains posing as challenges to vaccine efficacy, it is critical that researchers embrace the development of pharmacotherapeutics specific to SARS-CoV-2 pathophysiology. Neutrophil extracellular traps and their constituents, including citrullinated histones, display a linear connection with thrombotic manifestations in COVID-19 patients. Peptidylarginine deiminases (PADs) are a group of enzymes involved in the modification of histone arginine residues by citrullination, allowing for the formation of NETs. PAD inhibitors, specifically PAD-4 inhibitors, offer extensive pharmacotherapeutic potential across a broad range of inflammatory diseases such as COVID-19, through mediating NETs formation. Although numerous PAD-4 inhibitors exist, current literature has not explored the depth of utilizing these inhibitors clinically to treat thrombotic complications in COVID-19 patients. This review article offers the clinical significance of PAD-4 inhibitors in reducing thrombotic complications across various inflammatory disorders like COVID-19 and suggests that these inhibitors may be valuable in treating the origin of SARS-CoV-2 immunothrombosis.

scholarly journals Neutrophil extracellular traps and thrombosis in COVID-19

2020 ◽  
Author(s):  
Yu Zuo ◽  
Melanie Zuo ◽  
Srilakshmi Yalavarthi ◽  
Kelsey Gockman ◽  
Jacqueline A. Madison ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Histone H3 ◽  
Neutrophil Extracellular Traps ◽  
Neutrophil Extracellular Trap ◽  
Dna Complexes ◽  
Extracellular Traps ◽  
Free Dna ◽  
Extracellular Trap ◽  
Net Release ◽  
D Dimer

ABSTRACTHere, we report on four patients whose hospitalizations for COVID-19 were complicated by venous thromboembolism (VTE). All demonstrated high levels of D-dimer as well as high neutrophil-to-lymphocyte ratios. For three patients, we were able to test sera for neutrophil extracellular trap (NET) remnants and found significantly elevated levels of cell-free DNA, myeloperoxidase-DNA complexes, and citrullinated histone H3. Neutrophil-derived S100A8/A9 (calprotectin) was also elevated. Given strong links between hyperactive neutrophils, NET release, and thrombosis in many inflammatory diseases, the potential relationship between NETs and VTE should be further investigated in COVID-19.

scholarly journals Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation

2019 ◽  
Vol 119 (04) ◽  
pp. 542-552 ◽  
Author(s):  
Kristof Van Avondt ◽  
Lars Maegdefessel ◽  
Oliver Soehnlein
Keyword(s):  
Disease Risk ◽  
Neutrophil Extracellular Traps ◽  
Dnase I ◽  
Inflammasome Activation ◽  
Extracellular Traps ◽  
Thrombotic Complications ◽  
Atherothrombotic Disease ◽  
Coronary Events ◽  
Reactive Oxidants ◽  
Net Release

AbstractNeutrophils and neutrophil extracellular traps (NETs) have a robust relationship with atherothrombotic disease risk, which led to the idea that interfering with the release of NETs therapeutically would ameliorate atherosclerosis. In human studies, acute coronary events and the pro-thrombotic state cause markedly elevated levels of circulating deoxyribonucleic acid (DNA) and chromatin, suggesting that DNase I might produce cardiovascular benefit. DNase I reproduced the phenotype of peptidylarginine deiminase 4 (PAD4) deficiency and showed a significant benefit for atherothrombotic disease in experimental mouse models. However, the mechanisms of benefit remain unclear. Insights into the mechanisms underlying NET release and atherogenic inflammation have come from transgenic mouse studies. In particular, the importance of neutrophil NET formation in promoting atherothrombotic disease has been shown and linked to profound pro-inflammatory and pro-thrombotic effects, complement activation and endothelial dysfunction. Recent studies have shown that myeloid deficiency of PAD4 leads to diminished NET formation, which in turn protects against atherosclerosis burden, propagation of its thrombotic complications and notably macrophage inflammation in plaques. In addition, oxidative stress and neutrophil cholesterol accumulation have emerged as important factors driving NET release, likely involving mitochondrial reactive oxidants and neutrophil inflammasome activation. Further elucidation of the mechanisms linking hyperlipidaemia to the release of NETs may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for cardiovascular diseases.

scholarly journals Neutrophil Extracellular Traps in Arterial and Venous Thrombosis

2019 ◽  
Vol 45 (01) ◽  
pp. 086-093 ◽  
Author(s):  
Elodie Laridan ◽  
Kimberly Martinod ◽  
Simon De Meyer
Keyword(s):  
Myocardial Infarction ◽  
Thrombus Formation ◽  
Neutrophil Extracellular Traps ◽  
Major Health ◽  
Vein Thrombosis ◽  
Extracellular Traps ◽  
Thrombotic Complications ◽  
Decondensed Chromatin ◽  
Deep Vein ◽  
Novel Therapeutic

AbstractThrombotic complications are still a major health risk worldwide. Our view on the pathophysiology of thrombosis has significantly changed since the discovery of neutrophil extracellular traps (NETs) and their prothrombotic characteristics. Generated by neutrophils that release their decondensed chromatin as a network of extracellular fibers, NETs promote thrombus formation by serving as a scaffold that activates platelets and coagulation. The thrombogenic involvement of NETs has been described in various settings of thrombosis, including stroke, myocardial infarction, and deep vein thrombosis. The aim of this review is to summarize existing evidence showing the presence of NETs in human thrombus material. Following an introduction on NETs and their role in thrombus formation, the authors address studies showing the presence of NETs in arterial or venous thrombi. In addition, they focus on potential novel therapeutic opportunities to resolve or prevent thrombosis by targeting NETs.

scholarly journals Netting Liver Disease: Neutrophil Extracellular Traps in the Initiation and Exacerbation of Liver Pathology

2020 ◽  
Vol 46 (06) ◽  
pp. 724-734 ◽  
Author(s):  
Fien A. von Meijenfeldt ◽  
Craig N. Jenne
Keyword(s):  
Liver Disease ◽  
Clinical Evidence ◽  
Nuclear Dna ◽  
Inflammatory Cells ◽  
Neutrophil Extracellular Traps ◽  
Blood Stream ◽  
Vital Role ◽  
Extracellular Traps ◽  
Thrombotic Complications ◽  
Pathogen Clearance

AbstractThe liver plays a vital role in the immune system. Its unique position in the portal circulation and the architecture of the hepatic sinusoids, in combination with the wide-ranged population of immunocompetent cells, make the liver function as an immune filter. To aid in pathogen clearance, once challenged, the liver initiates the rapid recruitment of a wide variety of inflammatory cells, including neutrophils. These neutrophils, in conjunction with platelets, facilitate the release of neutrophil extracellular traps (NETs), which are web-like structures of decondensed nuclear DNA, histones, and neutrophil proteins. NETs function as both a physical and a chemical barrier, binding and killing pathogens circulating in the blood stream. In addition to their antimicrobial role, NETs also bind platelets, activate coagulation, and exacerbate host inflammatory response. This interplay between inflammation and coagulation drives microvascular occlusion, ischemia, and (sterile) damage in liver disease. Although direct clinical evidence of this interplay is scarce, preliminary studies indicate that NETs contribute to progression of liver disease and (thrombotic) complications. Here, we provide an overview of the pathological mechanisms of NETs in liver disease. In addition, we summarize clinical evidence for NETs in different disease etiologies and complications of liver disease and discuss the possible implications for the use of NETs as a diagnostic marker and a therapeutic target in liver disease.

scholarly journals SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology

2020 ◽  
Vol 217 (12) ◽  
Author(s):  
Flavio Protasio Veras ◽  
Marjorie Cornejo Pontelli ◽  
Camila Meirelles Silva ◽  
Juliana E. Toller-Kawahisa ◽  
Mikhael de Lima ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Tracheal Aspirate ◽  
Neutrophil Extracellular Traps ◽  
Angiotensin Converting Enzyme 2 ◽  
Extracellular Traps ◽  
Lung Epithelial ◽  
Activated Neutrophils ◽  
Epithelial Cell Death

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2–activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.

scholarly journals Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome

2016 ◽  
Vol 8 (4) ◽  
pp. 400-411 ◽  
Author(s):  
Maria Victoria Ramos ◽  
Maria Pilar Mejias ◽  
Florencia Sabbione ◽  
Romina Jimena Fernandez-Brando ◽  
Adriana Patricia Santiago ◽  
...  
Keyword(s):  
Renal Failure ◽  
Inflammatory Response ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Inflammatory Diseases ◽  
Neutrophil Extracellular Traps ◽  
Healthy Children ◽  
Extracellular Traps ◽  
Circulating Free Dna ◽  
Uremic Syndrome

Hemolytic uremic syndrome (HUS), a vascular disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure, is caused by enterohemorrhagic Shiga toxin (Stx)-producing bacteria, which mainly affect children. Besides Stx, the inflammatory response mediated by neutrophils (PMN) is essential to HUS evolution. PMN can release neutrophil extracellular traps (NET) composed of DNA, histones, and other proteins. Since NET are involved in infectious and inflammatory diseases, the aim of this work was to investigate the contribution of NET to HUS. Plasma from HUS patients contained increased levels of circulating free-DNA and nucleosomes in comparison to plasma from healthy children. Neutrophils from HUS patients exhibited a greater capacity to undergo spontaneous NETosis. NET activated human glomerular endothelial cells, stimulating secretion of the proinflammatory cytokines IL-6 and IL-8. Stx induced PMN activation as judged by its ability to trigger reactive oxygen species production, increase CD11b and CD66b expression, and induce NETosis in PMN from healthy donors. During HUS, NET can contribute to the inflammatory response and thrombosis in the microvasculature and thus to renal failure. Intervention strategies to inhibit inflammatory mechanisms mediated by PMN, such as NETosis, could have a potential therapeutic impact towards amelioration of the severity of HUS.

scholarly journals A Review of the Neutrophil Extracellular Traps (NETs) from Cow, Sheep and Goat Models

2021 ◽  
Vol 22 (15) ◽  
pp. 8046
Author(s):  
Mulumebet Worku ◽  
Djaafar Rehrah ◽  
Hamid D. Ismail ◽  
Emmanuel Asiamah ◽  
Sarah Adjei-Fremah
Keyword(s):  
One Health ◽  
Inflammatory Diseases ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Response Mechanism ◽  
Global Food Security ◽  
Extracellular Traps ◽  
Definition Of ◽  
Global Food ◽  
Insight Into

This review provides insight into the importance of understanding NETosis in cows, sheep, and goats in light of the importance to their health, welfare and use as animal models. Neutrophils are essential to innate immunity, pathogen infection, and inflammatory diseases. The relevance of NETosis as a conserved innate immune response mechanism and the translational implications for public health are presented. Increased understanding of NETosis in ruminants will contribute to the prediction of pathologies and design of strategic interventions targeting NETs. This will help to control pathogens such as coronaviruses and inflammatory diseases such as mastitis that impact all mammals, including humans. Definition of unique attributes of NETosis in ruminants, in comparison to what has been observed in humans, has significant translational implications for one health and global food security, and thus warrants further study.

scholarly journals Nontypeable Haemophilus influenzae redox recycling of protein thiols promotes resistance to oxidative killing and bacterial survival in biofilms in a smoke related infection model

2021 ◽  
Author(s):  
Benjamin C. Hunt ◽  
Xin Xu ◽  
Amit Gaggar ◽  
W. Edward Swords
Keyword(s):  
Oxidative Stress ◽  
Haemophilus Influenzae ◽  
Bacterial Load ◽  
Redox Homeostasis ◽  
Neutrophil Extracellular Traps ◽  
Immunofluorescent Staining ◽  
Extracellular Traps ◽  
Protein Thiols ◽  
Mutant Strains ◽  
Thiol Peroxidase

AbstractSmoke exposure is a risk factor for community acquired pneumonia, which is typically caused by host adapted opportunists like nontypeable Haemophilus influenzae (NTHi). Genomic analyses of NTHi revealed homologs of enzymes involved in thiol metabolism, which can have key roles in oxidant resistance. Using a clinical NTHi isolate (NTHi 7P49H1), we generated isogenic mutant bacterial strains in which homologs of glutathione reductase (NTHI 0251), thiol peroxidase (NTHI 0361), thiol peroxidase (NTHI 0907), thioredoxin reductase (NTHI 1327) and glutaredoxin/peroxiredoxin (NTHI 0705) were inactivated. Bacterial protein analyses revealed significant increases in protein oxidation after oxidative stress for all the mutant strains. Similarly, each of these mutants were less resistant to oxidative killing compared with the parental strain; these phenotypes were reversed by genetic complementation. Quantitative confocal analysis of biofilms showed reducted biofilm thickness and density, and significant sensitization of bacteria within the biofilm structure to oxidative killing for thiol mutant strains. Smoke-exposed mice infected with NTHi 7P49H1 showed significantly increased lung bacterial load, as compared to control mice. Immunofluorescent staining of lung tissues showed NTHi communities on the lung mucosa, interspersed with host neutrophil extracellular traps; these bacteria had surface moieties associated with the Hi biofilm matrix, and transcript profiles consistent with NTHi biofilms. In contrast, infection with the panel of NTHi mutants showed significant decrease in lung bacterial load. Comparable results were observed in bactericidal assays with neutrophil extracellular traps in vitro. Thus, we conclude that thiol mediated redox homeostasis promotes persistence of NTHi within biofilm communities.ImportanceChronic bacterial respiratory infections are a significant problem for smoke exposed individuals, especially those with chronic obstructive pulmonary disease (COPD). These infections often persist despite antibiotic use. Thus, the bacteria remain and contribute to the development of inflammation and other respiratory problems. Respiratory bacteria often form biofilms within the lungs, while growing in a biofilm their antibiotic and oxidative stress resistance is incredibly heightened. It is well documented that redox homeostasis genes are upregulated during this phase of growth. Many common respiratory pathogens such as NTHi and Streptococcus pneumoniae are reliant on scavenging from the host the necessary components they need to maintain these redox systems. This work here begins to lay down the foundation for exploiting this requirement and thiol redox homeostasis pathways of these bacteria as a therapeutic target for managing chronic respiratory bacterial infections, which are resistant to traditional antibiotic treatments alone.

scholarly journals Low-dose nanotherapy-mediated site-specific inhibition of neutrophil extracellular traps for immunoregulatory treatment of asthma

2021 ◽  
Author(s):  
Yongchang Ma ◽  
Lanlan Li ◽  
Yi Hu ◽  
Songling Han ◽  
Qinghua Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Severe Asthma ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Neutrophil Extracellular Traps ◽  
Great Promise ◽  
T Helper 17 ◽  
Site Specific ◽  
Extracellular Traps ◽  
Therapeutic Benefits

Abstract Asthma, one of the most common lung diseases, remains a serious global healthy problem. Currently there is still an urgent need for effective and safe therapies against severe asthma. Neutrophil extracellular traps (NETs) have emerged as a new therapeutic target for different diseases, while precision regulation of NETs is highly challenging. Here, we report site-specific attenuation of oxidative stress in lung neutrophils via a cyclic oligosaccharide-derived nanotherapy (termed as TPCN) effectively inhibited the development of mouse neutrophilic asthma, a typical phenotype of severe asthma. Therapeutically, TPCN delivered via either intravenous injection or inhalation can distribute in lung neutrophils of asthmatic mice, thereby significantly mitigating oxidative stress, suppressing inflammatory responses, reversing airway remodelling, and improving pulmonary function. Notably, TPCN is effective even at an actual inhalation dose as low as 0.063 mg/kg. Mechanistically, therapeutic benefits of TPCN are achieved by inhibiting reactive oxygen species (ROS)-induced formation of NETs, which further promotes immune homeostasis via regulating balance between regulatory T (Treg) and T helper 17 (Th17) cells. Thus, TPCN holds great promise for precision therapy of neutrophilic asthma, while the ROS-NETs-Treg/Th17 pathway can function as intriguing therapeutic targets for the treatment of severe asthma and other neutrophil-mediated inflammatory diseases.

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