scholarly journals Histone H3 Cleavage in Severe COVID-19 ICU Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Joram Huckriede ◽  
Femke de Vries ◽  
Michael Hultström ◽  
Kanin Wichapong ◽  
Chris Reutelingsperger ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Secondary Infection ◽  
Treatment Options ◽  
Histone H3 ◽  
Kidney Injury ◽  
Neutrophil Extracellular Trap ◽  
Icu Patients ◽  
Extracellular Histones ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

The severity of coronavirus disease 19 (COVID-19) is associated with neutrophil extracellular trap (NET) formation. During NET formation, cytotoxic extracellular histones are released, the presence of which is linked to the initiation and progression of several acute inflammatory diseases. Here we study the presence and evolution of extracellular histone H3 and several other neutrophil-related molecules and damage-associated molecular patterns (DAMPs) in the plasma of 117 COVID-19-positive ICU patients. We demonstrate that at ICU admission the levels of histone H3, MPO, and DNA-MPO complex were all significantly increased in COVID-19-positive patients compared to control samples. Furthermore, in a subset of 54 patients, the levels of each marker remained increased after 4+ days compared to admission. Histone H3 was found in 28% of the patients on admission to the ICU and in 50% of the patients during their stay at the ICU. Notably, in 47% of histone-positive patients, we observed proteolysis of histone in their plasma. The overall presence of histone H3 during ICU stay was associated with thromboembolic events and secondary infection, and non-cleaved histone H3 was associated with the need for vasoactive treatment, invasive ventilation, and the development of acute kidney injury. Our data support the validity of treatments that aim to reduce NET formation and additionally underscore that more targeted therapies focused on the neutralization of histones should be considered as treatment options for severe COVID-19 patients.

scholarly journals Recombinant human soluble thrombomodulin is associated with attenuation of sepsis-induced renal impairment by inhibition of extracellular histone release

2019 ◽  
Author(s):  
Masayuki Akatsuka ◽  
Yoshiki Masuda ◽  
Hiroomi Tatsumi ◽  
Michiaki Yamakage
Keyword(s):  
Histone H3 ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Treated Group ◽  
Cecal Ligation And Puncture ◽  
Soluble Thrombomodulin ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Vehicle Treated Group ◽  
Recombinant Human Soluble Thrombomodulin

AbstractMultiple organ dysfunction induced by sepsis often involves kidney injury. Extracellular histones released in response to damage-associated molecular patterns are known to facilitate sepsis-induced organ dysfunction. Recombinant human soluble thrombomodulin (rhTM) and its lectin-like domain (D1) exert anti-inflammatory effects and neutralize damage-associated molecular patterns. However, the effects of rhTM and D1 on extracellular histone H3 levels and kidney injury remain poorly understood. Our purpose was to investigate the association between extracellular histone H3 levels and kidney injury, and to clarify the effects of rhTM and D1 on extracellular histone H3 levels, kidney injury, and survival in sepsis-induced rats. Rats in whom sepsis was induced via cecal ligation and puncture were used in this study. Histone H3 levels, histopathology of the kidneys, and the survival rate of rats at 24 h after cecal ligation and puncture were investigated. Histone H3 levels increased over time following cecal ligation and puncture. Histopathological analyses indicated that the distribution of degeneration foci among tubular epithelial cells of the kidney and levels of histone H3 increased simultaneously. Administration of rhTM and D1 significantly reduced histone H3 levels compared with that in the vehicle-treated group and improved kidney injury. The survival rates of rats in rhTM- and D1-treated groups were significantly higher than that in the vehicle-treated group. The results of this study indicated that rhTM and its D1 similarly reduce elevated histone H3 levels, thereby reducing acute kidney injury. Our findings also proposed that rhTM and D1 show potential as new treatment strategies for sepsis combined with acute kidney injury.

scholarly journals Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joram Huckriede ◽  
Sara Bülow Anderberg ◽  
Albert Morales ◽  
Femke de Vries ◽  
Michael Hultström ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Patient Survival ◽  
Histone H3 ◽  
Scoring Systems ◽  
Severe Form ◽  
Immune Modulators ◽  
Icu Admission ◽  
Clinical Events ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

AbstractCoronavirus disease 19 (COVID-19) presents with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels and evolution of the damage associated molecular patterns (DAMPS) cell free DNA (cfDNA), extracellular histone H3 (H3) and neutrophil elastase (NE), and the immune modulators GAS6 and AXL in relation to clinical parameters, ICU scoring systems and mortality in patients (n = 100) with severe COVID-19. cfDNA, H3, NE, GAS6 and AXL were increased in COVID-19 patients compared to controls. These measures associated with occurrence of clinical events and intensive care unit acquired weakness (ICUAW). cfDNA and GAS6 decreased in time in patients surviving to 30 days post ICU admission. A decrease of 27.2 ng/mL cfDNA during ICU stay associated with patient survival, whereas levels of GAS6 decreasing more than 4.0 ng/mL associated with survival. The presence of H3 in plasma was a common feature of COVID-19 patients, detected in 38% of the patients at ICU admission. NETosis markers cfDNA, H3 and NE correlated well with parameters of tissue damage and neutrophil counts. Furthermore, cfDNA correlated with lowest p/f ratio and a lowering in cfDNA was observed in patients with ventilator-free days.

scholarly journals Immunopathogenesis of Acute Kidney Injury

2018 ◽  
Vol 46 (8) ◽  
pp. 930-943 ◽  
Author(s):  
Zaher A. Radi
Keyword(s):  
Acute Kidney Injury ◽  
T Cells ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Drug Induced ◽  
Inflammatory Damage ◽  
Anti Inflammatory ◽  
Renal Tubular ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Pathophysiologically, the classification of acute kidney injury (AKI) can be divided into three categories: (1) prerenal, (2) intrinsic, and (3) postrenal. Emerging evidence supports the involvement of renal tubular epithelial cells and the innate and adaptive arms of the immune system in the pathogenesis of intrinsic AKI. Pro-inflammatory damage-associated molecular patterns, pathogen-associated molecular patterns, hypoxia inducible factors, toll-like receptors, complement system, oxidative stress, adhesion molecules, cell death, resident renal dendritic cells, neutrophils, T and B lymphocytes, macrophages, natural killer T cells, cytokines, and secreted chemokines contribute to the immunopathogenesis of AKI. However, other immune cells and pathways such as M2 macrophages, regulatory T cells, progranulin, and autophagy exhibit anti-inflammatory properties and facilitate kidney tissue repair after AKI. Thus, therapies for AKI include agents such as anti-inflammatory (e.g., recombinant alkaline phosphatase), antioxidants (iron chelators), and apoptosis inhibitors. In preclinical toxicity studies, drug-induced kidney injury can be seen after exposure to a nephrotoxicant test article due to immune mechanisms and dysregulation of innate, and/or adaptive cellular immunity. The focus of this review will be on intrinsic AKI, as it relates to the immune and renal systems cross talks focusing on the cellular and pathophysiologic mechanisms of AKI.

scholarly journals Frequency of TGF-βand IFN-γGenotype as Risk Factors for Acute Kidney Injury and Death in Intensive Care Unit Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Caren Cristina Grabulosa ◽  
Marcelo Costa Batista ◽  
Miguel Cendoroglo ◽  
Beata Marie Redublo Quinto ◽  
Roberto Narciso ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Risk Factor ◽  
Genetic Polymorphisms ◽  
Cytokine Production ◽  
Case Control Study ◽  
Inflammatory Diseases ◽  
Kidney Injury ◽  
Icu Patients ◽  
Nested Case Control ◽  
Control Study

Genetic variations in TGF-βand IFN-γmay interfere with proinflammatory cytokine production and, consequently, may be involved with inflammatory diseases, as acute kidney injury (AKI). We considered that genetic polymorphisms of these cytokines may have a crucial role in the outcome of critically ill patients. To investigate whether the genetic polymorphisms of rs1800470 (codon 10 T/C), rs1800471 (codon 25 C/G) from the TGF-β, and rs2430561 (+874 T/A) from IFN-γmay be a risk factor for ICU patients to the development of AKI and/or death. In a prospective nested case-control study, were included 139 ICU patients who developed AKI, 164 ICU patients without AKI, and 244 healthy individuals. We observed a higher frequency to T/A genotype for IFN-γ(intermediate producer phenotype) and higher frequency of TT GG and TC GG genotype (high producer) for TGF-βpolymorphism in overall population. However, these polymorphisms have not been shown as a predictor of risk for AKI and death. We found an increased prevalence of high and intermediate producer phenotypes from TGF-βand IFN-γ, respectively, in patients in ICU setting. However, the studied genetic polymorphism of the TGF-βand IFN-γwas not associated as a risk factor for AKI or death in our population.

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.

DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation

2020 ◽  
Vol 15 (1) ◽  
pp. 493-518 ◽  
Author(s):  
Joel Zindel ◽  
Paul Kubes
Keyword(s):  
Immune Cell ◽  
Inflammatory Diseases ◽  
Sterile Inflammation ◽  
Lifestyle Choices ◽  
Inflammatory Site ◽  
Specific Receptors ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Killer T Cells ◽  
Invariant Natural Killer

Recognizing the importance of leukocyte trafficking in inflammation led to some therapeutic breakthroughs. However, many inflammatory pathologies remain without specific therapy. This review discusses leukocytes in the context of sterile inflammation, a process caused by sterile (non-microbial) molecules, comprising damage-associated molecular patterns (DAMPs). DAMPs bind specific receptors to activate inflammation and start a highly optimized sequence of immune cell recruitment of neutrophils and monocytes to initiate effective tissue repair. When DAMPs are cleared, the recruited leukocytes change from a proinflammatory to a reparative program, a switch that is locally supervised by invariant natural killer T cells. In addition, neutrophils exit the inflammatory site and reverse transmigrate back to the bloodstream. Inflammation persists when the program switch or reverse transmigration fails, or when the coordinated leukocyte effort cannot clear the immunostimulatory molecules. The latter causes inappropriate leukocyte activation, a driver of many pathologies associated with poor lifestyle choices. We discuss lifestyle-associated inflammatory diseases and their corresponding immunostimulatory lifestyle-associated molecular patterns (LAMPs) and distinguish them from DAMPs.

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