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1.
Int Immunopharmacol ; 103: 108463, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1587490

ABSTRACT

Therapeutics that impair the innate immune responses of the liver during the inflammatory cytokine storm like that occurring in COVID-19 are greatly needed. Much interest is currently directed toward Janus kinase (JAK) inhibitors as potential candidates to mitigate this life-threatening complication. Accordingly, this study investigated the influence of the novel JAK inhibitor ruxolitinib (RXB) on concanavalin A (Con A)-induced hepatitis and systemic hyperinflammation in mice to simulate the context occurring in COVID-19 patients. Mice were orally treated with RXB (75 and 150 mg/kg) 2 h prior to the intravenous administration of Con A (20 mg/kg) for a period of 12 h. The results showed that RXB pretreatments were efficient in abrogating Con A-instigated hepatocellular injury (ALT, AST, LDH), necrosis (histopathology), apoptosis (cleaved caspase-3) and nuclear proliferation due to damage (PCNA). The protective mechanism of RXB were attributed to i) prevention of Con A-enhanced hepatic production and systemic release of the proinflammatory cytokines TNF-α, IFN-γ and IL-17A, which coincided with decreasing infiltration of immune cells (monocytes, neutrophils), ii) reducing Con A-induced hepatic overexpression of IL-1ß and CD98 alongside NF-κB activation, and iii) lessening Con A-induced consumption of GSH and GSH peroxidase and generation of oxidative stress products (MDA, 4-HNE, NOx) in the liver. In summary, JAK inhibition by RXB led to eminent protection of the liver against Con A-deleterious manifestations primarily via curbing the inflammatory cytokine storm driven by TNF-α, IFN-γ and IL-17A.


Subject(s)
Concanavalin A/toxicity , Cytokine Release Syndrome/chemically induced , Cytokine Release Syndrome/drug therapy , Nitriles/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Aldehydes/metabolism , Animals , Chemical and Drug Induced Liver Injury , Dose-Response Relationship, Drug , Inflammation/chemically induced , Liver/drug effects , Liver/metabolism , Male , Malondialdehyde/metabolism , Mice , Mice, Inbred BALB C , Nitrates/metabolism , Nitriles/administration & dosage , Nitrites/metabolism , Oxidative Stress , Peroxidase/metabolism , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage
2.
Front Immunol ; 12: 714833, 2021.
Article in English | MEDLINE | ID: covidwho-1506100

ABSTRACT

Background: The most severe cases of Coronavirus-Disease-2019 (COVID-19) develop into Acute Respiratory Distress Syndrome (ARDS). It has been proposed that oxygenation may be inhibited by extracellular deoxyribonucleic acid (DNA) in the form of neutrophil extracellular traps (NETs). Dornase alfa (Pulmozyme, Genentech) is recombinant human deoxyribonuclease I that acts as a mucolytic by cleaving and degrading extracellular DNA. We performed a pilot study to evaluate the effects of dornase alfa in patients with ARDS secondary to COVID-19. Methods: We performed a pilot, non-randomized, case-controlled clinical trial of inhaled dornase for patients who developed ARDS secondary to COVID-19 pneumonia. Results: Improvement in arterial oxygen saturation to inhaled fraction of oxygen ratio (PaO2/FiO2) was noted in the treatment group compared to control at day 2 (95% CI, 2.96 to 95.66, P-value = 0.038), as well as in static lung compliance at days 3 through 5 (95% CI, 4.8 to 19.1 mL/cmH2O, 2.7 to 16.5 mL/cmH2O, and 5.3 to 19.2 mL/cmH2O, respectively). These effects were not sustained at 14 days. A reduction in bronchoalveolar lavage fluid (BALF) myeloperoxidase-DNA (DNA : MPO) complexes (95% CI, -14.7 to -1.32, P-value = 0.01) was observed after therapy with dornase alfa. Conclusion: Treatment with dornase alfa was associated with improved oxygenation and decreased DNA : MPO complexes in BALF. The positive effects, however, were limited to the time of drug delivery. These data suggest that degradation of extracellular DNA associated with NETs or other structures by inhaled dornase alfa can be beneficial. We propose a more extensive clinical trial is warranted. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT04402970.


Subject(s)
COVID-19/drug therapy , Deoxyribonuclease I/therapeutic use , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2/physiology , Administration, Inhalation , Adult , Aged , Aged, 80 and over , Case-Control Studies , DNA/metabolism , Extracellular Traps/metabolism , Female , Humans , Male , Middle Aged , Oxygen Consumption/drug effects , Peroxidase/metabolism , Pilot Projects , Recombinant Proteins/therapeutic use , Young Adult
3.
Dis Markers ; 2021: 5566826, 2021.
Article in English | MEDLINE | ID: covidwho-1341351

ABSTRACT

An excess formation of neutrophil extracellular traps (NETs), previously shown to be strongly associated with cytokine storm and acute respiratory distress syndrome (ARDS) with prevalent endothelial dysfunction and thrombosis, has been postulated to be a central factor influencing the pathophysiology and clinical presentation of severe COVID-19. A growing number of serological and morphological evidence has added to this assumption, also in regard to potential treatment options. In this study, we used immunohistochemistry and histochemistry to trace NETs and their molecular markers in autopsy lung tissue from seven COVID-19 patients. Quantification of key immunomorphological features enabled comparison with non-COVID-19 diffuse alveolar damage. Our results strengthen and extend recent findings, confirming that NETs are abundantly present in seriously damaged COVID-19 lung tissue, especially in association with microthrombi of the alveolar capillaries. In addition, we provide evidence that low-density neutrophils (LDNs), which are especially prone to NETosis, contribute substantially to COVID-19-associated lung damage in general and vascular blockages in particular.


Subject(s)
COVID-19/pathology , Extracellular Traps , Lung Injury/pathology , Neutrophils/pathology , Aged , Aged, 80 and over , Antigens, CD/metabolism , Autopsy , Cell Adhesion Molecules/metabolism , Extracellular Traps/virology , Female , GPI-Linked Proteins/metabolism , Humans , Immunohistochemistry , Lung/pathology , Lung/virology , Lung Injury/virology , Male , Neutrophils/metabolism , Neutrophils/virology , Peroxidase/metabolism
4.
J Inorg Biochem ; 223: 111546, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1313251

ABSTRACT

Recent studies have shown a correlation between COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the distinct, exaggerated immune response titled "cytokine storm". This immune response leads to excessive production and accumulation of reactive oxygen species (ROS) that cause clinical signs characteristic of COVID-19 such as decreased oxygen saturation, alteration of hemoglobin properties, decreased nitric oxide (NO) bioavailability, vasoconstriction, elevated cytokines, cardiac and/or renal injury, enhanced D-dimer, leukocytosis, and an increased neutrophil to lymphocyte ratio. Particularly, neutrophil myeloperoxidase (MPO) is thought to be especially abundant and, as a result, contributes substantially to oxidative stress and the pathophysiology of COVID-19. Conversely, melatonin, a potent MPO inhibitor, has been noted for its anti-inflammatory, anti-oxidative, anti-apoptotic, and neuroprotective actions. Melatonin has been proposed as a safe therapeutic agent for COVID-19 recently, having been given with a US Food and Drug Administration emergency authorized cocktail, REGEN-COV2, for management of COVID-19 progression. This review distinctly highlights both how the destructive interactions of HOCl with tetrapyrrole rings may contribute to oxygen deficiency and hypoxia, vitamin B12 deficiency, NO deficiency, increased oxidative stress, and sleep disturbance, as well as how melatonin acts to prevent these events, thereby improving COVID-19 prognosis.


Subject(s)
Antioxidants/pharmacology , COVID-19/drug therapy , Melatonin/pharmacology , Reactive Oxygen Species/metabolism , Anti-Inflammatory Agents/pharmacology , Apoptosis/drug effects , COVID-19/immunology , COVID-19/metabolism , Cytokine Release Syndrome/immunology , Cytokines/metabolism , Hemeproteins/metabolism , Humans , Hypochlorous Acid/metabolism , Nitric Oxide/metabolism , Oxidation-Reduction , Oxidative Stress/drug effects , Peroxidase/metabolism , SARS-CoV-2 , Sleep/drug effects , Vitamin B Deficiency/metabolism
5.
Int J Mol Sci ; 22(11)2021 May 24.
Article in English | MEDLINE | ID: covidwho-1273453

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.


Subject(s)
Acute Lung Injury/drug therapy , Amides/pharmacology , Cytokines/metabolism , Ethanolamines/pharmacology , MAP Kinase Signaling System/drug effects , Palmitic Acids/pharmacology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Amides/therapeutic use , Animals , Ethanolamines/therapeutic use , Immunohistochemistry , Inflammation/metabolism , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/toxicity , Macrophages/drug effects , Macrophages/immunology , Male , Mast Cells/drug effects , Mast Cells/pathology , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , NF-KappaB Inhibitor alpha/metabolism , NF-kappa B/metabolism , Neutrophils/drug effects , Neutrophils/immunology , Palmitic Acids/therapeutic use , Peroxidase/metabolism , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
6.
Adv Mater ; 33(8): e2005477, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1039151

ABSTRACT

Besides the pandemic caused by the coronavirus outbreak, many other pathogenic microbes also pose a devastating threat to human health, for instance, pathogenic bacteria. Due to the lack of broad-spectrum antibiotics, it is urgent to develop nonantibiotic strategies to fight bacteria. Herein, inspired by the localized "capture and killing" action of bacteriophages, a virus-like peroxidase-mimic (V-POD-M) is synthesized for efficient bacterial capture (mesoporous spiky structures) and synergistic catalytic sterilization (metal-organic-framework-derived catalytic core). Experimental and theoretical calculations show that the active compound, MoO3 , can serve as a peroxo-complex-intermediate to reduce the free energy for catalyzing H2 O2 , which mainly benefits the generation of •OH radicals. The unique virus-like spikes endow the V-POD-M with fast bacterial capture and killing abilities (nearly 100% at 16 µg mL-1 ). Furthermore, the in vivo experiments show that V-POD-M possesses similar disinfection treatment and wound skin recovery efficiencies to vancomycin. It is suggested that this inexpensive, durable, and highly reactive oxygen species (ROS) catalytic active V-POD-M provides a promising broad-spectrum therapy for nonantibiotic disinfection.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Biomimetic Materials/chemical synthesis , Oxides/chemical synthesis , Peroxidase/chemistry , Anti-Bacterial Agents/pharmacology , Biocompatible Materials/chemistry , Biomimetic Materials/pharmacology , Catalysis , Humans , Hydrogen Peroxide/metabolism , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Molecular Dynamics Simulation , Molybdenum/pharmacology , Oxides/pharmacology , Peroxidase/metabolism , Sterilization , Vancomycin/pharmacology
7.
JCI Insight ; 5(11)2020 06 04.
Article in English | MEDLINE | ID: covidwho-980226

ABSTRACT

In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have the potential to propagate inflammation and microvascular thrombosis - including in the lungs of patients with acute respiratory distress syndrome. We now report that sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and citrullinated histone H3 (Cit-H3); the latter 2 are specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute-phase reactants, including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.


Subject(s)
Cell-Free Nucleic Acids/metabolism , Coronavirus Infections/metabolism , Extracellular Traps/metabolism , Histones/metabolism , Neutrophils/metabolism , Peroxidase/metabolism , Pneumonia, Viral/metabolism , Adult , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , COVID-19 , Case-Control Studies , Citrullination , Coronavirus Infections/blood , Coronavirus Infections/therapy , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Lymphocyte Count , Male , Middle Aged , Pandemics , Platelet Count , Pneumonia, Viral/blood , Pneumonia, Viral/therapy , Respiration, Artificial , Severity of Illness Index
8.
Int J Biol Sci ; 17(1): 62-72, 2021.
Article in English | MEDLINE | ID: covidwho-948161

ABSTRACT

Multi-system involvement and rapid clinical deterioration are hallmarks of coronavirus disease 2019 (COVID-19) related mortality. The unique clinical phenomena in severe COVID-19 can be perplexing, and they include disproportionately severe hypoxemia relative to lung alveolar-parenchymal pathology and rapid clinical deterioration, with poor response to O2 supplementation, despite preserved lung mechanics. Factors such as microvascular injury, thromboembolism, pulmonary hypertension, and alteration in hemoglobin structure and function could play important roles. Overwhelming immune response associated with "cytokine storms" could activate reactive oxygen species (ROS), which may result in consumption of nitric oxide (NO), a critical vasodilation regulator. In other inflammatory infections, activated neutrophils are known to release myeloperoxidase (MPO) in a natural immune response, which contributes to production of hypochlorous acid (HOCl). However, during overwhelming inflammation, HOCl competes with O2 at heme binding sites, decreasing O2 saturation. Moreover, HOCl contributes to several oxidative reactions, including hemoglobin-heme iron oxidation, heme destruction, and subsequent release of free iron, which mediates toxic tissue injury through additional generation of ROS and NO consumption. Connecting these reactions in a multi-hit model can explain generalized tissue damage, vasoconstriction, severe hypoxia, and precipitous clinical deterioration in critically ill COVID-19 patients. Understanding these mechanisms is critical to develop therapeutic strategies to combat COVID-19.


Subject(s)
COVID-19/physiopathology , Clinical Deterioration , Peroxidase/metabolism , Reactive Oxygen Species/metabolism , COVID-19/metabolism , COVID-19/virology , Catalysis , Humans , Hypochlorous Acid/metabolism , Oxidation-Reduction , SARS-CoV-2/isolation & purification
9.
Med Hypotheses ; 144: 109999, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-598567

ABSTRACT

The majority of fatalities thus far in the COVID-19 pandemic have been attributed to pneumonia. As expected, the fatality rate reported in China is higher in people with chronic pulmonary disease (6.3%) and those who have cancer (5.6%). According to the American College of Cardiology Clinical Bulletin "COVID-19 Clinical Guidance for the CV Care Team", there is a significantly higher fatality rate in people who are elderly (8.0% 70-79 years; 14.8% ≥80 years), diabetic (7.3%), hypertensive (6.0%), or have known cardiovascular disease (CVD) (10.5%). We propose a biological reason for the higher mortality risk in these populations that is apparent. We further present a set of pathophysiological reasons for the heightened danger that could lead to therapies for enhanced management and prevention.


Subject(s)
COVID-19/epidemiology , Immunity, Innate , Pandemics , Adult , Aging/immunology , COVID-19/etiology , COVID-19/immunology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/immunology , Child , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Disease Susceptibility , Humans , Hydrogen Peroxide/metabolism , Hypertension/epidemiology , Hypertension/immunology , Hypochlorous Acid/metabolism , Lung/blood supply , Lung/immunology , Microcirculation , Microvessels/physiopathology , Neutrophils/immunology , Neutrophils/metabolism , Peroxidase/metabolism , Risk Factors , United States/epidemiology
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