Encarta 2013 sin virus

Given that eNOS is uncoupled in patients with blood vessel endothelial dysfunction, inhaled NO has been used as therapeutic option to replace the endogenous NO activity in patients with several pulmonary complications, including ARDS. Nevertheless, inhaled NO application remains debatable. Inhaled NO benefits on oxygenation is transitory and does not appear to be associated with increased survival.

Likewise, most ARDS patients die from multiple organ failure rather than hypoxemia [ 62 ]. Moreover, prolonged exposure to inhaled NO can cause sensitization, lowering the oxygenation benefit while exposing these patients to oxidative toxic damage, reducing its benefits [ 63 , 64 ]. Renal function in patients receiving inhaled NO treatment can also be compromised, increasing the need for renal replacement therapy [ 65 ].

In order to avoid complications, controlled therapies to regulate the metabolism of NO should be investigated, including an allosteric ASS activator, the step-limiting enzyme of NO-citrulline cycle [ 15 , 66 ]. Besides the deleterious effects of SARS-CoVinduced diffuse inflammation in pulmonary physiology and oxygen saturation, such virus can also induce coagulopathy.

Autopsies from COVIDpositive patients have shown diffuse alveolar damage, widespread lung vascular thrombosis, microvascular thromboembolic, capillary congestion and deep venous thrombosis [ 67 ]. Thus, high d-dimer levels in the blood, a coagulopathy marker, are associated with increased mortality in COVID patients.

Indeed, pulmonary embolism was the direct cause of death in some patients [ 42 , 67 , 68 ]. Multi-organ failure, observed in severe COVID cases, has been linked with diffuse intravascular coagulation and large-vessel thrombosis [ 42 , 69 , 70 ]. Therefore, National Institute of Health treatment guideline for COVID patients recommends anticoagulant therapy as prophylaxis for hospitalised individuals [ 71 ]. The inflammatory response, generated by virus infection, leads to the activation of coagulation cascade, thrombin generation and fibrinolysis shutdown [ [72] , [73] , [74] ].

Hypoxemia can also contribute to coagulopathy, increasing blood viscosity and triggering the release of hypoxia-inducible transcription factors, that in turn influence the coagulation and fibrinolysis cascades [ 75 ]. Furthermore, endothelial injury and dysfunction caused by pro-inflammatory cytokines and tropism of the virus for ACE2 receptors, decrease the bioavailability of NO and trigger venous thromboembolism and disruption of natural antithrombotic state [ 76 ].

Also, eNOS uncoupling due to low l -arginine levels, impairs NO production or bioavailability in ARDS patients, which induces vasoconstriction and can lead to arterial and venous thrombosis [ 77 ]. Nevertheless, there is no clinically available NO therapy that addresses endothelial dysfunction directly, which could prevent thrombosis in COVID patients [ 77 , 78 ].

Several therapeutic strategies with NO-enhancing and —releasing agents have been studied to develop new antithrombotic drugs [ 77 ]; even so, NO is not under studies to prevent coagulopathy in COVID NO is a key molecule in the regulation of immune response to pathogens [ [79] , [80] , [81] , [82] , [83] ].

Mainly, iNOS-synthesized NO is an important immunoregulatory mediator of the host's immune system against infectious organisms, and acts as a toxic agent. Futhermore, NO can regulate cellular function, growth and death of immune cells, such as macrophages, neutrophils, T cells and natural killers NK cells [ 21 ]. Although macrophages are the main NO producers in response to pathogens [ [84] , [85] , [86] ], many cells express iNOS, including fibroblasts, hepatocytes [ 87 ], endothelial and epithelial cells, keratinocytes and chondrocytes [ 88 , 89 ] antigen-presenting cells [ 90 ] and NK cells [ 21 , 91 ].

Therefore, iNOS provides continuous high concentrations of NO to chemically neutralize invading pathogens, and this level of synthesis is sustained for hours or days, depending on how long the enzyme is present in cells or tissue [ 21 ].

NO has several advantages as an antiviral agent, despite that, there are few studies investigating its potential therapeutic in viral infections. Firstly, it can easily pass through cell membranes to neighboring cells, as well as to viruses, not requiring a receptor [ 95 ]. Also, NO acts on a variety of viral targets, inhibiting viral replication; and cell specificity depends on its concentration, chemical reactivity, proximity of target cells and the way that target cells are designed to respond [ 21 ].

Finally, the NO effect is independent of the immune recognition of the infected cell, in contrast to antiviral lymphocytes. Given the highly reactive nature of NO, its antiviral effects are probably mediated by reactions with multiple cellular and viral targets which may be advantageous for host defense because it will limit the capacity of viruses to develop resistance.

Studies have shown that the NO antiviral effects are provided by NO donors [ [96] , [97] , [98] , [99] , [] ] or by iNOS directly activated by cytokines [ [92] , [93] , [94] ]. Rimmelzwaan et al. Reduction of infected cells and virus production proved to correlate with reduction of viral protein activity and viral RNA synthesis Fig.

This same group hypothesizes that iNOS-synthesized NO in airways epithelial cells, induced by cytokines synthesized after virus infection [ , ], provides an antiviral effect in these cells. Likewise, exposure to NO demonstrated dose-dependent antiviral effects in cells infected with influenza A, B and H1N1 [ ].

Additionally, it has been reported that peroxynitrite, an intermediate product formed by the reaction of NO with superoxide, inhibits the entry of RNA of some viruses into host cells [ ].

A Acting on viral proteases. The processing of the polyprotein region is a point of posttranslational control that is essential for virus replication. B Acting on host cell proteins. We hypothesize that metabolic enhancement of NO production and NO bioavailability through complex interventions can partially reverse deleterious physiological conditions associated with viral infection and unregulated pro-inflammatory processes.

NO generation is a tightly regulated process; the pathophysiological conditions that deregulate it lead to reactive oxygen species ROS generation [ 25 , , ]. Excessive ROS produced by the endothelium and epithelium, as well as by leukocytes, play an important role in ARDS progression and lung damage. ROS positively regulate the expression of proinflammatory cytokines and adhesion molecules, causing endothelial and epithelial dysfunctions, along with increasing oxidative stress in pulmonary duct tissues and airways, further altering the inflammatory state [ 25 , , ].

Throughout ARDS process, lung cells release large amounts of inflammatory factors that increase iNOS synthesis in alveolar macrophages, neutrophils and bronchial epithelium, providing abundant amounts of NO for release into lung tissues [ , ]. Moreover, airway stress can induce bronchial obstruction and worsen inflammation in ARDS patients, further inducing lung tissues to produce NO [ ]. Overproduction of NO leads to deleterious cell components damage when reacting with superoxide, and favors the formation of peroxynitrite that can nitrate and oxidize proteins, lipids and nucleotides [ ].

In case of increased plasma NO levels, the reaction between NO and superoxide to form peroxynitrite becomes very fast, where the production rate is about three times higher than the rate of superoxide decomposition by superoxide dismutase [ ]. Excessive peroxynitrite formation can lead to inhibition of mitochondrial respiration, protein dysfunction, depletion of cellular energy, damage to cell membranes and DNA [ ], in addition to contributing to resistance to anti-inflammatory drugs [ ].

NO-mediated oxidative stress is an important factor in the pathogenesis of lung injury. High levels of NO, represented by the increase of its stable metabolites, nitrate and nitrite, can intensify lipid peroxidation, cause necrosis and denaturation of pulmonary epithelial cells, aggravate inflammation and induce the onset of ARDS [ ].

A clinical study reported high concentrations of the NO, nitrate and nitrite metabolites in the bronchoalveolar lavage, not only in ARDS patients, but also in patients at risk for ARDS, suggesting that the oxidative stress detected at the beginning of ARDS begins when patients are at risk, before the clinically defined syndrome is recognized [ ].

Nevertheless, NO production pathways are affected in a different manner. On the other hand, NO production by iNOS is increased in effort to fight the virus; however, this pro-inflammatory state can cause a deleterious effect, leading to lung injury. Inhaled NO has been used in ARDS patients in the attempt to mitigate pulmonary physiological alterations caused by eNOS uncoupling, but the transitory effects and possible oxidative toxic damage may weaken the use of this therapy.

Here, we propose the investigation of therapies that promote NO production in a metabolic manner. Molecules that positively modulate the activity of ASS, a key enzyme in arginine metabolism, would increase arginine production, leading to eNOS recoupling and increasing NO metabolite production [ 66 ].

In conclusion, therapeutic approaches that modulate NO metabolism should be considered for the prevention or treatment of severe cases of COVID Authors have no conflicts of interest to declare. National Center for Biotechnology Information , U. Nitric Oxide. Published online Apr 6. Lara M. Author information Article notes Copyright and License information Disclaimer. All rights reserved. Elsevier hereby grants permission to make all its COVIDrelated research that is available on the COVID resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source.

This article has been cited by other articles in PMC. Keywords: Nitric oxide metabolism, Coronavirus disease, Acute respiratory distress syndrome, Coagulopathy, Antiviral effect. Graphical abstract. Open in a separate window. Coagulation pathway and endothelial dysfunction in COVID Besides the deleterious effects of SARS-CoVinduced diffuse inflammation in pulmonary physiology and oxygen saturation, such virus can also induce coagulopathy.

Nitric oxide in immune responses against viruses NO is a key molecule in the regulation of immune response to pathogens [ [79] , [80] , [81] , [82] , [83] ].

References 1. Wang H. Wiersinga W. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease COVID : a review. JAMA, J. Fehr A. Coronaviruses: an overview of their replication and pathogenesis. In: Maier H. Coronaviruses Methods Protoc. Springer; New York: Amer H. Bovine-like coronaviruses in domestic and wild ruminants.

Health Res. Chamings A. Detection and characterisation of coronaviruses in migratory and non-migratory Australian wild birds. Chu D. Avian coronavirus in wild aquatic birds.

Dong B. Detection of a novel and highly divergent coronavirus from asian leopard cats and Chinese ferret badgers in southern China. Institutes Heal; Dinicolantonio J. Open Hear. Kiplin Guy R. Science Pillat M. Cytometry A. Alvarez R. Care Med. Lameu C. L-Arginine signalling potential in the brain: the peripheral gets central, Recent Pat.

CNS Drug Discov. LeBaron T. A novel functional beverage for COVID and other conditions: hypothesis and preliminary data, increased blood flow, and wound healing.

Madhusoodanan K. NO-cGMP signaling and regenerative medicine involving stem cells. Xia Y. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Flam B. Endothelial nitric oxide production is tightly coupled to the citrulline-NO cycle, Nitric Oxide - Biol. Brain nitric oxide production by a proline-rich decapeptide from Bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats.

Coleman J. Nitric oxide in immunity and inflammation. Ridnour L. The chemistry of nitrosative stress induced by nitric oxide and reactive nitrogen oxide species.

Putting perspective on stressful biological situations. Lucas R. Arginase 1: an unexpected mediator of pulmonary capillary barrier dysfunction in models of acute lung injury.

Targeting arginase and nitric oxide metabolism in chronic airway diseases and their co-morbidities. Kellner M. Si su producto de Office es uno de los siguientes, tiene un producto de Microsoft para el hogar. Estos productos suelen estar asociados con una cuenta personal de Microsoft. Suscripciones a Microsoft Los siguientes productos incluyen las aplicaciones de Office completamente instaladas.

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