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| 2. |
- Akaberi, Dario, 1989-, et al.
(författare)
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Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro
- 2020
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Ingår i: Redox Biology. - : Elsevier. - 2213-2317. ; 37
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Tidskriftsartikel (refereegranskat)abstract
- The ongoing SARS-CoV-2 pandemic is a global public health emergency posing a high burden on nations' health care systems and economies. Despite the great effort put in the development of vaccines and specific treatments, no prophylaxis or effective therapeutics are currently available. Nitric oxide (NO) is a broad-spectrum antimicrobial and a potent vasodilator that has proved to be effective in reducing SARS-CoV replication and hypoxia in patients with severe acute respiratory syndrome. Given the potential of NO as treatment for SARS-CoV-2 infection, we have evaluated the in vitro antiviral effect of NO on SARS-CoV-2 replication. The NO-donor S-nitroso-N-acetylpenicillamine (SNAP) had a dose dependent inhibitory effect on SARS-CoV-2 replication, while the non S-nitrosated NAP was not active, as expected. Although the viral replication was not completely abolished (at 200 μM and 400 μM), SNAP delayed or completely prevented the development of viral cytopathic effect in treated cells, and the observed protective effect correlated with the level of inhibition of the viral replication. The capacity of the NO released from SNAP to covalently bind and inhibit SARS-CoV-2 3CL recombinant protease in vitro was also tested. The observed reduction in SARS-CoV-2 protease activity was consistent with S-nitrosation of the enzyme active site cysteine.
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| 3. |
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| 4. |
- Chen, Luni, et al.
(författare)
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Endothelin-1 and nitric oxide synthase in short rebound reaction to short exposure to inhaled nitric oxide
- 2001
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Ingår i: American Journal of Physiology. Heart and Circulatory Physiology. - 0363-6135 .- 1522-1539. ; 281, s. H124-31
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Tidskriftsartikel (refereegranskat)abstract
- On withdrawal of inhalation of nitric oxide (INO) administered after lung injury, pulmonary artery pressure (PAP) and arterial oxygen tension (Pa(O(2))) may deteriorate more than before INO (rebound response). In this study, we investigated the possible roles of endothelin (ET)-1 and nitric oxide (NO) synthase (NOS) activity in the short rebound reaction to short-term inhalation of NO. Twenty-six anesthetized mechanically ventilated piglets were given endotoxin infusion. Twelve animals then received INO (30 parts per million) for two 30-min periods. Nine controls were not given NO. Measurements were made of blood gases and hemodynamic parameters, lung tissue ET-1 expression and NOS activity, and plasma ET-1 concentration. INO decreased PAP and increased Pa(O(2)), but INO withdrawal caused a short rebound reaction with an increase in PAP. Lung tissue expression and plasma concentration of ET-1 increased during INO, and plasma ET-1 increased further after its withdrawal. Activity of constitutive NOS decreased during INO, whereas that of inducible NOS was unchanged. Upregulation of ET-1 and downregulation of NOS activity may have influenced the short rebound reaction to short-term INO.
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| 6. |
- Chen, Luni, 1962-
(författare)
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Inhaled Nitric Oxide Therapy : Non-response and Rebound Response
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Therapeutic inhaled nitric oxide (INO) has proved beneficial in patients with pulmonary hypertension. However, around 30-40% of the patients are non-responders to this therapy, and a life-threatening rebound response may occur during attempts to withdraw INO. This thesis investigated the link between vasoconstrictors and non- and rebound responses in piglets subjected to acute lung injury by exposure to endotoxin or oleic acid (OA). We found that INO had strong effect in mainly ET-1 related, endotoxin-induced pulmonary hypertension, and there was a rebound response after INO withdrawal. Thus, the weaker the response to INO, the greater the rebound. Neither response nor rebound was seen in oleic acid-induced, mainly prostaglandin related pulmonary hypertension. INO decreased expression of the ET-A receptor, and this might be another signal transduction pathway whereby INO relieves pulmonary vasoconstriction besides increasing c-GMP. Thus INO might have better effect in pulmonary vasoconstriction that is mainly mediated by ET-1 than when other vasoconstrictors are involved in the vascular reaction. Increased production and/or release of vasoconstrictor peptide endothelin-1 (ET-1) during INO, and release of prostaglandin TXA2 and PGF2α after INO withdrawal, were more important causes of the rebound, than a decreasing endogenous NO production during INO. The latter mechanism has been proposed in previous studies. An increase in prostaglandins after INO withdrawal is possibly secondary to the increase in ET-1 during INO. Combination of INO with the COX inhibitor diclofenac blocked the rebound reaction. These findings may open the way for new therapeutic modalities.
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| 7. |
- Da, Jiping, et al.
(författare)
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Nitric oxied up-regulates the glucocorticoid receptor and blunts the inflammatory reaction in porcine endotoxin sepsis
- 2007
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Ingår i: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 35:1, s. 26-32
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Nitric oxide inhibits the expression of many genes involved in inflammatory diseases. Glucocorticoids inhibit similar transcription factors. We hypothesized that there may be an interaction between nitric oxide and glucocorticoids, with the potential to enhance the anti-inflammatory effect when administered simultaneously. Design: Prospective, randomized, controlled study. Setting: Animal research laboratory. Subjects: A total of 45 anesthetized and mechanically ventilated pigs. Interventions: Lung and systemic injury was induced by intravenous infusion of endotoxin (lipopolysaccharide) for 6 hrs. After 2.5 hrs, one group received 3.5 mg/kg hydrocortisone, another group inhaled nitric oxide (30 ppm), and still another group received both steroid and nitric oxide. Control groups of healthy and endotoxin-exposed piglets were also studied. Measurements and Main Results: Central hemodynamics and gas exchange were measured. Detection of the glucocorticoid receptor and inflammatory markers in lung, liver, and kidney tissue were made by immunohistochemistry, and morphology was studied with light microscopy. Endotoxin infusion markedly reduced glucocorticoid receptor expression in lung, liver, and kidney and up-regulated activator protein-1 and the inflammatory markers nuclear factor-κB and tumor necrosis factor-a. When administered separately, steroids and nitric oxide had modest effect on the inflammatory response. However, nitric oxide up-regulated the glucocorticoid receptor expression. Simultaneous administration of steroids and nitric oxide attenuated the inflammatory response and almost preserved or restored normal histology of both lung and systemic organs. When the glucocorticoid receptor was blocked by a receptor antagonist (mifepristone, 600 mg) and inhaled nitric oxide was subsequently administered, no increase in the expression of the glucocorticoid receptor was seen. Conclusion: We suggest that up-regulation of glucocorticoid receptor expression by nitric oxide made steroid therapy more effective.
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| 8. |
- Hambraeus-Jonzon, Kristina, et al.
(författare)
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Pulmonary Vasoconstriction during Regional Nitric Oxide Inhalation : Evidence of a Blood-borne Regulator of Nitric Oxide Synthase Activity
- 2001
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Ingår i: Anesthesiology. - : Ovid Technologies (Wolters Kluwer Health). - 0003-3022 .- 1528-1175. ; 95:1, s. 102-112
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inhaled nitric oxide (INO) is thought to cause selective pulmonary vasodilation of ventilated areas. The authors previously showed that INO to a hyperoxic lung increases the perfusion to this lung by redistribution of blood flow, but only if the opposite lung is hypoxic, indicating a more complex mechanism of action for NO. The authors hypothesized that regional hypoxia increases NO production and that INO to hyperoxic lung regions (HL) can inhibit this production by distant effect. METHODS: Nitric oxide concentration was measured in exhaled air (NO(E)), NO synthase (NOS) activity in lung tissue, and regional pulmonary blood flow in anesthetized pigs with regional left lower lobar (LLL) hypoxia (fraction of inspired oxygen [FIO2] = 0.05), with and without INO to HL (FIO2 = 0.8), and during cross-circulation of blood from pigs with and without INO. RESULTS: Left lower lobar hypoxia increased exhaled NO from the LLL (NO(E)LLL) from a mean (SD) of 1.3 (0.6) to 2.2 (0.9) parts per billion (ppb) (P < 0.001), and Ca2+-dependent NOS activity was higher in hypoxic than in hyperoxic lung tissue (197 [86] vs. 162 [96] pmol x g(-1) x min(-1), P < 0.05). INO to HL decreased the Ca2+-dependent NOS activity in hypoxic tissue to 49 [56] pmol x g(-1) x min(-1) (P < 0.01), and NO(E)LLL to 2.0 [0.8] ppb (P < 0.05). When open-chest pigs with LLL hypoxia received blood from closed-chest pigs with INO, NO(E)LLL decreased from 2.0 (0.6) to 1.5 (0.4) ppb (P < 0.001), and the Ca2+-dependent NOS activity in hypoxic tissue decreased from 152 (55) to 98 (34) pmol x g(-1) x min(-1) (P = 0.07). Pulmonary vascular resistance increased by 32 (21)% (P < 0.05), but more so in hypoxic (P < 0.01) than in hyperoxic (P < 0.05) lung regions, resulting in a further redistribution (P < 0.05) of pulmonary blood flow away from hypoxic to hyperoxic lung regions. CONCLUSIONS: Inhaled nitric oxide downregulates endogenous NO production in other, predominantly hypoxic, lung regions. This distant effect is blood-mediated and causes vasoconstriction in lung regions that do not receive INO.
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| 9. |
- Hedenstierna, Göran, 1941-, et al.
(författare)
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Nitric oxide dosed in short bursts at high concentrations may protect against Covid 19.
- 2020
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Ingår i: Nitric oxide. - : Elsevier. - 1089-8603 .- 1089-8611. ; 103, s. 1-3
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Tidskriftsartikel (refereegranskat)abstract
- It has long been suggested that NO may inhibit an early stage in viral replication. Furthermore, in vitro tests have shown that NO inhibits the replication cycle of severe acute respiratory syndrome coronavirus. Despite smoking being listed as a risk factor to contract Covid-19, only a low proportion of the smokers suffered from SARS-corona infection in China 2003, and from Covid-19 in China, Europe and the US. We hypothesize, that the intermittent bursts of high NO concentration in cigarette smoke may be a mechanism in protecting against the virus. Mainstream smoke from cigarettes contains NO at peak concentrations of between about 250 ppm and 1350 ppm in each puff as compared to medicinal use of no more than 80 to a maximum of 160 ppm. The diffusion of NO through the cell wall to reach the virus should be significantly more effective at the very high NO concentration in the smoke, according to classic laws of physics. The only oxide of nitrogen in the mainstream smoke is NO, and the NO2 concentration that is inhaled is very low or undetectable, and methemoglobin levels are lower in smokers than non-smokers, reasonably explained by the breaths of air in between the puffs that wash out the NO. Specialized iNO machines can now be developed to provide the drug intermittently in short bursts at high concentration dose, which would then provide both a preventative drug for those at high risk, as well as an effective treatment, without the health hazards associated with smoking.
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| 10. |
- Hedenstierna, Göran, 1941-, et al.
(författare)
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Treatment of COVID-19 by Inhaled NO to Reduce Shunt?
- 2020
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 202:4
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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