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            -nitrosothiol repletion by an inhaled gas regulates pulmonary function

Moya, Martín P; Gow, Andrew J.; McMahon, Timothy J.; Toone, Eric J.; Cheifetz, Ira M.; Goldberg, Ronald N.; Stamler, Jonathan S.

doi:10.1073/pnas.091109498

Cited by 69 publications

(54 citation statements)

References 43 publications

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“…In addition, NO might indiscriminately inactivate critical metalloproteins (e.g., cytochrome c oxidase), also inducing further lung injury (2). The reactions of ENO, unlike those of NO, are nitrosonium (NO 1 ) based, which favors the formation of antiinflammatory SNO compounds and limits the potential for toxic NO reactions (11). Indeed, one study comparing inhaled ENO with NO as preventive therapy in a rat model of bronchopulmonary dysplasia found ENO to be superior in protection from hyperoxiaimpaired postnatal lung development (12).…”

Section: Lung Omentioning

confidence: 99%

“…Inhaled ENO is superior to NO in augmenting intracellular SNO formation in vitro (11) and airway SNO in vivo with minimal associated RNS production (12). However, although inhaled ENO has been shown to be effective in restoring SNOmediated vasodilation in pulmonary hypertension (13,14), and is an antiinflammatory agent in hyperoxia-impaired neonatal lung development (12), its therapeutic value in ALI/ARDS has not been investigated.…”

mentioning

confidence: 99%

“…Ethyl nitrite (ENO) is a gas with chemical properties favoring reaction with thiol to induce SNO formation (11). Inhaled ENO is superior to NO in augmenting intracellular SNO formation in vitro (11) and airway SNO in vivo with minimal associated RNS production (12).…”

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confidence: 99%

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Protection from Lipopolysaccharide-induced Lung Injury by Augmentation of Airway S-Nitrosothiols

Marshall¹,

Potts²,

Kelleher³

et al. 2009

Am J Respir Crit Care Med

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Rationale: S-Nitrosothiols (SNO) inhibit immune activation of the respiratory epithelium and airway SNO levels are decreased in inflammatory lung disease. Ethyl nitrite (ENO) is a gas with chemical properties favoring SNO formation. Augmentation of airway SNO by inhaled ENO treatment may decrease lung inflammation and subsequent injury by inhibiting activation of the airway epithelium. Objectives: To determine the effect of inhaled ENO on airway SNO levels and LPS-induced lung inflammation/injury. Methods: Mice were treated overnight with inhaled ENO (10 ppm) or air, followed immediately by exposure to aerosolized LPS or saline. Parameters of inflammation and lung injury were quantified 1 hour after completion of the aerosol exposure and correlated to lung airway and tissue SNO levels. Measurements and Main Results: Aerosolized LPS induced a decrease in airway and lung tissue SNO levels including S-nitrosylated NF-kB. The decrease in lung SNO was associated with an increase in lung NF-kB activity, cytokine/chemokine expression (keratinocyte-derived chemokine, tumor necrosis factor-a, and IL-6), airway neutrophil influx, and worsened lung compliance. Pretreatment with inhaled ENO restored airway SNO levels and reduced LPS-mediated NF-kB activation thereby inhibiting the downstream inflammatory response and preserving lung compliance. Conclusions: Airway SNO serves an antiinflammatory role in the lung. Inhaled ENO can be used to augment airway SNO and protect from LPS-induced acute lung injury.

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Section: Lung Omentioning

confidence: 99%

mentioning

confidence: 99%

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Protection from Lipopolysaccharide-induced Lung Injury by Augmentation of Airway S-Nitrosothiols

Marshall¹,

Potts²,

Kelleher³

et al. 2009

Am J Respir Crit Care Med

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“…Patients with pulmonary hypertension and mild hypoxemia exhibit RSNO depletion and their pulmonary arterial pressures are inversely related to the amount of NO bound to hemoglobin (20). Inhalation of a RSNO-generating gas (e.g., ethyl nitrite, ENO) can fortify the "RSNO reservoir" and reverses hypoxia-associated pulmonary hypertension in humans (21). RSNO depletion may therefore be the main cause of hypoxia-induced pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

Increased Nitrosoglutathione Reductase Activity in Hypoxic Pulmonary Hypertension in Mice

et al. 2010

J Pharmacol Sci

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Abstract. Altered S-nitrosothiols (RSNO) signaling is linked to pulmonary hypertension. Recent studies have shown that S-nitrosoglutathione (GSNO) reductase (GSNOR) catalyzes the degradation of GSNO and indirectly regulates the level of RSNO in vivo. Our present study tested the hypothesis that chronic hypoxia causes pulmonary hypertension, in part, by the change of GSNOR activity that contributes to the depletion of RSNO. Male mice were exposed to normobaric hypoxia in a ventilated chamber for 1 to 21 days or normoxia for 21 days. Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels increased significantly after 21 days of hypoxic exposure. Hypoxia induced the overexpression of endothelial nitric oxide synthase and inducible nitric oxide synthase. The mRNA expression of GSNOR decreased on day 1 of hypoxic exposure, but increased significantly on day 7 compared with the normoxic group. The protein expression of GSNOR increased significantly in the lung tissue after 7 days of hypoxic exposure and its enzymatic activities also increased. Both the ratios of glutathione to glutathione disulfide and nitrate to nitrite were significantly lower in the hypoxic groups than in the normoxic controls. The results suggest an increased GSNOR activity interfered with the metabolism of RSNO in mice with hypoxic pulmonary hypertension. An imbalanced of redox status is associated with the pathogenesis of hypoxic pulmonary hypertension.

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“…To establish that RBC-SNO can affect PVR in vivo and to assess its effect on oxygenation, we performed two complementary experiments in an adult porcine model. In the first experiment, RBC-SNO levels were raised in vivo by ventilating pigs for 15 min with 100 ppm ENO, a SNO-generating prodrug (28,29), after which the gas was stopped and SNO-Hb levels were correlated with hemody- namic response and gas exchange for an additional 30 min. In the second experiment, porcine RBCs (100 ml) containing or depleted of SNO (through hypoxic exposures; see Methods) were infused directly into the main pulmonary artery, and the effects on arterial blood gases were compared over 30 min.…”

Section: Effects Of Rbc-sno On Hemodynamics and Gas Exchange In Vivomentioning

confidence: 99%

A nitric oxide processing defect of red blood cells created by hypoxia: Deficiency of S-nitrosohemoglobin in pulmonary hypertension

McMahon

Ahearn

Moya

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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118

138

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The mechanism by which hypoxia [low partial pressure of O2 (pO2)] elicits signaling to regulate pulmonary arterial pressure is incompletely understood. We considered the possibility that, in addition to its effects on smooth muscle, hypoxia may influence pulmonary vascular tone through an effect on RBCs. We report that exposure of native RBCs to sustained hypoxia is accompanied by a buildup of heme iron-nitrosyl (FeNO) species that are deficient in pO 2-governed intramolecular transfer of NO to cysteine thiol, yielding a deficiency in the vasodilator S-nitrosohemoglobin (SNO-Hb). hemoglobin ͉ red blood cell vasodilation ͉ S-nitrosylation I n the systemic microcirculation, blood flow is regulated by physiological O 2 gradients that couple the O 2 content of blood to regulated vasodilation and vasoconstriction (1-3). Blood flow is thereby matched to tissue O 2 demand. An analogous mechanism operates in the lungs, where O 2 uptake (ventilation) is optimized through regulated vasodilation and vasoconstriction (perfusion). Blood flow is thereby matched to alveolar ventilation (2). Because it is Hb O 2 saturation, not the partial pressure of O 2 (pO 2 ), that is coupled to blood flow in vivo (1, 3) it has been deduced that RBCs may serve as O 2 sensors within the integrated vascular system. In support of this idea, it has been shown recently that RBCs can act as O 2 -responsive transducers of vasodilator and vasoconstrictor activity (4-10), at least partly by modulating the availability of [6][7][8]10,11). According to these studies, RBCs release NO bioactivity under hypoxia and sequester it at hyperoxia. The release of NO bioactivity would facilitate hypoxic vasodilation in peripheral tissues and oppose hypoxic pulmonary vasoconstriction (HPV) in the lungs. S-nitrosothiol (SNO)-deficientThe mechanism by which NO bioactivity escapes from RBCs is incompletely understood. It is generally accepted that the rapid reaction of NO with the hemes of Hb produces a heme-iron nitrosyl adduct (Hb [FeNO]) that exhibits no vasodilator activity (4,7,12). Hb also sustains S-nitrosylation at two cysteine residues conserved in all mammals and birds. Biochemical and mutational analyses (␤93Cys3Ala) indicate that S-nitrosohemoglobin (SNO-Hb) is formed upon oxygenation of Hb [FeNO] by means of heme-to-Cys NO transfer (13-15) and by transnitrosylative transfer from low-mass S-nitrosothiols (SNOs) (16,17). SNO-Hb is very stable in the oxygenated (or R) structure and thus cannot effectively dilate blood vessels (5, 10, 18). However, upon deoxygenation [or with change in the spin state of the hemes (3)], the vasodilator potency of SNO-Hb is markedly potentiated (5,16,18). Crystal structures and molecular models show that the ␤-Cys NO gains solvent access in the deoxygenated (or T) state (3, 19). Solvent-exposed NO can exchange with acceptor thiols within the N-terminal cytoplasmic domain of the RBC membrane anion exchange protein (AE1; band 3) (4, 15). Transnitrosylation of AE1 by SNO-Hb involves a direct protein-protein interaction. The st...

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S -nitrosothiol repletion by an inhaled gas regulates pulmonary function

Cited by 69 publications

References 43 publications

Protection from Lipopolysaccharide-induced Lung Injury by Augmentation of Airway S-Nitrosothiols

Protection from Lipopolysaccharide-induced Lung Injury by Augmentation of Airway S-Nitrosothiols

Increased Nitrosoglutathione Reductase Activity in Hypoxic Pulmonary Hypertension in Mice

A nitric oxide processing defect of red blood cells created by hypoxia: Deficiency of S-nitrosohemoglobin in pulmonary hypertension

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