Nitric oxide synthase 3 contributes to ventilator-induced lung injury

Vaporidi, Katerina; Francis, Roland C. E.; Bloch, Kenneth D.; Zapol, Warren M.

doi:10.1152/ajplung.00341.2009

Cited by 41 publications

(45 citation statements)

References 44 publications

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“…Alternatively, preserved NO production might be a marker of less uncoupling of NOS with less superoxide production. Together with the current study by Vaporidi and colleagues (21), an intriguing hypothesis emerges that therapies that target maintenance of coupling of NOS might be beneficial in VILI and in acute lung injury in general. Several potential strategies are possible.…”

supporting

confidence: 51%

Understanding the role of NOS-3 in ventilator-induced lung injury: don't take NO for an answer

Ware

Summar

2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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ALTHOUGH NITRIC OXIDE SYNTHASES (NOSs) were first described in 1989 (12), these complex enzymes are still not fully understood, and their role in human lung disease remains unclear. Three NOS isoforms have been described in humans: neuronal or nNOS (NOS-1), inducible or iNOS (NOS-2), and endothelial or eNOS (NOS-3). All isoforms of NOS are modular enzymes with a reductase domain and an oxygenase domain. When electron transfer between the reductase and oxygenase domains is coupled, synthesis of nitric oxide (NO) and Lcitrulline from the substrate L-arginine is catalyzed via coupling of L-arginine oxidation with O 2 reduction. Dimerization of NOS monomers is required for this NO synthesis and occurs in the presence of heme protein. The NOS product NO is a ubiquitous signaling molecule that regulates vascular tone and blood flow, leukocyte adhesion, platelet aggregation, and mitochondrial oxygen consumption (9).There are several conditions under which the tightly linked reductase and oxygenase functions of NOS can become uncoupled, inhibiting NO production. Under uncoupled conditions, NOS preferentially catalyzes the reduction of molecular oxygen to form superoxide ion. One well-described factor leading to NOS uncoupling is substrate deficiency (5). LArginine is the only known substrate for NO synthesis by NOS. Although not an essential amino acid, L-arginine can become conditionally essential in situations of metabolic stress such as sepsis. L-Arginine can be synthesized in vivo from the urea cycle intermediate product L-citrulline (also generated by NOS), by argininosuccinate synthase, and argininosuccinate lyase. Factors that lead to reductions in citrulline/arginine availability include ischemia reperfusion and physiological stress (3,13,18). A second factor that can lead to uncoupling of NOS is insufficiency of the NOS cofactor tetrahydrobiopterin (BH 4 ), which is normally bound to the oxygenase domain (22). Factors that can lead to reductions in BH 4 include oxidative stress (8) and ischemia reperfusion (22). Reactive oxygen species can also react with NO to form peroxynitrite. Peroxynitrite can, in and of itself, lead to uncoupling of NOS. Another factor that can contribute to NOS uncoupling is endogenous production of asymmetric dimethyl arginine (ADMA), a competitive inhibitor of NOS that has been shown to cause uncoupling of NOS-3 (2, 17). Chronic uncoupling of NOS has been implicated in several human diseases including diabetes (9), hypertension (9), and diastolic dysfunction (16).The role of NOS in ventilator-induced lung injury is not well understood, and data from experimental models have provided conflicting results. Frank and colleagues (6) reported that ventilator-induced lung injury (VILI) in rats was associated with induction of NOS-2. Inhibition of NOS-2 in this model ameliorated VILI. Peng and colleagues (14) reported that in a mouse model of VILI using NOS-2Ϫ/Ϫ mice, NOS-2 deficiency was protective. Peng and colleagues also studied NOS-3Ϫ/Ϫ mice (15). Contrary to their findings in NOS-2Ϫ/Ϫ mi...

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confidence: 51%

Understanding the role of NOS-3 in ventilator-induced lung injury: don't take NO for an answer

Ware

Summar

2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Nitrite and nitrate levels in EBC, individually or combined, are often used as biomarkers of lung nitrosative stress. Increased nitric oxide metabolites reflect activation of macrophages, neutrophils or other various lung cell types 27,44,45 through the inducible or endothelial nitric oxide synthase 46,47,48 . Nitrite in EBC and nitric oxide in exhaled air are accepted by the American Thoracic Society as complementary but not equivalent measurements of nitrosative stress 42,49,50 .…”

Section: Discussionmentioning

confidence: 99%

Early Effect of Tidal Volume on Lung Injury Biomarkers in Surgical Patients With Healthy Lungs

Fernandez-Bustamante

Klawitter

Repine

et al. 2015

Survey of Anesthesiology

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“…25 Vaporidi et al provided in vivo evidence for eNOS uncoupling in VILI, leading to superoxide production and tissue injury. 26 Because evaluating NOS pathways in VILI was not the main focus of our study, we did not quantify the contribution of eNOS in nitrite-mediated protection. However, the failure of higher nitrite concentrations to reduce injury in our experiments may have been due to uncoupled eNOS superoxide production.…”

Section: Discussionmentioning

confidence: 99%

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

Pickerodt

Emery²,

Zarndt

et al. 2012

Anesthesiology

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Background Nitrite (NO2) is a physiologic source of nitric oxide and protects against ischemia-reperfusion injuries. We hypothesized that nitrite would be protective in a rat model of ventilator-induced lung injury and sought to determine if nitrite protection is mediated by enzymic catalytic reduction to nitric oxide. Methods Rats were anesthetized and mechanically ventilated. Group 1 had low tidal volume ventilation (LVT) (6 ml/kg and 2 cm H2O positive end-expiratory pressure; n=10); group 2 had high tidal volume ventilation (HVT) (2 h of 35 cm H2O inspiratory peak pressure and 0 cm H2O positive end-expiratory pressure; n=14); groups 3-5: HVT with sodium nitrite (NaNO2) pretreatment (0.25, 2.5, 25 μmol/kg IV; n=6-8); group 6: HVT+NaNO2+nitric oxide scavenger 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide(n=6); group 7: HVT+NaNO2+nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (n=7); and group 8: HVT+NaNO2+xanthine oxidoreductase inhibitor allopurinol (n=6). Injury assessment included physiologic measurements (gas exchange, lung compliance, lung edema formation, vascular perfusion pressures) with histologic and biochemical correlates of lung injury and protection. Results Injurious ventilation caused statistically significant injury in untreated animals. NaNO2 pretreatment mitigated the gas exchange deterioration, lung edema formation, and histologic injury with maximal protection at 2.5 μmol/kg. Decreasing nitric oxide bioavailability by nitric oxide scavenging, nitric oxide synthase inhibition, or xanthine oxidoreductase inhibition abolished the protection by NaNO2. Conclusions Nitrite confers protection against ventilator-induced lung injury in rats. Catalytic reduction to nitric oxide and mitigation of ventilator-induced lung injury is dependent on both xanthine oxidoreductase and nitric oxide synthases.

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Nitric oxide synthase 3 contributes to ventilator-induced lung injury

Cited by 41 publications

References 44 publications

Understanding the role of NOS-3 in ventilator-induced lung injury: don't take NO for an answer

Understanding the role of NOS-3 in ventilator-induced lung injury: don't take NO for an answer

Early Effect of Tidal Volume on Lung Injury Biomarkers in Surgical Patients With Healthy Lungs

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

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