Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

McClintock, Dana; Ware, Lorraine B.; Eisner, Mark D.; Wickersham, Nancy; Thompson, B. Taylor; Matthay, Michael A.

doi:10.1164/rccm.200607-947oc

Cited by 64 publications

(48 citation statements)

References 45 publications

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“…Our findings may also provide a rationale for the treatment of pulmonary oedema with exogenous NO or NO donors in order to restore normal endothelial NO levels. Interestingly, acute lung injury patients with higher urinary NO levels had reduced mortality and patients experienced more ventilator-free days and more organ failure-free days [28]. Finally, our observations raise the hypothesis that interference with ASM activity inside caveolae may explain some of the short-term effects of steroids.…”

Section: Discussionmentioning

confidence: 51%

Platelet-activating factor reduces endothelial nitric oxide production: role of acid sphingomyelinase

Yang¹,

Yin²,

Baumgärtner³

et al. 2009

European Respiratory Journal

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Platelet-activating factor (PAF) is a mediator of pulmonary oedema in acute lung injury that increases vascular permeability within minutes, partly through activation of acid sphingomyelinase (ASM). Since caveolae are rich in sphingomyelin and caveolin-1, which block endothelial nitric oxide (NO) synthase (eNOS) by direct binding, we examined the relationship between ASM, caveolin-1 and eNOS activity in the regulation of vascular permeability by PAF.In caveolar fractions from pulmonary vascular endothelial cells (isolated from perfused rat lungs) the abundance of caveolin-1 and eNOS increased rapidly after PAF perfusion. PAF treatment decreased endothelial NO (eNO) formation as assessed by in situ fluorescence microscopy. Restoration of eNO levels with PAPA-NONOate ((Z)-1-[N-(3-ammoniopropyl)-N-(npropyl)amino]diazen-1-ium-1,2-diolate) mitigated the PAF-induced oedema.PAF treatment increased the ASM activity in caveolar fractions and perfusion with ASM decreased eNO production. Pharmacological inhibition of the ASM pathway with imipramine, D609 or dexamethasone blocked the PAF-induced increase of caveolin-1 and eNOS in caveolae, and the decrease in eNO production and oedema formation.We conclude that PAF causes ASM-dependent enrichment of caveolin-1 in caveolae of endothelial cells, leading to decreased eNO production which contributes to pulmonary oedema formation. These findings suggest rapid reduction in eNO production as a novel mechanism in the regulation of vascular permeability.

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Section: Discussionmentioning

confidence: 51%

Platelet-activating factor reduces endothelial nitric oxide production: role of acid sphingomyelinase

Yang¹,

Yin²,

Baumgärtner³

et al. 2009

European Respiratory Journal

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“…44 Nitrogen oxide (NO) species are markers of oxidative stress, and are modulated by HMG-CoA reductase inhibitors. 45 Endotoxin and inflammatory cytokines activate inducible NO synthase and prolong NO production, which causes hypotension, decreased vasopressor response, and a tendency for multi-organ failure in sepsis, whereas they decrease eNOS. 46,47 A recent, multicenter study by McClintock et al 45 found that higher urine NO level was associated with better survival, and they suggested that higher NO level is associated with less severe pulmonary and systemic endothelial injury, as indicated by more ventilator-free days and organ-failure free days.…”

Section: Histopathology Analysismentioning

confidence: 99%

Long-Term Simvastatin Attenuates Lung Injury and Oxidative Stress in Murine Acute Lung Injury Models Induced by Oleic Acid and Endotoxin

Altıntaş

Atilla²,

İskit

et al. 2011

Respir Care

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BACKGROUND: 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors have several pleiotropic effects, including anti-inflammatory properties, and are reported to improve endothelial functions. Pathophysiologically, acute lung injury (ALI) is caused by a severe inflammatory response and endothelial dysfunction. OBJECTIVE: To investigate the effects of simvastatin (an HMG-CoA reductase inhibitor) on oxidative stress and lung histopathology in 2 murine models of ALI, induced by oleic acid and endotoxin. METHODS: The mice were randomly divided into 2 groups: one received 2 mg/kg/d intraperitoneal simvastatin for 15 days. Then the groups were further divided into 3, which received saline, oleic acid, or endotoxin. Four hours after inducing ALI we obtained lung samples for histopathology analysis, myeloperoxidase, glutathione, and malondialdehyde measurement, and blood samples for malondialdehyde measurement. RESULTS: Endotoxin and oleic acid lung injury increased tissue myeloperoxidase (P ‫؍‬ .009 for both), decreased tissue glutathione (P ‫؍‬ .02 and P ‫؍‬ .009, respectively), and increased tissue malondialdehyde (P ‫؍‬ .009 for both), compared to the control group. Simvastatin decreased myeloperoxidase only in the oleic acid group (P ‫؍‬ .01). Simvastatin increased glutathione (P ‫؍‬ .005 and P ‫؍‬ .003, respectively) and lowered malondialdehyde in both the endotoxin and oleic acid groups (P ‫؍‬ .003 for both). Histopathology revealed that simvastatin protected the lung tissue in both ALI models, but the protection was greater in the endotoxin group. CONCLUSIONS: Pretreatment with simvastatin decreased the severity of ALI in oleic acid and endotoxin ALI models, by decreasing inflammation and oxidative stress.

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“…In a large randomized controlled trial of lower-vs. higher-tidal volume ventilation, urine levels of the NO products nitrate and nitrite were higher in survivors than non-survivors and rose more between enrollment and day 3 in patients treated with a low-tidal volume protective ventilatory strategy compared with patients treated with a higher-tidal volume ventilatory strategy (11). These data suggest that preserved NO production is an important marker of better outcomes in acute lung injury that is improved with a protective ventilator strategy.…”

mentioning

confidence: 76%

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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Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

Cited by 64 publications

References 45 publications

Platelet-activating factor reduces endothelial nitric oxide production: role of acid sphingomyelinase

Platelet-activating factor reduces endothelial nitric oxide production: role of acid sphingomyelinase

Long-Term Simvastatin Attenuates Lung Injury and Oxidative Stress in Murine Acute Lung Injury Models Induced by Oleic Acid and Endotoxin

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

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