Role of different nitric oxide synthase isoforms in a murine model of acute lung injury and sepsis

Lange, Matthias; Nakano, Yoshimitsu; Traber, Daniel L.; Hamahata, Atsumori; Esechie, Aimalohi; Jonkam, Collette; Bansal, Kamna; Traber, Lillian D.; Enkhbaatar, Perenlei

doi:10.1016/j.bbrc.2010.07.071

Cited by 26 publications

(24 citation statements)

References 28 publications

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“…Pulmonary artery pressures did not change significantly, although the Pao 2 /Fio 2 ratio and lung compliance were better preserved after BH4 administration. Alveolar capillary endothelial cells and alveolar epithelial cells are injured as a result of sepsis-induced oxidative stress, resulting in increased permeability and lung edema with impaired gas exchange and decreased lung compliance (47,48). Our study showed that this effect was blunted by supplementing with BH4 at an early stage of sepsis, which was corroborated by the lower lung wet/dry weight ratio compared with the control group.…”

Section: Discussionsupporting

confidence: 75%

Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock*

Velissaris

et al. 2012

Critical Care Medicine

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Section: Discussionsupporting

confidence: 75%

Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock*

Velissaris

et al. 2012

Critical Care Medicine

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“…Cytokine-triggered production of excessive NO is suspected to be an important contributor to sepsisinduced vascular hyperpermeability and edema formation [4,18,19]. To assess the effects of pulmonary infection in mice on vascular permeability and lung edema formation, we used the plasma protein concentration and lung edema formation as previously described [9,10,18,20]. We observed an early and sustained decrease in plasma protein concentration which is typically seen in fluid-resuscitated patients or animals with sepsis-induced microvascular hyperpermeability [18].…”

Section: Discussionmentioning

confidence: 92%

“…It is well established that sepsis by any infectious source (e.g., pneumonia) may impair the function of distant organs (e.g., renal failure) by complex [7,9,10]. We have previously described the time changes in NO synthases, nitrosative stress, and poly(ADP ribosylation) in an ovine model of pulmonary sepsis [17].…”

Section: Discussionmentioning

confidence: 95%

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Time course of the inflammatory and oxidative stress response to pulmonary infection in mice

Lange

Nakano

Traber

et al. 2012

Experimental Lung Research

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The pathophysiological response to pulmonary infection includes a surge of proinflammatory cytokines and excessive production of nitric oxide (NO), but the time changes are not sufficiently defined. The current study was designed to assess the time course of proinflammatory cytokines and NO production in a murine model of pulmonary infection. The injury was induced by intranasal administration of live Pseudomonas aeruginosa (3.2 × 10(7) colony-forming units) in C57BL/6 wild-type mice. The animals were euthanized at 3, 6, 9, 12, and 15 hours postinjury. Additional mice received sham injury (0 hours; control). Lung tissue and plasma samples were harvested at the respective time points. The injury induced an early increase in interleukin (IL)-1 β protein in lung tissue that persisted during the entire study period with a peak at the 9-hour time point. The increases in TNF-α and IL-6 proteins in lung tissue were less intense, but showed a peak about 9 hours postinjury. The plasma levels of IL-1 β and tumor necrosis factor (TNF)-α protein were not elevated during the experimental period, but only an increase in plasma levels of IL-6 plasma protein was detected. These findings compensate for the limitations of previous experiments with similar infection models and improve the understanding of pathophysiologic alterations in response to pulmonary infection. In addition, the identification of the time changes of the described pathogenetic factors may enhance the timing of innovate therapeutic approaches in future experiments.

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“…This vasoprotective effect of iNOS contrasts with its harmful effects in more severe pathological conditions (e.g. diabetes, atherosclerosis, or sepsis), in which upregulation of iNOS can mediate increased oxidative stress and related vascular pathology [16]–[19], [37], [43]. Our study design was comprehensive in that we examined the modulating effects of iNOS deficiency in both vascular and cardiac tissues in mice with diet-induced hyperhomocysteinemia.…”

Section: Discussionmentioning

confidence: 99%

Protective Vascular and Cardiac Effects of Inducible Nitric Oxide Synthase in Mice with Hyperhomocysteinemia

et al. 2014

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Diet-induced hyperhomocysteinemia produces endothelial and cardiac dysfunction and promotes thrombosis through a mechanism proposed to involve oxidative stress. Inducible nitric oxide synthase (iNOS) is upregulated in hyperhomocysteinemia and can generate superoxide. We therefore tested the hypothesis that iNOS mediates the adverse oxidative, vascular, thrombotic, and cardiac effects of hyperhomocysteinemia. Mice deficient in iNOS (Nos2−/−) and their wild-type (Nos2+/+) littermates were fed a high methionine/low folate (HM/LF) diet to induce mild hyperhomocysteinemia, with a 2-fold increase in plasma total homocysteine (P<0.001 vs. control diet). Hyperhomocysteinemic Nos2+/+ mice exhibited endothelial dysfunction in cerebral arterioles, with impaired dilatation to acetylcholine but not nitroprusside, and enhanced susceptibility to carotid artery thrombosis, with shortened times to occlusion following photochemical injury (P<0.05 vs. control diet). Nos2−/− mice had decreased rather than increased dilatation responses to acetylcholine (P<0.05 vs. Nos2+/+ mice). Nos2−/− mice fed control diet also exhibited shortened times to thrombotic occlusion (P<0.05 vs. Nos2+/+ mice), and iNOS deficiency failed to protect from endothelial dysfunction or accelerated thrombosis in mice with hyperhomocysteinemia. Deficiency of iNOS did not alter myocardial infarct size in mice fed the control diet but significantly increased infarct size and cardiac superoxide production in mice fed the HM/LF diet (P<0.05 vs. Nos2+/+ mice). These findings suggest that endogenous iNOS protects from, rather than exacerbates, endothelial dysfunction, thrombosis, and hyperhomocysteinemia-associated myocardial ischemia-reperfusion injury. In the setting of mild hyperhomocysteinemia, iNOS functions to blunt cardiac oxidative stress rather than functioning as a source of superoxide.

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Role of different nitric oxide synthase isoforms in a murine model of acute lung injury and sepsis

Cited by 26 publications

References 28 publications

Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock*

Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock*

Time course of the inflammatory and oxidative stress response to pulmonary infection in mice

Protective Vascular and Cardiac Effects of Inducible Nitric Oxide Synthase in Mice with Hyperhomocysteinemia

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