Neuronal nitric oxide synthase inhibition attenuates cardiopulmonary dysfunctions after combined burn and smoke inhalation injury in sheep

Westphal, Martin; Enkhbaatar, Perenlei; Schmalstieg, Frank C.; Kulp, Gabriela A.; Traber, Lillian D.; Morita, Naoki; Cox, Robert A.; Hawkins, Hal K.; Westphal-Varghese, Beena B.; Rudloff, Helen E.; Maybauer, Dirk M.; Maybauer, Marc O.; Burke, Ann S.; Murakami, Kazunori; Saunders, Fiona; Horváth, Eszter; Szabó, Csaba; Traber, Daniel L.

doi:10.1097/ccm.0b013e31816a1a0c

Cited by 44 publications

(51 citation statements)

References 37 publications

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“…However, NO production is mainly due to iNOS during sepsis [33]. NO induced by iNOS reacts with O 2 -to create the potent oxidants ONOO-, leading to an increase in the production of RNS, which further aggravates pulmonary injury in ALI [11,[38][39][40].The most well-known effect of ONOO-on proteins is the formation of 3-NT [41]. Moreover, 3-NT is a putative marker of NO-induced oxidant stress and peroxynitrite action.…”

Section: Effects Of Gyy4137 On Inos Expression and No Production In Lmentioning

confidence: 99%

H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation

Zhang

Liu

Tang

et al. 2016

Cell Physiol Biochem

118

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Background: Hydrogen sulfide (H₂S), known as the third endogenous gaseous transmitter, has received increasing attention because of its diverse effects, including angiogenesis, vascular relaxation and myocardial protection.We aimed to investigate the role of H₂S in oxidative/nitrative stress and inflammation in acute lung injury (ALI) induced by endotoxemia. Methods: Male ICR mice were divided in six groups: (1) Control group; (2) GYY4137treatment group; (3) L-NAME treatment group; (4) lipopolysaccharide (LPS) treatment group; (5) LPS with GYY4137 treatment group; and (6) LPS with L-NAME treatment group. The lungs were analysed by histology, NO production in the mouse lungs determined by modified Griess (Sigma-Aldrich) reaction, cytokine levels utilizing commercialkits, and protein abundance by Western blotting. Results: GYY4137, a slowly-releasing H₂S donor, improved the histopathological changes in the lungs of endotoxemic mice. Treatment with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, increased anti-oxidant biomarkers such as thetotal antioxidant capacity (T-AOC) and theactivities of catalase (CAT) and superoxide dismutase (SOD) but decreased a marker of peroxynitrite (ONOO-) action and 3-nitrotyrosine (3-NT) in endotoxemic lung. L-NAME administration also suppressed inflammation in endotoxemic lung, as evidenced by the decreased pulmonary levels of interleukin (IL)-6, IL-8, and myeloperoxidase (MPO) and the increased level of anti-inflammatory cytokine IL-10. GYY4137 treatment reversed endotoxin-induced oxidative/nitrative stress, as evidenced by a decrease in malondialdehyde (MDA), hydrogenperoxide (H₂O₂) and 3-NT and an increase in the antioxidant biomarker ratio of reduced/oxidized glutathione(GSH/GSSG ratio) and T-AOC, CAT and SOD activity. GYY4137 also attenuated endotoxin-induced lung inflammation. Moreover, treatment with GYY4137 inhibited inducible NOS (iNOS) expression and nitric oxide (NO) production in the endotoxemia lung. Conclusions: GYY4137 conferred protection against acute endotoxemia-associated lung injury, which may have beendue to the anti-oxidant, anti-nitrative and anti-inflammatory properties of GYY4137. The present findings warrant further exploration of the clinical applicability of H₂S in the prevention and treatment of ALI.

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Section: Effects Of Gyy4137 On Inos Expression and No Production In Lmentioning

confidence: 99%

H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation

Zhang

Liu

Tang

et al. 2016

Cell Physiol Biochem

118

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“…The formation of NO in the lung results in the loss of hypoxic pulmonary vasoconstriction (HPV) that, in turn, leads to ventilation/perfusion mismatching and subsequently poor oxygenation. In a recent study by Westphal et al (52), it was shown that the loss of HPV in sheep with ALI can be prevented by inhibition of nNOS-derived NO. The exact molecular mechanisms, however, remained to be determined.…”

mentioning

confidence: 99%

Molecular biological effects of selective neuronal nitric oxide synthase inhibition in ovine lung injury

Saunders

Westphal

Enkhbaatar

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Neuronal nitric oxide synthase is critically involved in the pathogenesis of acute lung injury resulting from combined burn and smoke inhalation injury. We hypothesized that 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, blocks central molecular mechanisms involved in the pathophysiology of this double-hit insult. Twenty-five adult ewes were surgically prepared and randomly allocated to 1) an uninjured, untreated sham group ( n = 7), 2) an injured control group with no treatment ( n = 7), 3) an injury group treated with 7-nitroindazole from 1-h postinjury to the remainder of the 24-h study period ( n = 7), or 4) a sham-operated group subjected only to 7-nitroindazole to judge the effects in health. The combination injury was associated with twofold increased activity of neuronal nitric oxide synthase and oxidative/nitrosative stress, as indicated by significant increases in plasma nitrate/nitrite concentrations, 3-nitrotyrosine (an indicator of peroxynitrite formation), and malondialdehyde lung tissue content. The presence of systemic inflammation was evidenced by twofold, sixfold, and threefold increases in poly(ADP-ribose) polymerase, IL-8, and myeloperoxidase lung tissue concentrations, respectively (each P < 0.05 vs. sham). These molecular changes were linked to tissue damage, airway obstruction, and pulmonary shunting with deteriorated gas exchange. 7-Nitroindazole blocked, or at least attenuated, all these pathological changes. Our findings suggest 1) that nitric oxide formation derived from increased neuronal nitric oxide synthase activity represents a pivotal reactive agent in the patho-physiology of combined burn and smoke inhalation injury and 2) that selective neuronal nitric oxide synthase inhibition represents a goal-directed approach to attenuate the degree of injury.

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“…13 The chosen dosage of 7-NI has been established in previous studies using the same and a similar animal model. 6,14,15 It has previously been demonstrated that infusion of 7-NI in sheep at a dose of 1 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 effectively suppresses plasma nitrate/nitrite levels 6,14,15 and establishes plasma concentrations of 7-NI 15 far below the IC 50 reported for endothelial and inducible NOS. 16 All sheep were mechanically ventilated (Servo Ventilator 900C; Siemens, Elema, Sweden) with a tidal volume of 12-15 ml/kg and a positive-end expiratory pressure of 5 cm H 2 O during the entire study period of 24 h. The fraction of inspired oxygen was set at 1.0 for the first 3 h postinjury and was then adjusted to maintain sufficient oxygenation (arterial oxygen saturation more than 90%, partial arterial oxygen pressure 80 -100 mmHg) whenever possible.…”

Section: Experimental Protocolmentioning

confidence: 97%

Effects of Early Neuronal and Delayed Inducible Nitric Oxide Synthase Blockade on Cardiovascular, Renal, and Hepatic Function in Ovine Sepsis

et al. 2010

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Neuronal nitric oxide synthase inhibition attenuates cardiopulmonary dysfunctions after combined burn and smoke inhalation injury in sheep

Abstract: The present study provides evidence that neuronal NOS-derived nitric oxide plays a pivotal role in the pathogenesis of acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.

Cited by 44 publications

References 37 publications

H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation

H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation

Molecular biological effects of selective neuronal nitric oxide synthase inhibition in ovine lung injury

Effects of Early Neuronal and Delayed Inducible Nitric Oxide Synthase Blockade on Cardiovascular, Renal, and Hepatic Function in Ovine Sepsis

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