Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury

Kan, Wen Hong; Hsu, Jung-Lung; Schwacha, Martin G.; Choudhry, Mashkoor A.; Raju, Raghavan; Bland, Kirby I.; Chaudry, Irshad H.

doi:10.1152/japplphysiol.90495.2008

Cited by 46 publications

(44 citation statements)

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“…Instead we measured nitrotyrosine, a downstream, validated surrogate of nitric oxide formation. 18,19 Nitrotyrosine (Northwest Life Science Specialties, LLC) was detected by enzyme-linked immunoadsorbent assay (ELISA). Cytokines were also measured by ELISA (R&D Systems).…”

Section: Study Protocolmentioning

confidence: 99%

Intraosseous Versus Intravenous Infusion of Hydroxocobalamin for the Treatment Of Acute Severe Cyanide Toxicity in a Swine Model

Bebarta

Pitotti

Boudreau

et al. 2014

Academic Emergency Medicine

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Objectives: Easily administrated cyanide antidotes are needed for first responders, military troops, and emergency department staff after cyanide exposure in mass casualty incidents or due to smoke inhalation during fires involving many victims. Hydroxocobalamin has proven to be an effective antidote, but cannot be given intramuscularly because the volume of diluent needed is too large. Thus, intraosseous (IO) infusion may be an alternative, as it is simple and has been recommended for the administration of other resuscitation drugs. The primary objective of this study was to compare the efficacy of IO delivery of hydroxocobalamin to intravenous (IV) injection for the management of acute cyanide toxicity in a well-described porcine model. Methods:Twenty-four swine (45 to 55 kg) were anesthetized, intubated, and instrumented with continuous mean arterial pressure (MAP) and cardiac output monitoring. Cyanide was continuously infused until severe hypotension (50% of baseline MAP), followed by IO or IV hydroxocobalamin treatment. Animals were randomly assigned to receive IV (150 mg/kg) or IO (150 mg/kg) hydroxocobalamin and monitored for 60 minutes after start of antidotal infusion. The primary outcome measure was the change in MAP after antidotal treatment from onset of hypotension (time zero) to 60 minutes. A sample size of 12 animals per group was determined by group size analysis based on power of 80% to detect a one standard deviation of the mean MAP between the groups with an alpha of 0.05. Whole blood cyanide, lactate, pH, nitrotyrosine (nitric oxide marker) levels, cerebral and renal near infrared spectrometry (NIRS) oxygenation, and inflammatory markers were also measured. Repeated-measures analysis of variance was used to determine statistically significant changes between groups over time.Results: At baseline and at the point of hypotension, physiologic parameters were similar between groups. At the conclusion of the study, 10 out of 12 animals in the IV group and 10 out of 12 in IO group survived (p = 1.0). Both groups demonstrated a similar return to baseline MAP (p = 0.997). Cardiac output, oxygen saturation, and systemic vascular resistance were also found to be similar between groups (p > 0.4), and no difference was detected between bicarbonate, pH, and lactate levels (p > 0.8). Cyanide levels were undetectable after the hydroxocobalamin infusion throughout the study in both groups (p = 1.0). Cerebral and renal NIRS oxygenation decreased in parallel to MAP during cyanide infusion and increased after antidote infusion in both groups. Serum nitrotyrosine increased during cyanide infusion in all animals and then decreased in both study arms after hydroxocobalamin infusion (p > 0.5). Serum cytokines increased starting at cyanide infusion and no difference was detected between groups (tumor necrosis factor-a, interleukin [IL]-1b, IL-6, and IL-10).

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Section: Study Protocolmentioning

confidence: 99%

Intraosseous Versus Intravenous Infusion of Hydroxocobalamin for the Treatment Of Acute Severe Cyanide Toxicity in a Swine Model

Bebarta

Pitotti

Boudreau

et al. 2014

Academic Emergency Medicine

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“…Therefore, we used the highly selective iNOS inhibitor 1400W in our present study. It has been reported that 1400W inhibited iNOS activity by binding with iNOS [27] , but some studies found that 1400W could decrease iNOS expression [28,29] . In this study, we also found that iNOS expression was increased significantly in vascular tissue of aged rats.…”

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confidence: 99%

Inhibition of iNOS protects endothelial-dependent vasodilation in aged rats

Tian

Yan

et al. 2010

Acta Pharmacol Sin

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Aim: To examine whether iNOS contributes to endothelial dysfunction in aged rats. Methods: Male Sprague Dawley rats were divided into three groups: young rats, aged rats treated with vehicle and aged rats treated with N-[3-(Aminomethyl) benzyl] acetamidine (1400W, 1 mg/kg, ip). Vasorelaxation was measured in isolated thoracic aorta. iNOS expression of thoracic aortic arteries was detected using immunohistochemistry and Western blot. Nitrotyrosine (a marker for peroxynitrite formation) content and expression in thoracic aortic tissue were determined using enzyme linked immunosorbent assay and immunohistochemistry. Results: Maximal relaxation induced by acetylcholine (10 -9 to 10 -5 mol/L) in the aged rats treated with vehicle was significantly decreased (70%±15%, P<0.01), as compared with the young rats (95%±8%). However, the maximal relaxation induced by acidified NaNO2 (an endothelium-independent vasodilator) had no significant difference between the two groups. Moreover, iNOS and nitrotyrosine expression increased in the vessels of the aged rats. In the aged rats treated with 1400W (a highly selective iNOS inhibitor) nitrotyrosine expression was reduced and acetylcholine-induced vasorelaxation was markedly improved (maximal relaxation was increased to 87%±8%, P<0.05), but the acidified NaNO 2 -induced vasorelaxation had no significant change. Conclusion: Our study demonstrated that inhibition of iNOS by 1400W increased endothelium-dependent vasodilation in aged rats. The mechanism was related with attenuation of peroxynitrite formation.Keywords: aging; nitric oxide synthase; endothelium; vasodilation; 1400W Acta Pharmacologica Sinica (2010Sinica ( ) 31: 1324Sinica ( -1328 doi: 10.1038/aps.2010 published online 13 Sep 2010 Original Article * To whom correspondence should be addressed. [17,18] , respectively. Thirty minutes after 1400W treatment [18,19] young and aged rats were sacrificed to obtain vessel tissues (n=7 rats per group) for nitrotyrosine content and immunohistochemical studies of iNOS and nitrotyrosine. Determination of endothelial functionEndothelial function was determined by comparing the vasorelaxation response to acetylcholine (ACh), an endothelium-dependent vasodilator, with that of acidified NaNO 2 , an endothelium-independent vasodilator, as described previously [20] . Briefly, thoracic aortic rings were mounted onto hooks, suspended in organ chambers filled with Krebs buffer (mmol/L: NaCl 118.3, KCl 4.7, CaCl 2 2.5, MgSO 4 1.2, KH 2 PO 4 1.2, NaHCO 3 25.0, glucose 11.0, pH=7.4) [21] and aerated with 95% O 2 and 5% CO 2 at 37 °C, and connected to force transducers to record changes in tension via a Chart 5.3 data acquisition system. After equilibration for 60 min at a preload of 1 g, the rings were precontracted with norepinephrine (NE, 1 μmol/L). Once a stable contraction was achieved, the rings were exposed to cumulative concentrations of ACh (10 -9 to 10 -5 mol/L). After the cumulative response was stabilized, the rings were washed and allowed to equilibrate to baseline. The procedur...

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“…T he innate immune system has been shown to contribute to immune-mediated liver damage associated with hepatic ischemia/reperfusion (I/R) injury, hepatitis, hemorrhagic shock, and other inflammatory liver disease states (1)(2)(3)(4)(5)(6). NKT cells represent a unique group of T lymphocytes that are reactive to self and foreign glycolipid Ags presented by the MHC class Irelated molecule CD1d (7)(8)(9).…”

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confidence: 99%

A Critical Role for IFN Regulatory Factor 1 in NKT Cell-Mediated Liver Injury Induced by α-Galactosylceramide

Cao

Dhupar

Cai

et al. 2010

The Journal of Immunology

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NKT cells are remarkably abundant in mouse liver. Compelling experimental evidence has suggested that NKT cells are involved in the pathogenesis of many liver diseases. Activation of NKT cells with α-galactosylceramide (α-GalCer) causes liver injury through mechanisms that are not well understood. We undertook studies to characterize the key pathways involved in α-GalCer–induced liver injury. We found that expression of the transcription factor IFN regulatory factor 1 (IRF-1) in mouse liver was dramatically upregulated by α-GalCer treatment. Neutralization of either TNF-α or IFN-γ inhibited α-GalCer–mediated IRF-1 upregulation. α-GalCer–induced liver injury was significantly suppressed in IRF-1 knockout mice or in wild-type C56BL/6 mice that received a microRNA specifically targeting IRF-1. In contrast, overexpression of IRF-1 greatly potentiated α-GalCer–induced liver injury. α-GalCer injection also induced a marked increase in hepatic inducible NO synthase expression in C56BL/6 mice, but not in IRF-1 knockout mice. Inducible NO synthase knockout mice exhibited significantly reduced liver injury following α-GalCer treatment. Finally, we demonstrated that both NKT cells and hepatocytes expressed IRF-1 in response to α-GalCer. However, it appeared that the hepatocyte-derived IRF-1 was mainly responsible for α-GalCer–induced liver injury, based on the observation that inhibition of IRF-1 by RNA interference did not affect α-GalCer–induced NKT cell activation. Our findings revealed a novel mechanism of NKT cell-mediated liver injury in mice, which has implications in the development of human liver diseases.

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Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury

Abstract: IH. Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury.

Cited by 46 publications

References 44 publications

Intraosseous Versus Intravenous Infusion of Hydroxocobalamin for the Treatment Of Acute Severe Cyanide Toxicity in a Swine Model

Intraosseous Versus Intravenous Infusion of Hydroxocobalamin for the Treatment Of Acute Severe Cyanide Toxicity in a Swine Model

Inhibition of iNOS protects endothelial-dependent vasodilation in aged rats

A Critical Role for IFN Regulatory Factor 1 in NKT Cell-Mediated Liver Injury Induced by α-Galactosylceramide

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