THE ROLES OF iNOS IN LIVER ISCHEMIA-REPERFUSION INJURY

Lee, Vincent G.; Johnson, Mark; Baust, Jeffrey; Laubach, Victor E.; Watkins, Simon C.; Billiar, Timothy R.

doi:10.1097/00024382-200116050-00006

Cited by 106 publications

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“…5 In a warm ischemia-reperfusion model of liver injury, iNOS knockout mice showed decreased levels of plasma transaminases, suggesting that local iNOS production contributes to hepatic injury. 6 Taken together with this recent report, these 436 …”

supporting

confidence: 71%

Give me iNOS or give me death

Kim

Billiar

2001

Hepatology

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Concanavalin A (Con A) causes severe TNF-␣-mediated and IFN-␥-mediated liver injury in mice. In addition to their other functions, TNF-␣ and IFN-␥ both induce the inducible nitric oxide (NO) synthase (iNOS). Using different models of liver injury, NO was found to either mediate or prevent liver damage. To further elucidate the relevance of NO for liver damage we investigated the role of iNOS-derived NO in the Con A model. We report that iNOS mRNA was induced in livers of Con A-treated mice within 2 hours, with iNOS protein becoming detectable in hepatocytes as well as in Kupffer cells within 4 hours. iNOS ؊/؊ mice were protected from liver damage after Con A treatment, as well as in another TNF-␣-mediated model that is inducible by LPS in D-galactosamine-sensitized (GalN-sensitized) mice. iNOSdeficient mice were not protected after direct administration of recombinant TNF-␣ to GalN-treated mice. Accordingly, pretreatment of wild-type mice with a potent and specific inhibitor of iNOS significantly reduced transaminase release after Con A or GalN/LPS, but not after GalN/TNF-␣ treatment. Furthermore, the amount of plasma TNF-␣ and of intrahepatic TNF-␣ mRNA and protein was significantly reduced in iNOS ؊/؊ mice. Our results demonstrate that iNOS-derived NO regulates proinflammatory genes in vivo, thereby contributing to inflammatory liver injury in mice by stimulation of TNF-␣ production. COMMENTSIn the liver, where hepatocytes and immune cells coexist in harmonious balance to regulate many of the important metabolic functions of the body, cellular battles of life and death are waged at times with powerful weapons of defense and attack. One potent weapon is nitric oxide (NO), a radical molecule produced by nitric oxide synthase (NOS). As a soluble gas, NO can stealthily pass through membranes from cell to cell and interact with multiple proteins and reactive oxygen species. These interactions send ripples of signaling information through the cellular and organ milieu that can tip the scales of homeostasis towards cell death or proliferation.Nitric oxide, the 1992 Science journal molecule of the year, seems to be everywhere. In 1998, Furchgott, Murad, and Ignarro won the Nobel Prize in Physiology or Medicine for uncovering the role of NO in the cardiovascular system. Problems and controversies have grown from observations that NO can have widely disparate effects, depending on its local concentration and the nature of its target proteins and cells. In the quickly expanding world of apoptosis, multiple roles for NO have been identified, that either block or induce cell death. 1 As they are in many other tissues and organs, the cytotoxic and cytoprotective roles of NO in liver are both complex and controversial. Many in vivo studies suggest that NO and inducible nitric oxide synthase (iNOS) protect against hepatocyte apoptosis. 2,3 However, in the article highlighted above, Sass et al. show convincingly that "iNOS-derived NO regulates proinflammatory genes in vivo, thereby contributing to inflammatory liver in...

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supporting

confidence: 71%

Give me iNOS or give me death

Kim

Billiar

2001

Hepatology

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“…Systemic arginine depletion due to arginase release after I/R may lead to decreased NO production and affect hepatic blood flow. Prior work has shown that mice deficient in endothelial NOS (eNOS) have worsened liver damage following I/R compared to wild type mice [6]. The protective effects of eNOS derived NO appears to be partly due to alterations in total hepatic blood flow.…”

Section: Discussionmentioning

confidence: 99%

“…The pathophysiology of liver I/R injury includes both direct cellular damage as the result of the ischemic insult as well as delayed dysfunction and damage resulting from activation of inflammatory pathways [1][2][3][4]. There is evidence that the L-arginine-nitric oxide pathway plays an important role in mediating this injury [5][6][7]. In liver preservation injury and various warm ischemia reperfusion models, nitric oxide has been shown to have effects ranging from alterations in perfusion through vasodilatory effects, antiinflammatory properties through inhibition of neutrophil activation, and various antiapoptotic properties.…”

Section: Introductionmentioning

confidence: 99%

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

et al. 2008

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Background-Liver ischemia reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. Nitric oxide (NO), shown to have protective effects in I/R, is produced by nitric oxide synthase (NOS) from the substrate arginine. The purpose of this study was to determine if nor-NOHA, a novel arginase inhibitor, would be able to increase circulating arginine levels and decrease hepatic damage following warm I/R.

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“…During NO synthesis by NOS, if L-arginine levels decrease or consumption of NO increases via cell-free plasma hemoglobin and ROS, then oxidative damage occurs, HbS denatures, and superoxide production increases. It was shown that iNOS inhibition significantly limits tissue ischemiareperfusion injury in the liver and kidneys [10][11]; however, inhibition of iNOS attenuated ischemiareperfusion injury in the rat heart [12], but not in the rat lung [13]. Increased iNOS expression was reported in the kidneys of transgenic mice [9], but Nath et al [14] reported the lack of iNOS upregulation in intrarenal vasculature and increased iNOS expression in the glomeruli and distal tubules of sickle mice.…”

Section: Discussionmentioning

confidence: 99%

“…Increased iNOS expression and a consequent increase in tissue nitrite and nitrate production have been observed in the kidneys and liver of SCD patients [8], mice [2,3,8,9], and pigs [4]. Additionally, it was shown that iNOS inhibition significantly limits tissue ischemia-reperfusion injury in the liver and kidneys [10,11]; however, inhibition of iNOS attenuated ischemia-reperfusion injury in the rat heart [12] and did not affect ischemia-reperfusion injury in the rat lung [13]. Increased levels of iNOS expression were shown in the kidneys of transgenic mice [9], but Nath et al [14] reported the lack of upregulation of iNOS in the intrarenal vasculature and increased expression of iNOS in the [15][16][17] and in vitro [18].…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide in gingival crevicular fluid and nitric oxide synthase expression in the gingiva of patients with sickle cell disease

Güzeldemir

Toygar²,

Bal³

et al. 2011

Turk J Hematol

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Objective: This study aimed to biochemically measure the production of nitric oxide in gingival crevicular fluid and immunohistochemically measure the expression of inducible nitric oxide synthase in the gingiva of patients with sickle cell disease. Additionally, we aimed to obtain insight into the immunopathology of sickle cell disease by comparing inducible nitric oxide synthase levels in patients with sickle cell disease and controls using gingiva and gingival crevicular fluid. Materials and Methods: The study included 20 sickle cell disease patients and 20 healthy controls. Immunohistochemical analysis was used to measure inducible nitric oxide synthase expression in gingiva and nitric oxide levels in gingival crevicular fluid were spectrophotometrically measured. Results: Nitric oxide levels in the patients and controls did not differ significantly (21.2±4.5 and 23.1±2.3 μM L -1 , respectively, p>0.05). There weren't any statistically significant differences in infiltrated inflammatory cells, density of inflammatory cells that stained with inducible nitric oxide synthase, or nitric oxide expression in gingiva between the patient and control groups (p>0.05). Conclusion: To the best of our knowledge this is the first study to examine the expression of inducible nitric oxide synthase in the gingiva and gingival crevicular fluid in patients with sickle cell disease. Using the gingiva and gingival crevicular fluid we were unable to observe sickle cell disease-associated inducible nitric oxide synthase expression and a difference in nitric oxide levels.

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THE ROLES OF iNOS IN LIVER ISCHEMIA-REPERFUSION INJURY

Cited by 106 publications

References 0 publications

Give me iNOS or give me death

Give me iNOS or give me death

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

Nitric oxide in gingival crevicular fluid and nitric oxide synthase expression in the gingiva of patients with sickle cell disease

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