Does Upregulation of Inducible Nitric Oxide Synthase Play a Role in Hepatic Injury?

Liu, Terrence H.; Robinson, Emily K.; Helmer, Kenneth S.; West, Sonlee D.; Castaneda, Antonio A.; Chang, Lily; Mercer, David

doi:10.1097/00024382-200212000-00011

Cited by 29 publications

(25 citation statements)

References 24 publications

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“…Inducible nitric oxide synthase is a key mediator of tissue injury in both the LPS infusion and hindpaw injection models of inflammation. 32,33 Thus, our demonstration that bilirubin treatment is associated with a significant decrease in nitrate production in response to endotoxin suggests a potential mechanism whereby bilirubin exerts a cytoprotective effect. An inverse association between HO-1 and iNOS has previously been described, such that NO levels decline in the face of increasing HO-1 activity.…”

Section: Discussionmentioning

confidence: 82%

“…The cytoplasmic fraction was isolated through centrifugation and the pellet was processed further to obtain nuclear protein, which was quantified using the BioRad assay (Biorad Laboratories, Hercules, CA). Nuclear extracts (6 g protein) were incubated at 25°C in 125 mmol/L hydroxyethylpiperazine-N-2 ethanesulfonic acid (pH 7.9), 2.5 mmol/L ethylenediaminetetraacetic acid, 2.5 mmol/L dithiothreitol, 1% Non-idet-P40, 25% glycerol, 250 mmol/L NaCl, and 1 g dIdC containing 32 Plabeled double-stranded oligonucleotide sequence for the nuclear factor B (NF-B) binding site (5Ј-AGTT-GAGGGGACTTTCCCAGGC-3Ј).…”

Section: Methodsmentioning

confidence: 99%

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Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats

2004

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The inducible isoform of heme oxygenase (HO), HO-1, has been shown to play an important role in attenuating tissue injury. Because HO-1 catalyzes the rate-limiting step in bilirubin synthesis, we examined the hypothesis that bilirubin is a key mediator of HO-1 cytoprotection, employing a rat model of endotoxemia. Bilirubin treatment resulted in improved survival and attenuated liver injury in response to lipopolysaccharide infusion. Serum levels of NO and tumor necrosis factor ␣, key mediators of endotoxemia, and hepatic inducible nitric oxide synthase (iNOS) expression were significantly lower in bilirubin-treated rodents versus control animals. Both intraperitoneal and local administration of bilirubin also was found to ameliorate hindpaw inflammation induced by the injection of -carrageenan. Consistent with in vivo results, bilirubin significantly inhibited iNOS expression and suppressed NO production in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. In contrast, bilirubin treatment induced a threefold increase in LPS-mediated prostaglandin synthesis in the absence of significant changes in cyclooxygenase expression or activity, suggesting that bilirubin enhances substrate availability for eicosanoid synthesis. Bilirubin had no effect on LPS-mediated activation of nuclear factor B or p38 mitogenactivated protein kinase, consistent with a nuclear factor B-independent mechanism of action. Taken together, these data support a cytoprotective role for bilirubin that is mediated, at least in part, through the inhibition of iNOS expression and, potentially, through stimulation of local prostaglandin E 2 production. In conclusion, our findings suggest a role for bilirubin in mollifying tissue injury in response to inflammatory stimuli and support the possibility that the phenomenon of "jaundice of sepsis" represents an adaptive physiological response to endotoxemia. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

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Section: Discussionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats

2004

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“…Several isoforms of NOS have been identified and classified as either constitutive enzymes (nNOS and eNOS) dependent on Ca 2+ and calmodulin or inducible (iNOS) independent of Ca 2+ and calmodulin. Inducible NOS (iNOS) is expressed by hepatocytes, and is known to play an important role in a number of pathological conditions including liver injury and disease [3][4][5]. However, it is unclear what role hepatic iNOS plays in the diabetic state.…”

Section: Introductionmentioning

confidence: 99%

Inducible Nitric Oxide Synthase Activity and Expression in Liver and Hepatocytes of Diabetic Rats

Madar

Kalet-Litman

Stark³

2005

Pharmacology

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Inducible nitric oxide synthase (iNOS) is expressed by the liver in a number of physiological and pathophysiological conditions. The aim of this study was to investigate the relationship between the diabetic state, iNOS and oxidative stress in the rat liver and isolated hepatocytes. Hepatic iNOS expression and activity was measured in both healthy and streptozotocin-induced diabetic rats and determined in hepatocytes in the presence and absence of insulin. Cu/Zn superoxide dismutase (SOD) and phosphatidylinositol-3-kinase (PI3K) were also measured. In a separate experiment lasting 3 weeks, diabetic rats received either no treatment, two daily injections of insulin or aminoguanidine in the drinking water. Diabetes led to increased activity (45%) and expression (70%) of liver iNOS, an effect that was attenuated by insulin treatment both in vitro and in whole animals. Hepatocyte iNOS expression increased by 56%. Hepatic SOD expression was elevated in the diabetic state, but activity levels were similar to healthy controls. Insulin treatment in vivo led to increased enzyme activity but expression was not modified. Levels of PI3K protein were significantly lower in diabetic rats while insulin treatment markedly increased expression. Aminoguanidine did not inhibit hepatic iNOS in this study. Glycemic control via insulin administration was able to downregulate enhanced hepatic iNOS activity and expression in the liver observed in the diabetic state and improve SOD activity, responses that can potentially reduce the free radical damage associated with diabetes.

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“…This variability in the results may be due to differences in the parameters measured, the experimental models employed, and, most important, the selectivity of NOS inhibitors used (19,32). Studies have shown that N G -nitro-L-arginine methyl ester (L-NAME), a nonspecific NOS inhibitor, increases hepatic and intestinal injury following ischemia-reperfusion (I/R) (24,31). A clinical study was recently discontinued because treatment with N G -monomethyl-L-arginine showed higher mortality (25).…”

mentioning

confidence: 99%

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

Kan

Hsu

Schwacha

et al. 2008

Journal of Applied Physiology

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Does Upregulation of Inducible Nitric Oxide Synthase Play a Role in Hepatic Injury?

Cited by 29 publications

References 24 publications

Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats

Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats

Inducible Nitric Oxide Synthase Activity and Expression in Liver and Hepatocytes of Diabetic Rats

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

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