Nitric Oxide Ameliorates Actinomycin D/Endotoxin-Induced Apoptotic Liver Failure in Mice

doi:10.1006/jsre.1999.5621

Journal of Surgical Research

Volume 85, Issue 2, August 1999, Pages 286-293

https://doi.org/10.1006/jsre.1999.5621 Get rights and content

Abstract

Liver damage induced by lipopolysaccharide (LPS) in actinomycin D-sensitized mice was initiated by a Fas/CD95-independent apoptotic process that produced DNA fragmentation in hepatocytes followed by an increase of plasma ALT. The metabolic inhibitor actinomycin D blocked most of the LPS-induced increase of plasma nitrite/nitrate levels, as did administration of a nitric oxide synthase inhibitor, N^G-monomethyl- $l$ -arginine, which also promoted LPS-induced apoptotic liver damage. Administration of nitric oxide donors (hydroxylamine, S-nitroso-N-acetylpenicillamine or 2,2′-(hydroxynitrosohydrazino)bis-ethanamine) resulted in elevation of the plasma nitrite/nitrate level and amelioration of actinomycin D/LPS-induced apoptotic liver damage. The protective effect of nitric oxide against apoptotic liver damage was partially reproduced by a membrane-permeable analog of cyclic GMP. On the other hand, treatment with the soluble guanylate cyclase inhibitor LY83583 overcame the protective effect of nitric oxide against apoptotic liver damage. These results suggest that nitric oxide may regulate programmed cell death in the mouse liver and that induction of genes, including inducible nitric oxide synthase, plays an important role in protecting the liver against LPS-induced apoptotic damage. This effect appears to be mediated, at least in part, via the soluble guanylate pathway.

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Clinical observations and experiments conducted on animals have shown acute injury accompanied by noncardiogenic pulmonary edema, pulmonary inflammation and severe systemic hypoxemia in the lung possessing high levels of TNF-α [16,59]. The different aspects of organ failure were mostly studied by injecting TNF-α and low-dose lipopolysaccharide to the animals previously sensitized to damage by Act D or d-galactosamine, transcriptional inhibitors in the lung, liver, intestine and kidney [2,3,19,20,41]. Oztay and colleagues noted that TNF-α/d-galactosamine treatment given to mice resulted in dilated alveolar ducts and alveoli in addition to swelling of pneumocytes [41].
Teduglutide is a long-acting synthetic analogue of human glucagon-like peptide-2 (GLP-2). GLP-2 regulates cell proliferation and apoptosis as well as normal physiology in the gastrointestinal tract. In the present study, possible cytoprotective and reparative effects of teduglutide were analyzed on a mouse model with lung injury induced by tumor necrosis factor-alpha (TNF-α) and actinomycin D (Act D). BALB/c mice were divided into six groups: control mice (I), mice injected intraperitoneally with 15 μg/kg TNF-α (II), 800 μg/kg Act D (III), Act D 2 min prior to TNF-α administration with the same doses (IV), mice injected subcutaneously with 200 μg/kg teduglutide every 12 h for 10 consecutive days (V), and mice given Act D 2 min prior to TNF-α administration on day 11 after receiving teduglutide for 10 days (VI). The TNF-α/Act D administration made the lung a sensitive organ to damage. Mice lung subjected to TNF-α/Act D were characterized by the disruption of alveolar wall, induced pulmonary endothelial/epithelial cell apoptosis and expression of active caspase-3. These mice exhibited an increase in lipid peroxidation, glutathione levels, and activities of myeloperoxidase, superoxide dismutase, catalase, glutathione peroxidase and xanthine oxidase, as well as reduced tissue factor and sodium–potassium/ATPase activities. Teduglutide pretreatment regressed the structural damage, cell apoptosis and oxidative stress by reducing lipid peroxidation in mice received TNF-α/Act D. GLP-2 receptors were present on the cell membrane of type II pneumocytes and interstitial cells. Thus, teduglutide can be suggested as a novel protective agent, which possesses anti-apoptotic and anti-oxidant properties, against lung injury.
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Hepatic encephalopathy is neuropsychiatric derangement secondary to hepatic decompensation or portal-systemic shunting. Nitric oxide (NO) synthase inhibition aggravates encephalopathy and increases mortality in rats with thioacetamide (TAA)-induced acute liver failure, suggesting a protective role of NO. This study investigated the roles of endothelium-derived constitutive NO synthase (eNOS) and inducible NOS (iNOS) in the liver of rats with fulminant hepatic failure and encephalopathy.
Male Sprague-Dawley rats (300-350 g) were randomized to receive TAA 350 mg/kg/day, by intraperitoneal injection or normal saline for 3 days. Severity of encephalopathy was assessed with the Opto-Varimex animal activity meter. Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin were measured. Hepatic iNOS and eNOS RNA and protein expressions were assessed by reverse transcription-polymerase chain reaction and Western blot analyses, respectively.
The TAA group showed lower motor activity counts than the normal saline group. Hepatic eNOS, but not iNOS, mRNA and protein expressions were enhanced in the TAA group. In addition, hepatic eNOS mRNA expression was negatively correlated with total movement but positively correlated with ALT and AST. Protein expression of hepatic eNOS was positively correlated with ALT, AST and bilirubin.
Upregulation of hepatic eNOS was observed in rats with TAA-induced fulminant hepatic failure and encephalopa-thy, which might play a regulatory role.
The nitric oxide donor molsidomine improves survival and reduces hepatocyte apoptosis in cholestasis and endotoxemia
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Cholestasis and endotoxemia have been demonstrated to cause hepatocyte apoptosis through caspase-mediated pathways. In vitro nitric oxide (NO) donors reduce hepatocyte apoptosis and caspase activation in several models. The nitric oxide donor molsidomine improves survival in an in vivo model of endotoxemia. We tested the effect of molsidomine on survival and hepatocyte apoptosis in a model of obstructive jaundice and endotoxemia.
Sprague-Dawley rats underwent common bile duct ligation on day 1. On day 3, animals were given either 100 mg/kg of molsidomine or an equivalent volume of saline, and 30 minutes later they were given endotoxin 3 mg/kg or 10 mg/kg intravenously. Animals were sacrificed 4 or 16 hours after endotoxin injection. Serum samples were analyzed for alanine aminotransferase and frozen liver samples were analyzed for caspase 3 activity. Paraffin-embedded liver sections were assayed for apoptosis using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Survival was measured in a separate experiment in which animals underwent the same protocol, but were given three different doses of endotoxin and were observed for 72 hours before sacrifice.
At endotoxin 3 mg/kg, the 72-hour survival in saline-treated animals was 92%, which decreased to 45% at 10 mg/kg and to 29% at 15 mg/kg. All of the molsidomine-treated animals survived all endotoxin doses. Alanine aminotransferase was reduced in molsidomine-treated animals compared with those treated with saline. Apoptosis was attenuated in molsidomine-treated animals. Caspase 3 activity was decreased in molsidomine-treated animals compared with those given saline.
Molsidomine attenuates caspase activation and hepatocyte apoptosis and improves survival after cholestatic endotoxic injury.
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GTP cyclohydrolase I is the rate-controlling enzyme in the production of tetrahydrobiopterin (BH₄), an essential cofactor for nitric oxide (NO) synthase. Here we show that GTP cyclohydrolase I mRNA was present in unstimulated hepatocytes and was up-regulated 2- to 3-fold concurrently with iNOS induction induced in vivo by LPS injection and in vitro by stimulation with LPS and inflammatory cytokines tumor necrosis factor α, interleukin-1 β, and interferon-γ. Hepatocyte GTP cyclohydrolase I enzyme activity increased 2-fold in vivo after LPS. This coinduction of GTP cyclohydrolase I resulted in increased total intracellular biopterin which supported induced NO synthesis. The addition of a GTP cyclohydrolase I inhibitor to the stimulated hepatocytes decreased intracellular biopterin levels and resulted in a decrease in NO production. The results show that GTP cyclohydrolase I is up-regulated by certain acute inflammatory conditions. Further, the results indicate that biopterin is essential as a cofactor for induced NO synthase activity in hepatocytes.
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^☆: Part of this manuscript has previously been published in a Japanese-language review article (Surg. Trauma Immunol. Responses5, 120, 1996).

²: To whom correspondence should be addressed at Department of Emergency and Critical Care Medicine, Kansai Medical University, Fumizono-cho 10-15, Moriguchi, Osaka 570-8507, Japan. Fax: +81-6-6991-5779. E-mail: [email protected].

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Regular ArticleNitric Oxide Ameliorates Actinomycin D/Endotoxin-Induced Apoptotic Liver Failure in Mice☆

Abstract

Toxicon

J. Biol. Chem.

Hepatology

Gastroenterology

Cell

Anal. Biochem.

Cell

Gastroenterology

Biochem. Pharmacol.

Hepatology

Cell

FEBS Lett.

Biochem. Biophys. Res. Commun.

Galactosamine-induced sensitization to the lethal effects of endotoxin

Proc. Natl. Acad. Sci. USA

Possible alteration of normal mechanisms of endotoxin toxicity in vivo by actinomycin D

J. Infect. Dis.

Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-α requires transcriptional arrest

J. Immunol.

Heat shock protects WEH1-164 target cells from the cytolysis by tumor necrosis factors γ and β

Eur. J. Immunol.

MnSOD induction by TNF and its protective role

Regular Article
Nitric Oxide Ameliorates Actinomycin D/Endotoxin-Induced Apoptotic Liver Failure in Mice☆