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Article: A voluntary oral ethanol-feeding rat model associated with necroinflammatory liver injury

TitleA voluntary oral ethanol-feeding rat model associated with necroinflammatory liver injury
Authors
Issue Date2008
PublisherBlackwell Publishing, Inc. The Journal's web site is located at http://www.alcoholism-cer.com
Citation
Alcoholism: Clinical And Experimental Research, 2008, v. 32 n. 4, p. 669-682 How to Cite?
AbstractBackground: The intragastric (IG) ethanol infusion model results in fatty liver, necrosis, inflammation and fibrosis. This model was utilized to study the pathogenesis of alcoholic liver disease (ALD). Disadvantages of the IG model include maintenance of the animals and equipment expense. To develop a voluntary feeding model for ALD, we took advantage of two important observations in the IG model: (i) female rats demonstrate greater severity of alcohol-induced liver injury than males and (ii) rats fed fish oil as a source of fatty acids develop more severe alcoholic liver injury than rats fed other fatty acids with ethanol. Methods: Female Wistar rats (205 to 220 g) were fed for 8 weeks a diet containing 8% ethanol, fish oil (30% of calories), protein, and dextrose. Pair-fed controls (FD) received dextrose in amounts isocaloric to ethanol. The following measurements were made: liver pathology [fatty liver (0 to 4), necrosis, inflammation and fibrosis by Sirius Red], endotoxin and alanine aminotransferase (ALT) in plasma, urine ethanol, lipid peroxidation, nuclear factor kappa-B (NF-κB) and mRNA levels for tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Protein levels for iNOS and nitrotyrosine were evaluated by immunohistochemistry and Western Blot analysis. Liver proteasome and cytochrome P450 2E1 activity and protein levels of asialoglycoprotein receptor (ASGPR) were also evaluated. In addition, mRNA levels of fibrogenic markers were assessed. Results: All animals lost weight for the initial 2 to 3 weeks but then gained weight until killing at 8 weeks. There was, however, a significant difference (p < 0.05) in weight between the ethanol-fed (Etoh) and (FD) groups at the end of the experiment. The mean urine ethanol levels ranged between 190 and 240 mg/dl. The severity of pathological changes was greater (p < 0.01) in Etoh vs. FD: fatty liver, 3.0 ± 1.2 vs. 1.2 ± 0.4; necrosis (foci/mm2), 3.9 ± 2.3 vs. 0.4 ± 0.3; inflammation (cells/mm2), 19.0 ± 6.3 vs. 1.8 ± 0.6. Centrilobular collagen deposition (% area), assessed by Sirius Red staining, was greater in Etoh vs. FD. Levels of endotoxin, ALT, CYP2E1 and lipid peroxidation markers were also higher (p < 0.01) in Etoh vs. FD. Levels of NF-κB and mRNA of pro-inflammatory mediators (TNF-α, COX-2, iNOS) and procollagen-I were increased (p < 0.05) in ethanol-fed rats. Immunohistochemical analysis showed more intense staining for both iNOS and nitrotyrosine in the centrilobular areas in the Etoh vs. FD groups. The greater area of positive staining for iNOS and nitrotyrosine in Etoh vs. FD was confirmed by Western Blot analysis. An increase in the expression of mRNA for profibrogenic genes (p < 0.05) was seen in ethanol-fed rats. Conclusions: A voluntary feeding regimen consisting of fish oil and ethanol in female rats is technically less demanding yet produces pathological and biochemical changes similar to those observed with the IG model. Pathological changes include fatty liver, necrosis and inflammation. Increased NF-κB and mRNA and protein levels of the pro-inflammatory mediators TNF-α, COX-2 and iNOS, coincided with the presence of necroinflammatory changes. The voluntary feeding regimen is proposed as an alternative to the IG model in the study of alcoholic liver injury. © 2008 by the Research Society on Alcoholism.
Persistent Identifierhttp://hdl.handle.net/10722/149689
ISSN
2015 Impact Factor: 2.829
2015 SCImago Journal Rankings: 1.416
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorTipoe, GLen_US
dc.contributor.authorLiong, ECen_US
dc.contributor.authorCasey, CAen_US
dc.contributor.authorDonohue Jr, TMen_US
dc.contributor.authorEagon, PKen_US
dc.contributor.authorSo, Hen_US
dc.contributor.authorLeung, TMen_US
dc.contributor.authorFogt, Fen_US
dc.contributor.authorNanji, AAen_US
dc.date.accessioned2012-06-26T05:57:08Z-
dc.date.available2012-06-26T05:57:08Z-
dc.date.issued2008en_US
dc.identifier.citationAlcoholism: Clinical And Experimental Research, 2008, v. 32 n. 4, p. 669-682en_US
dc.identifier.issn0145-6008en_US
dc.identifier.urihttp://hdl.handle.net/10722/149689-
dc.description.abstractBackground: The intragastric (IG) ethanol infusion model results in fatty liver, necrosis, inflammation and fibrosis. This model was utilized to study the pathogenesis of alcoholic liver disease (ALD). Disadvantages of the IG model include maintenance of the animals and equipment expense. To develop a voluntary feeding model for ALD, we took advantage of two important observations in the IG model: (i) female rats demonstrate greater severity of alcohol-induced liver injury than males and (ii) rats fed fish oil as a source of fatty acids develop more severe alcoholic liver injury than rats fed other fatty acids with ethanol. Methods: Female Wistar rats (205 to 220 g) were fed for 8 weeks a diet containing 8% ethanol, fish oil (30% of calories), protein, and dextrose. Pair-fed controls (FD) received dextrose in amounts isocaloric to ethanol. The following measurements were made: liver pathology [fatty liver (0 to 4), necrosis, inflammation and fibrosis by Sirius Red], endotoxin and alanine aminotransferase (ALT) in plasma, urine ethanol, lipid peroxidation, nuclear factor kappa-B (NF-κB) and mRNA levels for tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Protein levels for iNOS and nitrotyrosine were evaluated by immunohistochemistry and Western Blot analysis. Liver proteasome and cytochrome P450 2E1 activity and protein levels of asialoglycoprotein receptor (ASGPR) were also evaluated. In addition, mRNA levels of fibrogenic markers were assessed. Results: All animals lost weight for the initial 2 to 3 weeks but then gained weight until killing at 8 weeks. There was, however, a significant difference (p < 0.05) in weight between the ethanol-fed (Etoh) and (FD) groups at the end of the experiment. The mean urine ethanol levels ranged between 190 and 240 mg/dl. The severity of pathological changes was greater (p < 0.01) in Etoh vs. FD: fatty liver, 3.0 ± 1.2 vs. 1.2 ± 0.4; necrosis (foci/mm2), 3.9 ± 2.3 vs. 0.4 ± 0.3; inflammation (cells/mm2), 19.0 ± 6.3 vs. 1.8 ± 0.6. Centrilobular collagen deposition (% area), assessed by Sirius Red staining, was greater in Etoh vs. FD. Levels of endotoxin, ALT, CYP2E1 and lipid peroxidation markers were also higher (p < 0.01) in Etoh vs. FD. Levels of NF-κB and mRNA of pro-inflammatory mediators (TNF-α, COX-2, iNOS) and procollagen-I were increased (p < 0.05) in ethanol-fed rats. Immunohistochemical analysis showed more intense staining for both iNOS and nitrotyrosine in the centrilobular areas in the Etoh vs. FD groups. The greater area of positive staining for iNOS and nitrotyrosine in Etoh vs. FD was confirmed by Western Blot analysis. An increase in the expression of mRNA for profibrogenic genes (p < 0.05) was seen in ethanol-fed rats. Conclusions: A voluntary feeding regimen consisting of fish oil and ethanol in female rats is technically less demanding yet produces pathological and biochemical changes similar to those observed with the IG model. Pathological changes include fatty liver, necrosis and inflammation. Increased NF-κB and mRNA and protein levels of the pro-inflammatory mediators TNF-α, COX-2 and iNOS, coincided with the presence of necroinflammatory changes. The voluntary feeding regimen is proposed as an alternative to the IG model in the study of alcoholic liver injury. © 2008 by the Research Society on Alcoholism.en_US
dc.languageengen_US
dc.publisherBlackwell Publishing, Inc. The Journal's web site is located at http://www.alcoholism-cer.comen_US
dc.relation.ispartofAlcoholism: Clinical and Experimental Researchen_US
dc.subject.meshAdministration, Oralen_US
dc.subject.meshAlcohol Drinking - Adverse Effects - Pathologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshDisease Models, Animalen_US
dc.subject.meshEthanol - Administration & Dosage - Toxicityen_US
dc.subject.meshFatty Acids, Unsaturated - Administration & Dosageen_US
dc.subject.meshFemaleen_US
dc.subject.meshLiver Diseases, Alcoholic - Etiology - Pathologyen_US
dc.subject.meshNecrosis - Chemically Induced - Etiology - Pathologyen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Wistaren_US
dc.titleA voluntary oral ethanol-feeding rat model associated with necroinflammatory liver injuryen_US
dc.typeArticleen_US
dc.identifier.emailTipoe, GL:tgeorge@hkucc.hku.hken_US
dc.identifier.authorityTipoe, GL=rp00371en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1111/j.1530-0277.2008.00623.xen_US
dc.identifier.pmid18341647-
dc.identifier.scopuseid_2-s2.0-41149121737en_US
dc.identifier.hkuros141232-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-41149121737&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume32en_US
dc.identifier.issue4en_US
dc.identifier.spage669en_US
dc.identifier.epage682en_US
dc.identifier.isiWOS:000254271200014-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridTipoe, GL=7003550610en_US
dc.identifier.scopusauthoridLiong, EC=6602732210en_US
dc.identifier.scopusauthoridCasey, CA=7101758605en_US
dc.identifier.scopusauthoridDonohue Jr, TM=7101758288en_US
dc.identifier.scopusauthoridEagon, PK=7003702541en_US
dc.identifier.scopusauthoridSo, H=14068993500en_US
dc.identifier.scopusauthoridLeung, TM=7202110149en_US
dc.identifier.scopusauthoridFogt, F=7006446193en_US
dc.identifier.scopusauthoridNanji, AA=35885060300en_US
dc.identifier.citeulike2600853-

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