RGD Reference Report - Inhibition of tumor necrosis factor alpha secretion and prevention of liver injury in ethanol-fed rats by antisense oligonucleotides. - Rat Genome Database

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Inhibition of tumor necrosis factor alpha secretion and prevention of liver injury in ethanol-fed rats by antisense oligonucleotides.

Authors: Ponnappa, Biddanda C  Israel, Yedy  Aini, Maria  Zhou, Feng  Russ, Rachel  Cao, Qing-na  Hu, Yiyang  Rubin, Raphael 
Citation: Ponnappa BC, etal., Biochem Pharmacol. 2005 Feb 15;69(4):569-77. doi: 10.1016/j.bcp.2004.11.011. Epub 2004 Dec 30.
RGD ID: 14995456
Pubmed: PMID:15670576   (View Abstract at PubMed)
DOI: DOI:10.1016/j.bcp.2004.11.011   (Journal Full-text)

Elevated serum tumor necrosis factor alpha (TNF-alpha) levels predict mortality in patients with alcoholic liver disease. Administration of anti-TNF-alpha antibodies, obliteration of Kupffer cells or gut sterilization protect against ethanol-induced hepatocellular injury in animal models. In this study, we evaluated the in vivo efficacy of an antisense phosphorothioate oligodeoxynucleotide (S-ODN) targeted against TNF-alpha mRNA (TJU-2755). Naive rats that were administered TJU-2755 (10 mg/(kg body weight (BW)/day) for 2 days) in the free form were challenged with LPS to induce TNF-alpha secretion. Antisense TJU-2755 treatment reduced serum TNF-alpha levels by 62%. A comparison of the efficacies of mismatched and random S-ODNs with that of TJU-2755 showed that some non-specific inhibition might accompany the sequence-specific effects of TJU-2755. To optimize the targeting of the S-ODN, TJU-2755 was encapsulated in pH-sensitive liposomes for in vivo delivery to macrophages. The efficacy of liposome-encapsulated TJU-2755 was assessed in ethanol-fed animals that were administered LPS to induce liver injury. Liposomal delivery of TJU-2755 allowed a much lower dose (1.9 mg/kg BW/day, for 2 days) of the S-ODN to reduce LPS-induced serum TNF-alpha (by 54%) and liver injury (by 60%) in ethanol-fed rats. These data indicate that liposome-encapsulated S-ODNs targeted against TNF-alpha have therapeutic potential in the treatment of alcoholic liver disease.




  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
TNFHumanAlcoholic Liver Diseases treatmentISOTnf (Rattus norvegicus) RGD 
TnfRatAlcoholic Liver Diseases treatmentIMP  RGD 
TnfMouseAlcoholic Liver Diseases treatmentISOTnf (Rattus norvegicus) RGD 


Genes (Rattus norvegicus)
Tnf  (tumor necrosis factor)

Genes (Mus musculus)
Tnf  (tumor necrosis factor)

Genes (Homo sapiens)
TNF  (tumor necrosis factor)