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Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2010 Jul; Vol. 334 (1), pp. 33-43. Date of Electronic Publication: 2010 Apr 02. - Publication Year :
- 2010
-
Abstract
- We reported previously that vascular endothelial growth factor (VEGF) was increased in acetaminophen (APAP) toxicity in mice and treatment with a VEGF receptor inhibitor reduced hepatocyte regeneration. The effect of human recombinant VEGF (hrVEGF) on APAP toxicity in the mouse was examined. In early toxicity studies, B6C3F1 mice received hrVEGF (50 microg s.c.) or vehicle 30 min before receiving APAP (200 mg/kg i.p.) and were sacrificed at 2, 4, and 8 h. Toxicity was comparable at 2 and 4 h, but reduced in the APAP/hrVEGF mice at 8 h (p < 0.05) compared with the APAP/vehicle mice. Hepatic glutathione (GSH) and APAP protein adduct levels were comparable between the two groups of mice, with the exception that GSH was higher at 8 h in the hrVEGF-treated mice. Subsequently, mice received two doses (before and 10 h) or three doses (before and 10 and 24 h) of hrVEGF; alanine aminotransferase values and necrosis were reduced at 24 and 36 h, respectively, in the APAP/hrVEGF mice (p < 0.05) compared with the APAP/vehicle mice. Proliferating cell nuclear antigen expression was enhanced, and interleukin-6 expression was reduced in the mice that received hrVEGF (p < 0.05) compared with the APAP/vehicle mice. In addition, treatment with hrVEGF lowered plasma hyaluronic acid levels and neutrophil counts at 36 h. Cumulatively, the data show that treatment with hrVEGF reduced toxicity and increased hepatocyte regeneration in APAP toxicity in the mouse. Attenuation of sinusoidal cell endothelial dysfunction and changes in neutrophil dynamics may be operant mechanisms in the hepatoprotection mediated by hrVEGF in APAP toxicity.
- Subjects :
- Animals
Chemical and Drug Induced Liver Injury etiology
Chemical and Drug Induced Liver Injury immunology
Chemical and Drug Induced Liver Injury pathology
Cytokines immunology
Disease Models, Animal
Hepatocytes drug effects
Hepatocytes immunology
Hepatocytes physiology
Humans
Immunoblotting
Immunohistochemistry
Liver immunology
Liver pathology
Liver physiology
Male
Mice
Mice, Inbred Strains
Necrosis
Recombinant Proteins administration & dosage
Recombinant Proteins therapeutic use
Vascular Endothelial Growth Factor A administration & dosage
Acetaminophen toxicity
Analgesics, Non-Narcotic toxicity
Chemical and Drug Induced Liver Injury prevention & control
Hepatocytes pathology
Liver drug effects
Liver Regeneration drug effects
Vascular Endothelial Growth Factor A therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 334
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 20363854
- Full Text :
- https://doi.org/10.1124/jpet.109.163840