Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity. J Pharmacol Exp Ther 2010 Jul;334(1):33-43
Date
04/07/2010Pubmed ID
20363854Pubmed Central ID
PMC2912052DOI
10.1124/jpet.109.163840Scopus ID
2-s2.0-77953762064 (requires institutional sign-in at Scopus site) 39 CitationsAbstract
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.
Author List
Donahower BC, McCullough SS, Hennings L, Simpson PM, Stowe CD, Saad AG, Kurten RC, Hinson JA, James LPAuthor
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetaminophenAnalgesics, Non-Narcotic
Animals
Chemical and Drug Induced Liver Injury
Cytokines
Disease Models, Animal
Hepatocytes
Humans
Immunoblotting
Immunohistochemistry
Liver
Liver Regeneration
Male
Mice
Mice, Inbred Strains
Necrosis
Recombinant Proteins
Vascular Endothelial Growth Factor A
