TY - JOUR T1 - Human recombinant Vascular Endothelial Growth Factor (hrVEGF) Reduces Necrosis and Enhances Hepatocyte Regeneration in a Mouse Model of Acetaminophen Toxicity JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.109.163840 SP - jpet.109.163840 AU - Brian Donahower AU - Sandra McCullough AU - Leah Hennings AU - Pippa M. Simpson AU - Cindy D Stowe AU - Ali G Saad AU - Richard C Kurten AU - Jack A. Hinson AU - Laura P James Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/early/2010/04/02/jpet.109.163840.abstract N2 - We previously reported that vascular endothelial growth factor (VEGF) was increased in acetaminophen (APAP) toxicity in mice and that treatment with a VEGF receptor inhibitor reduced hepatocyte regeneration. The effect of human recombinant (hr)VEGF on APAP toxicity in the mouse was examined. In early toxicity studies, B6C3F1 mice received hrVEGF (50 ug SQ) or vehicle 30 min prior to APAP (200 mg/kg (IP) and were sacrificed at 2, 4, and 8 hr. Toxicity was comparable at 2 and 4 hr, but reduced in the APAP/hrVEGF mice at 8 hr (p<0.05) compared to 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 hr in the hrVEGF treated mice. Subsequently, mice received two (pre- and 10 hr) or three doses (pre-, 10, 24 hr) of hrVEGF; ALT values and necrosis were reduced at 24 and 36 hr, respectively, in the APAP/hrVEGF mice (p<0.05) compared to the APAP/vehicle mice. Proliferating cell nuclear antigen (PCNA) expression was enhanced and IL6 expression was reduced in the mice that received hrVEGF (p<0.05), compared to the APAP/vehicle mice. In addition, treatment with hrVEGF lowered plasma hyaluronic acid levels and neutrophils counts at 36 hr. 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.The American Society for Pharmacology and Experimental Therapeutics ER -