Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity

Brian C. Donahower, Sandra S. McCullough, Leah Hennings, Pippa M. Simpson, Cindy D. Stowe, Ali Saad, Richard C. Kurten, Jack A. Hinson, Laura P. James

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 μg 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.

Original languageEnglish (US)
Pages (from-to)33-43
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume334
Issue number1
DOIs
StatePublished - Jul 1 2010

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Acetaminophen
Regeneration
Hepatocytes
Necrosis
Vascular Endothelial Growth Factor A
human VEGFA protein
Neutrophils
Vascular Endothelial Growth Factor Receptor
Proliferating Cell Nuclear Antigen
Hyaluronic Acid
Alanine Transaminase
Glutathione
Interleukin-6
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity. / Donahower, Brian C.; McCullough, Sandra S.; Hennings, Leah; Simpson, Pippa M.; Stowe, Cindy D.; Saad, Ali; Kurten, Richard C.; Hinson, Jack A.; James, Laura P.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 334, No. 1, 01.07.2010, p. 33-43.

Research output: Contribution to journalArticle

Donahower, Brian C. ; McCullough, Sandra S. ; Hennings, Leah ; Simpson, Pippa M. ; Stowe, Cindy D. ; Saad, Ali ; Kurten, Richard C. ; Hinson, Jack A. ; James, Laura P. / Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 334, No. 1. pp. 33-43.
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