Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity.
VEGF or VEGF-A is a major regulator of angiogenesis and has been recently shown to be important in organ repair. The potential role of VEGF in acetaminophen (APAP)-induced hepatotoxicity and recovery was investigated in B6C3F1 male mice. Mice were treated with APAP (300 mg/kg ip) and killed at various time points that reflect both the acute and recovery stages of toxicity. VEGF-A protein levels were increased 7-fold at 8 h and followed the development of hepatotoxicity. VEGF receptor 1, 2, and 3 (VEGFR1, VEGFR2, and VEGFR3, respectively) expression increased throughout the time course, with maximal expression at 48, 8, and 72 h, respectively. Treatment with the VEGF receptor inhibitor SU5416 (25 mg/kg ip at 3 h) had no effect on toxicity at 6 or 24 h. In further studies, the role of SU5416 on the late stages of toxicity was examined. Treatment of mice with APAP and SU5416 (25 mg/kg ip at 3 h) resulted in decreased expression of PCNA, a marker of cellular proliferation. Expression of platelet endothelial cell adhesion molecule, a measure of small vessel density, and endothelial nitric oxide synthase (NOS), a downstream target of VEGFR2, were increased at 48 and 72 h following toxic doses of APAP, and treatment with SU5416 decreased their expression. These data indicate that endogenous VEGF is critically important to the process of hepatocyte regeneration in APAP-induced hepatotoxicity in the mouse.
Donahower
Brian
B
Department of Pharmacology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
McCullough
Sandra S
SS
Kurten
Richard
R
Lamps
Laura W
LW
Simpson
Pippa
P
Hinson
Jack A
JA
James
Laura P
LP
D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018675:Toxicity Tests; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; D042461:Vascular Endothelial Growth Factor A; D000082:Acetaminophen; D040262:Receptors, Vascular Endothelial Growth Factor