Salvage effect of the vascular endothelial growth factor on chemically induced acute severe liver injury in rats Tadashi Namisaki 1 , Hitoshi Yoshiji 1, * , Hideyuki Kojima 1 , Junichi Yoshii 1 , Yasuhide Ikenaka 1 , Ryuichi Noguchi 1 , Shinya Sakurai 1 , Koji Yanase 1 , Mitsuteru Kitade 1 , Masaharu Yamazaki 1 , Kiyoshi Asada 1 , Masahito Uemura 1 , Mitsutoshi Nakamura 2 , Hiroshi Fukui 1 1 Third Department of Internal Medicine, Nara Medical University, School of Medicine, Shijo-cho 840, Kashihara, Nara 634-8522, Japan 2 Department of Pathology, Nara Medical University, School of Medicine, Shijo-cho 840, Kashihara, Nara 634-8522, Japan Background/Aims: The role of the vascular endothelial growth factor (VEGF), a potent angiogenic factor, in liver regeneration following acute severe liver injury (ALI) has not been elucidated. The aims of the current study were to investigate the role of VEGF, and to find out whether VEGF can improve the outcome of ALI in rats. Methods: ALI was induced in male rats by combination of D-galactosamine (Gal-N) and lipopolysaccharide (LPS). The survival rate and several indices were chronologically compared with or without VEGF treatment. Results: The overall survival rate of the VEGF-treated group significantly improved as compared with the untreated group (100 vs. 27%, respectively). The serum ALT elevation, with a peak at 24 h after Gal-NCLPS intoxication, was markedly attenuated with VEGF treatment. The proliferation of hepatocytes and sinusoidal endothelial cells (SEC) was stimulated by VEGF with a peak at 36 and 96 h, respectively. The immunohistochemical analysis revealed that VEGF drastically prevented destruction of the SEC architecture in ALI. Our in vitro study showed that VEGF significantly prevented the Gal-NCLPS-induced cytotoxicity and apoptosis of SEC. Conclusions: VEGF treatment significantly reduced the mortality rate of ALI in the rat, and it may provide a new therapeutic strategy for ALI. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Angiogenesis; Acute severe liver injury; VEGF 1. Introduction Acute severe liver injury (ALI), such as acute hepatic failure, is defined as a dramatic clinical syndrome resulting from massive hepatic necrosis [1]. ALI can result from acute aggravation of chronic viral hepatitis, alcohol abuse, drugs, and autoimmune disorders. Regardless of the etiology, once extensive hepatocyte necrosis develops, ALI associated with impaired liver regeneration follows. Over the last decade, there has been an explosion in the therapeutic options for ALI, including several new drugs, bioartificial liver support system, and liver transplantation [1,2]. Of these modalities, liver transplantation has been accepted to improve the mortality rate, but it is not widely available because of the lack of donor organs, and expertise. Since the mortality of ALI remains high, an alternative new therapeutic strategy should be developed to improve the overall survival of the ALI patients. Angiogenesis is the development of new vasculature from the pre-existing blood vessels and/or circulating endothelial cells (EC) progenitor cells [3]. Emerging evidences have shown that angiogenesis plays a pivotal role in many physiological and pathological processes, such as tumor growth, arthritis, psoriasis, and diabetic retino- pathy [4]. Although previous studies conducted to determine the molecular process associated with liver regeneration and angiogenesis were performed indepen- dently, recent studies have revealed that both biological phenomena develop synergistically [5]. It was shown that Journal of Hepatology 44 (2006) 568–575 www.elsevier.com/locate/jhep 0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.08.018 Received 16 February 2005; received in revised form 12 July 2005; accepted 16 August 2005; available online 23 September 2005 * Corresponding author. Tel.: C81 744 22 3051; fax: C81 744 24 7122. E-mail address: yoshijih@naramed-u.ac.jp (H. Yoshiji).