Dual Role of Vascular Endothelial Growth Factor in Hepatic Ischemia-Reperfusion Injury

Tsurui, Yoshikazu; Sho, Masayuki; Kuzumoto, Yukiyasu; Hamada, Kaoru; Akashi, Satoru; Kashizuka, Hisanori; Ikeda, Naoya; Nomi, Takeo; Mizuno, Takashi; Kanehiro, Hiromichi; Nakajima, Yoshiyuki

doi:10.1097/01.tp.0000161627.84481.5e

Cited by 40 publications

(32 citation statements)

References 26 publications

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“…Furthermore, treatment with a VEGF receptor (VEGFR) inhibitor reduced hepatocyte proliferation in APAP-treated mice (Donahower et al, 2006). In addition to these data in the mouse model of APAP toxicity (Donahower et al, 2006), VEGF has been shown to be up-regulated in other models of liver injury, such as partial hepatectomy, ischemia reperfusion, and carbon tetrachloride toxicity (Taniguchi et al, 2001;Tsurui et al, 2005). Collectively, these data prompted us to examine the possible role of exogenous human recombinant VEGF (hrVEGF) as a potential treatment for APAP toxicity.…”

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confidence: 88%

Human Recombinant Vascular Endothelial Growth Factor Reduces Necrosis and Enhances Hepatocyte Regeneration in a Mouse Model of Acetaminophen Toxicity

Donahower¹,

McCullough²,

Hennings³

et al. 2010

J Pharmacol Exp Ther

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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 g 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 Ͻ 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 Ͻ 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 Ͻ 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.Acetaminophen (APAP; C 8 H 9 NO 2 ) overdose is the most common cause of acute liver failure is the United States (Larson et al., 2005). N-acetylcysteine is the only available treatment of APAP overdose, but its efficacy is limited primarily to the initial, early stages of APAP toxicity. Currently, no other therapies exist for the management of APAP-induced liver failure, other than the management of coagulopathy and support of vital organ functions.Previous studies have shown that numerous proinflammatory and anti-inflammatory cytokines and chemokines are up-regulated in animal models of APAP toxicity, including interleukin (IL) 1␤, IL-6, IL-10, IL-13, macrophage inhibitory protein 2, and monocyte chemotactic protein 1 (Jaeschke, 2005). The role of cytokines and inflammation in APAP toxicity has been reviewed (Jaeschke, 2005), and the available data suggest that cytokines may play a role in the aggravation of cellular injury, but may also limit cell injury and initiate cell and organ repair processes (Hogaboam et al.,

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confidence: 88%

Human Recombinant Vascular Endothelial Growth Factor Reduces Necrosis and Enhances Hepatocyte Regeneration in a Mouse Model of Acetaminophen Toxicity

Donahower¹,

McCullough²,

Hennings³

et al. 2010

J Pharmacol Exp Ther

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“…Warm liver ischemia has been shown to induce VEGF expression. 8 VEGF can augment NO production. 8,13 NO induces a decrease in the cytosolic free calcium concentration leading to the dissociation of calcium and calmodulin from the myosin light chain kinase.…”

Section: Discussionmentioning

confidence: 99%

“…8 VEGF can augment NO production. 8,13 NO induces a decrease in the cytosolic free calcium concentration leading to the dissociation of calcium and calmodulin from the myosin light chain kinase. Under these conditions, myosin light chain phosphatase dephosphorylates the myosin light chain and causes relaxation of fenestrae.…”

Section: Discussionmentioning

confidence: 99%

“…To overcome the sinusoidal endothelial cell barrier and to increase transgene DNA levels in hepatocytes in NZW rabbits, we speculated that transient liver ischemia may increase the diameter of fenestrae by increasing vascular endothelial growth factor (VEGF) production and subsequent enhanced nitric oxide (NO) synthesis. 8 Transient warm liver ischemia combined with preceding N-acetylcysteine injection increases the diameter of fenestrae, enhances transgene DNA levels in hepatocytes and augments transgene expression.…”

Section: Introductionmentioning

confidence: 99%

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Species differences in transgene DNA uptake in hepatocytes after adenoviral transfer correlate with the size of endothelial fenestrae

et al. 2007

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“…The mechanisms of hepatic IR injury J Gastrointestin Liver Dis, September 2017 Vol. 26 No 3: 253-259 are complex and involve multiple mechanisms [11]. Ischemia reperfusion injury can lead to primary graft nonfunction and need for retransplantation and predisposes the recipient to both acute and chronic rejection and graft loss [12].…”

Section: Introductionmentioning

confidence: 99%

Molecular Biomarkers as Predictors for Biliary Complications Following Liver Transplantation. A Prospective Study

Dorobanţu

Popescu

Dima

et al. 2017

JGLD

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Background: The biliary complications (BC) have been always considered the „Achilles’ heel” of liver transplantation (LT), being one of the leading causes of postoperative morbidity. Aim: To analyse predictors of BC, by monitoring in the peripheral blood the biomarkers involved in the inflammation and hepatic fibrosis, such as the matrix metalloproteinases (MMP 2, 9) and their tissue inhibitors (TIMP1), the interleukins (IL 2, 8), alfa-TNF, the endothelins and their receptors.Methods: Thirty LT patients were followed-up prospectively for 5 years. The mRNA for the following biomarkers was quantified in the peripheral blood by qRTPCR and protein expression investigated by ELISA: MMP 2, 9, TIMP1, IL 2, IL 8, TNF-alfa, and endothelins and their receptors.Results: Five patients developed anastomotic stenosis (AS). There was no difference regarding mRNA levels for all studied genes between AS and non-AS patients. Two cytokines were significantly different: pre-LT TNF alpha was higher in the non-AS group and post-LT endothelin-1 at day 7 and month 3 were higher in the AS group. There was a trend for lower levels of serum cytokines for patients without AS compared to patients with AS.Conclusion: BC play an important role in the patients‘ postoperative morbidity and molecular biomarkers prediction should improve their early recognition and treatment..Abbreviations: ALT: alanine aminotransferase; AS: anastomotic stenosis; AST: aspartate aminotransferase; BC: Biliary complications ; HBV: hepatitis B virus; HCV: hepatitis C virus; HDV: hepatitis D virus; HSC: hepatic stellate cells; IL: interleukin; IR: ischemia reperfusion; LT: liver transplantation ; MMP: matrix metalloproteinases; TIMP: metalloproteinases tissue inhibitor; TGF: tumor growth factor; TNF: tumor necrosis factor.

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Dual Role of Vascular Endothelial Growth Factor in Hepatic Ischemia-Reperfusion Injury

Cited by 40 publications

References 26 publications

Human Recombinant Vascular Endothelial Growth Factor Reduces Necrosis and Enhances Hepatocyte Regeneration in a Mouse Model of Acetaminophen Toxicity

Human Recombinant Vascular Endothelial Growth Factor Reduces Necrosis and Enhances Hepatocyte Regeneration in a Mouse Model of Acetaminophen Toxicity

Species differences in transgene DNA uptake in hepatocytes after adenoviral transfer correlate with the size of endothelial fenestrae

Molecular Biomarkers as Predictors for Biliary Complications Following Liver Transplantation. A Prospective Study

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