Gastrointestinal
Vascular Endothelial Growth Factor Increases in Serum and Protects Against the Organ Injuries in Severe Acute Pancreatitis1

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Background

We have demonstrated that apoptosis was detected in liver and kidney cells in severe acute pancreatitis and that cellular injury because of apoptosis may be involved in the mechanism of multiple organ dysfunction syndrome. Vascular endothelial growth factor (VEGF) is a glycoprotein with potent angiogenic, mitogenic, and vascular permeability-enhancing activities specific for endothelial cells. It has been reported that VEGF is implicated in many diseases such as cancer and inflammation.

Methods

Serum VEGF concentrations were determined in patients with acute pancreatitis at the time of admission, and the relationships with severity, blood biochemical parameters on admission, organ dysfunction during the clinical course, and prognosis were analyzed. Moreover, to clarify the role of VEGF in acute pancreatitis, effects of VEGF were investigated in experimental severe acute pancreatitis.

Results

Serum VEGF levels were significantly elevated in patients with acute pancreatitis. Serum VEGF levels were not related to severity or prognosis. In male patients, among the various blood biochemical parameters, serum lactate dehydrogenase, and blood urea nitrogen levels were positively correlated with serum VEGF levels. Serum VEGF levels with organ dysfunction (liver and kidney) were higher than those without organ dysfunction. In rat experimental severe acute pancreatitis, serum VEGF levels were significantly elevated. Recombinant VEGF did not affect the lung water content, volume of ascitic fluid, hematocrit, or serum amylase, but improved the hepatic and renal dysfunctions. Apoptosis of liver and kidney was significantly inhibited by the administration of VEGF.

Conclusions

These results suggest that VEGF is closely related to organ dysfunction in severe acute pancreatitis, and that VEGF may function as not a vascular permeability factor, but a protective factor via the anti-apoptotic effect against the organ injuries in this disease.

Introduction

Multiple organ dysfunction syndrome (MODS) is the most serious complication in the early phase of severe acute pancreatitis, and it remains the main contributing factor to the high mortality of this disease [1, 2, 3]. Evidence has accumulated of the significance of apoptotic cell death in the systemic manifestations associated with severe acute pancreatitis [4]. Since we identified apoptosis-inducing activity in pancreatitis-associated ascitic fluid (PAAF) in 1995 [5], a number of investigators, including our group, have reported, through animal experiments, that apoptosis occurred in the parenchymal cells constituting organs, such as alveolar epithelial cells in the lung, renal tubular cells in the kidney [6], and hepatocytes in the liver [7], and that apoptotic cell injury was involved in the mechanism of MODS in this disease [8, 9].

Vascular endothelial growth factor (VEGF) [10], also known as vascular permeability factor [11], is a heparin-binding glycoprotein with potent angiogenic, mitogenic, and vascular permeability-enhancing activities specific for endothelial cells [12]. VEGF can also stimulate cell migration and inhibit apoptosis [13]. VEGF has been suggested to be important mediators for inflammation and during normal and pathological angiogenesis, a process that is associated with wound healing, embryonic development, and growth and metastasis of solid tumors [14]. Elevated levels of VEGF have been reported in synovial fluids of rheumatoid arthritis [15] and in sera from cancer patients [16, 17]. Several studies have shown that high serum levels of VEGF are associated with poor prognosis in cancer patients.

In the present study, to clarify whether VEGF is implicated in acute pancreatitis, serum VEGF concentrations were determined in patients with acute pancreatitis. Moreover, to clarify the role of VEGF in acute pancreatitis, effects of VEGF were investigated in experimental severe acute pancreatitis.

Section snippets

Clinical Study

Serum samples were obtained from 50 patients with acute pancreatitis in our department (35 males and 15 females) at the time of admission (within the initial 72 h after the onset of disease), and had been stored at −80°C until they were assayed. The diagnosis and evaluation of the severity of acute pancreatitis were made according to the criteria for clinical diagnosis and grading severity (1990) formulated by the Intractable Diseases of the Pancreas, Japanese Ministry of Health, Labor and

Serum VEGF Levels in Patients with Acute Pancreatitis

First, we investigated the serum VEGF levels in clinical pancreatitis. The mean value of serum VEGF levels in patients with acute pancreatitis was 358 ± 48 pg/ml, and was significantly higher than that in healthy volunteer (11 ± 3 pg/ml) (P < 0.05) (Fig. 1A). The mean value of serum VEGF levels in female patients (455 ± 72 pg/ml) was much higher than that in male patients (316 ± 61 pg/ml), though significant differences were not observed between two groups (Fig. 1A). Therefore, data analyses

Discussion

In this paper, we have shown for the first time that serum VEGF levels are significantly elevated in patients with acute pancreatitis and that VEGF is closely related to organ dysfunction in this disease. Moreover, the results obtained in rat experimental model suggest that VEGF may function as not a vascular permeability factor, but a protective factor against the organ injuries in severe acute pancreatitis. As the mechanism, it is conceivable that the protective effect of VEGF against hepatic

References (42)

  • L. Pertovaara et al.

    Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells

    J Biol Chem

    (1994)
  • B.I. Terman et al.

    Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor

    Biochem Biophys Res Commun

    (1992)
  • K. Miyamoto et al.

    Protective effect of vascular endothelial growth factor/vascular permeability factor 165 and 121 on glomerular endothelial cell injury in the rat

    Lab Invest

    (2004)
  • Y. Takeyama et al.

    Thymic atrophy caused by thymocyte apoptosis in experimental severe acute pancreatitis

    J Surg Res

    (1998)
  • Y. Takeyama et al.

    Peripheral lymphocyte reduction in severe acute pancreatitis is caused by apoptotic cell death

    J Gastrointest Surg

    (2000)
  • R. Isenmann et al.

    Early severe acute pancreatitisCharacteristics of a new subgroup

    Pancreas

    (2001)
  • A. Buter et al.

    Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis

    Br J Surg

    (2002)
  • Y. Takeyama

    Significance of apoptotic cell death in systemic complications with severe acute pancreatitis

    J Gastroenterol

    (2005)
  • D.R. Senger et al.

    Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid

    Science

    (1983)
  • N. Ferrara et al.

    The biology of vascular endothelial growth factor

    Endocr Rev

    (1997)
  • T. Alon et al.

    Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity

    Nat Med

    (1995)
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    This investigation was supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, and Grant-in-Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan.

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