GastrointestinalVascular Endothelial Growth Factor Increases in Serum and Protects Against the Organ Injuries in Severe Acute Pancreatitis1
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
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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.