Effect of the microtubule-disrupting drug colchicine on rat cerulein-induced pancreatitis in comparison with the microtubule stabilizer taxol.

Effects of colchicine, a microtubule-disrupting agent, on rate exocrine pancreas were examined in comparison with the microtubule stabilizer Taxol for the purpose of analyzing the pathogenesis of cerulein-induced acute pancreatitis. Taxol ameliorated the inhibition of pancreatic secretion, elevation of serum amylase level, pancreatic edema, and histological alterations induced by supramaximal cerulein stimulation. In contrast, colchicine by itself and colchicine followed by cerulein stimulation (maximal and supramaximal) inhibited pancreatic secretion but did not induce the hyperamylasemia, pancreatic edema, or formation of large vacuoles, which characterized cerulein-induced pancreatitis. Electron microscopic studies in the colchicine-treated rats revealed that transport vesicles were accumulated in the supranuclear region and that no large vacuoles were observed in the apical lesion. Immunofluorescence studies confirmed that colchicine inhibited pancreatic secretion and disrupted the arrangement of microtubules. Posttreatment of colchicine did not prevent the development of cerulein-induced pancreatitis. Vinblastine, another microtubule-disrupting drug, as well as colchicine, inhibited pancreatic secretion but did not induce acute pancreatitis. The results obtained in this study suggest that microtubule disorganization at a specific step in the process of intracellular vesicular transport causes cerulein-induced pancreatitis and that this step is more apical than that at which colchicine inhibits secretion in the pancreatic acinar cell.

Significant elevation of serum human hepatocyte growth factor levels in patients with acute pancreatitis.

Serum levels of human hepatocyte growth factor (HGF) were determined in 38 patients with acute pancreatitis by an enzyme-linked immunosorbent assay. The mean value of serum HGF levels on admission in the 38 patients was 1.69 +/- 0.40 (SEM) ng/ml. In 35 patients, serum HGF levels were found to be positive (> 0.39 ng/ml), with an incidence of 92.1%. In 17 patients, they were > 1.0 ng/ml, which was the cutoff value for fulminant hepatic failure. Serum HGF levels in the patients with severe acute pancreatitis (2.30 +/- 0.61 ng/ml; mean +/- SEM) were significantly higher than those in the patients with mild and moderate acute pancreatitis (0.63 +/- 0.06 ng/ml). Sixteen of seventeen patients whose serum HGF levels were > 1.0 ng/ml were evaluated as severe acute pancreatitis. Serum HGF levels were significantly elevated in the patients with higher Ranson scores, higher APACHE II scores, or higher computed tomography grades. Serum HGF levels in the patients with organ dysfunction (liver, kidney, or lung) were significantly higher than those in the patients without organ dysfunction. Moreover, serum HGF levels on admission in the nonsurvivors (3.17 +/- 1.30 ng/ml) were significantly higher than those in the survivors (1.22 +/- 0.33 ng/ml). The mortality rate of the patients showing serum HGF levels > 2.0 ng/ml on admission was 50%. In the patients with a lethal outcome, the mean serum HGF level remained constantly > 2.50 ng/ml during hospitalization. The serum HGF level reflected the clinical course of the disease rapidly and distinctly. Serum HGF levels increased with complications such as organ failure, infected pancreatic necrosis, and sepsis and decreased with successful intensive and surgical treatments. These results suggest that serum human HGF levels may reflect the severity, organ dysfunction, and prognosis in acute pancreatitis.

[A case of gastric cancer with multiple bone metastasis treated by nocturnal 5-fluorouracil infusion combined with pamidronate].

Nocturnal infusion of 5-fluorouracil (5-FU) combined with pamidronate was performed in a 62-year-old male gastric cancer patient with multiple bone metastasis. The patient was administered 500 mg of 5-FU five days a week continuously for 10 hours per day from 21 o'clock to 7 o'clock for 5 months. In addition to 5-FU, 45 mg of pamidronate was administered intravenously every two weeks. Remarkable sclerotic changes were shown during the treatment in the bone metastatic foci, and the range of motion was enlarged. Serum levels of CEA and CA19-9 were decreased to the normal levels. There were no serious side effects such as myelosuppression, diarrhea or palmo-plantar dermatitis. This combination therapy of nocturnal infusion of 5-FU with pamidronate was considered effective for gastric cancer in patients with multiple bone metastasis without serious side effects.

[Activation of peritoneal macrophages in rats with caerulein-induced pancreatitis].

We examined the stimulatory state of peritoneal macrophages (M phi) in caerulein-induced pancreatitis. Edematous pancreatitis was developed by the intravenous continuous injection of caerulein (5 micrograms/kg/hr) for 4 hr. Thereafter peritoneal M phi were collected and the activity for free radical production was measured by the reduction of nitro blue tetrazorium in the presence of phorbol myristate acetate. The increase in free radical production reached a statistical significance at 12 hr and a maximum at 20 hr after the beginning of caerulein infusion. These results suggested that the peritoneal M phi are activated even in mild edematous pancreatitis, and that their activation is involved into the mechanism of the development of remote organ failure in acute pancreatitis.

[Possible involvement of activation of pulmonary macrophages in respiratory failure with acute pancreatitis].

We examined the stimulatory state of pulmonary macrophages (Mø) in rats with caerulein-induced pancreatitis by measuring their activity for free radical production in vitro and in situ using nitroblue tetrazolium (NBT) under treatment of phorbol myristate acetate. The Mø from bronchoalveolar lavage were significantly activated 24 h after caerulein administration. The lung perfusion with NBT in the presence of PMA confirmed in situ that pulmonary Mø were also significantly activated in the same condition. Thereafter significant hypoxia was observed. These results indicate that the activation of pulmonary Mø may be involved in the respiratory failure in acute pancreatitis.