Pancreatic and pulmonary mast cells activation during experimental acute pancreatitis.

AIM: To study the activation of pancreatic and pulmonary mast cells and the effect of mast cell inhibition on the activation of peritoneal and alveolar macrophages during acute pancreatitis. METHODS: Pancreatitis was induced by intraductal infusion of 5% sodium taurodeoxycholate in rats. The mast cell inhibitor cromolyn was administered intraperitoneally (i.p.) 30 min before pancreatitis induction. The pancreatic and pulmonary tissue damage was evaluated histologically and mast cells and their state of activation were evaluated. Peritoneal and alveolar macrophages were obtained and the expression of tumor necrosis factor alpha was determined. Myeloperoxidase activity was measured to evaluate the effect of mast cell inhibition on the progression of the inflammatory process. Finally, the effect of plasma on cultured mast cells or macrophages was evaluated in vitro. RESULTS: The mast cell stabilizer significantly reduced inflammation in the pancreas and lung and the activation of alveolar macrophages but had no effect on peritoneal macrophages. Mast cell degranulation was observed in the pancreas during pancreatitis but no changes were observed in the lung. Plasma from rats with pancreatitis could activate alveolar macrophages but did not induce degranulation of mast cells in vitro. CONCLUSION: Pancreatic mast cells play an important role in triggering the local and systemic inflammatory response in the early stages of acute pancreatitis. In contrast, lung mast cells are not directly involved in the inflammatory response related to pancreatic damage.

A polyamine analog bismethylspermine ameliorates severe pancreatitis induced by intraductal infusion of taurodeoxycholate.

BACKGROUND: Stable polyamine homeostasis is important for cell survival and regeneration. Our experimental studies have shown that catabolism of spermidine and spermine to putrescine is associated with the development of pancreatitis. We investigated the pathogenetic role of polyamine catabolism by studying the effect of a methylated polyamine analog on taurodeoxycholate-induced acute experimental pancreatitis. METHODS: Acute pancreatitis was induced by infusion of sodium taurodeoxycholate (2%) into the pancreatic duct. Bismethylspermine (Me(2)Spm) was administered as a pretreatment before the induction of pancreatitis or as a treatment after the induction of pancreatitis. The sham operation included laparotomy only. Pancreas tissue and blood were sampled at 24 h and 72 h after the infusion of taurodeoxycholate and studied for pancreatitis severity (serum amylase activity, pancreatic water content, and histology) and polyamine catabolism, which includes spermidine/spermine N(1)-acetyltransferase (SSAT) activity as well as spermidine, spermine, and putrescine concentrations in the pancreas. RESULTS: Sodium taurodeoxycholate-induced acute pancreatitis manifests as increases in serum amylase and pancreatic water content, leukocytosis, and acinar cell necrosis in the pancreas. The activity of SSAT increased significantly together with an increase in the ratios of pancreatic putrescine/spermidine and putrescine/spermine at 24 h, which indicates SSAT-induced polyamine catabolism. Pancreatic water content and necrosis were reduced significantly by the treatment with Me(2)Spm at 24 h but not at 72 h when the polyamine homeostasis had recovered, and the pancreatitis had progressed. CONCLUSIONS: Taurodeoxycholate-induced acute pancreatitis was associated with activation of polyamine catabolism in the pancreas. The polyamine analog Me(2)Spm ameliorated the injury in the early stage, but it did not ameliorate the late progression of the pancreatic necrosis at 72 h. Thus, besides proteolytic enzyme activation and the cascades of inflammation, polyamine catabolism may be an important pathogenetic mediator of the early stages of acute pancreatitis.

Role of mast cells in the development of pancreatitis-induced multiple organ dysfunction.

BACKGROUND: Activated mast cells can produce and release a number of inflammatory mediators involved in the pathophysiology of acute conditions. The aim of the present study was to evaluate the role of activated tissue mast cells in the pathogenesis of multiple organ dysfunction syndrome following acute pancreatitis (AP). METHODS: AP was induced by the intraductal infusion of 5 per cent sodium taurodeoxycholate in the rat. Some 30 min before induction of AP, a mast cell stabilizer (sodium cromoglycate (SCG)) or antihistamines (pyrilamine, cyproheptadine, meclizine and amitriptyline) were administered intra peritoneally. Plasma exudation of radiolabelled albumin, histamine, myeloperoxidase (MPO), monocyte chemoattractant protein (MCP) 1 and adhesion molecules (platelet endothelial cell adhesion molecule (PECAM) 1 and L-selectin) were measured. RESULTS: The mast cell stabilizer significantly reduced plasma exudation in the pancreas, colon and lungs (P < 0.05), decreased the release of histamine at 1 h (P < 0.05), and reduced MPO activity and MCP-1 levels in the colon and lungs (P < 0.05) but not in the pancreas. Expression of PECAM-1 and L-selectin on total circulating leucocytes in rats with AP and SCG pretreatment did not differ from that in sham controls, while levels in animals that had AP and saline pretreatment were half of those seen following sham operation. CONCLUSION: Activation of mast cells after induction of AP is involved in the development of endothelial barrier dysfunction in both the pancreas and extrapancreatic organs/tissues, particularly in the lungs and colon. This may, at least partly, contribute to the sequential development of multiple organ dysfunction and organ/tissue-specific endothelial barrier dysfunction.

[Interrelationship of reflux bile acid concentration and the gastric mucosal change with reference to the pathophysiologic significance of taurine conjugated deoxycholic acid and chenodeoxycholic acid].

Since chronic gastritis is adversely affected by reflux bile acids, we are interested in which of these bile acids cause the most damage to the gastric mucosa as ulcerogenic factors in the stomach. We examined 34 patients suffering from the peptic ulcers, and have assumed that taurine conjugated deoxycholic acid (TDC) and chenodeoxycholic acid (TCDC) may act as the mst ulcerogenic factors. Moreover TCDC was suggested to be associated with the cystic dilatation of the gastric gland. It was also suggested that TDC is involved in the increased frequency of intestinal metaplasia as a factor backgrounding cancer.

[Taurodeoxycholic acid in the treatment of primary biliary cirrhosis. A controlled study in comparison to ursodeoxycholic acid]. / L'acido tauroursodesossicolico nel trattamento della cirrosi biliare primitiva. Studio controllato in confronto ad acido ursodesossicolico.

Thirty patients with primary biliary cirrhosis were enrolled; 25 completed the study period (6 months). Of these, 12 were randomised to TUDCA treatment and 13 to UDCA. Dosage range 12-15 mg/kg daily for both groups which were comparable at to age, sex, duration and stage of the disease, as well as for all liver laboratory tests. Altogether, the results obtained were satisfactory in both groups. What was surprising was that clinical experience failed to confirm the greater efficacy of TUDCA compared to UDCA. On the contrary, UDCA appeared to be more effective than TUDCA in improving liver function (even significantly so as far as GGT was concerned). Also with regard to tolerability, UDCA was definitely superior to TUDCA.

Alkaline esophagitis: a comparison of the ability of components of gastroduodenal contents to injure the rabbit esophagus.

Esophagitis is now recognized to occur in the absence of gastric acid. We have compared the potentially injurious effect of physiologic concentrations of trypsin, taurodeoxycholate, and pepsin at pH 7.5 using a continuously perfused rabbit esophagus model. Gross and microscopic esophagitis, tissue hemorrhage, and indexes of esophageal mucosal barrier function were assessed. Trypsin caused the most severe morphologic changes and hemorrhage, but only minimal disruption of the esophageal mucosal barrier. In contrast, taurodeoxycholate caused only minimal esophagitis and no hemorrhage, but caused extensive disruption of the esophageal mucosal barrier. Neither pepsin, at this alkaline pH, nor alkaline test solution alone (pH 7.5) caused esophageal injury by any criteria. These results show that the degree of esophageal mucosal barrier disruption cannot always be equated with the degree of morphologic injury, and that different components of the gastroduodenal contents may differ in their sites or mechanisms of esophageal injury. Finally, among the gastroduodenal contents we tested, trypsin was the most noxious agent in alkaline reflux esophagitis in terms of causing mucosal erosion, inflammation, and hemorrhage.

Differing ulcerogenic potential of dihydroxy and trihydroxy bile acids in canine gastric mucosa.

Although recent clinical reports suggest that greater than normal amounts of dihydroxy secondary bile acids appear in the gastric content of patients with postoperative alkaline reflux gastritis, the pathophysiologic significance of these observations is unclear. We addressed this problem by usiong chambered ex vivo wedges of proximal canine gastric wall. The effects of 1 and 2 mM concentrations of the dihydroxy secondary bile acid, taurodeoxycholic, were compared with those of its parent trihydroxy primary bile acid, taurocholic. The parameters of mucosal function evaluated included the net flux of hydrogen ion, the transmural electrical potential difference, mucosal blood flow determined by radiolabeled microsphere embolization, and the severity of mucosal damage induced in mucosa rendered ischemic by wedge-specific intra-arterial low-dose vasopressin infusin. The results indicate that at each concentration in both ischemic and nonischemic mucosa the dihydroxy secondary bile acid induced a greater depression in potential difference, a more profound increase in mucosal permeability to hydrogen ion, and in ischemic mucosa a more severe degree of gross mucosal damage than did the trihydroxy primary bile acid. These effects may be related to a greater lipid solubility and consequent capacity to disrupt cell membranes.

The effect of antacids on the occurrence of bile acid and aspirin-induced gastric lesions in rats.

Taurodeoxycholic acid increases the incidence of aspirin induced gastric bleeding in rats and in vitro is well bound by Aludrox (aluminium hydroxide) and poorly bound by Maalox (aluminium hydroxide and magnesium hydroxide). We studied the relevance of this binding, as demonstrated in vitro, by observing the effect of the antacids on the occurrence of taurodeoxycholic acid and aspirin-induced bleeding in vivo in rats. Six groups of fasting male Sprague-Dawley rats (n = 24) were intubated and given either water, Aludrox or Maalox and, 30 min later, aspirin or aspirin plus taurodeoxycholic acid. 4 h later the stomachs were examined and rats were scored positive if a lesion greater than 1 mm across was found (incidence of bleeding); a lesion scoring system was also used (severity of bleeding). The incidence of bleeding was increased from 63% with aspirin to 92% with aspirin plus taurodeoxycholic acid (P less than 0.05). The incidence was reduced to 33% and 67% respectively by Aludrox and to 29% (P less than 0.05) and 71% by Maalox. The severity of bleeding (median lesion score, quartiles in parentheses) was increased from 3 (1;6.5) (aspirin) to 10.5 (6;15) (aspirin plus taurodeoxycholic acid); P less than 0.001. These were reduced to 0.5 (0;3); P less than 0.02 and 5 (0.5;9.5); P less than 0.05 respectively by Aludrox and to 0 (0;3); P less than 0.02 and 3 (2;8); P less than 0.02 by Maalox. The severity of bleeding was reduced by both antacids but the effect appeared to be mainly on the aspirin rather than the bile acid component of the damage.