Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute necrotizing pancreatitis induced by infusion of bile salt into the pancreatic duct in rats is consistently associated with acute lung injury similar to the adult respiratory distress syndrome. The role of platelet-activating factor (PAF) in this pancreatitis-associated remote organ failure (lung injury) was investigated. Pulmonary tissue levels of PAF were increased gradually and reached a level of 1345 +/- 455 pg/g (6 times the control level) at 12 hours after induction of pancreatitis, whereas pancreatic PAF levels were undetectable and blood PAF remained unchanged. This local pulmonary PAF accumulation occurred at approximately the same time as the progression of lung injury. Pulmonary responses detected (i.e., eicosanoid production, leukocytic infiltration, Evan's blue extravasation, beta-glucuronidase release) were attenuated to varying degrees by treatment of rats in which pancreatitis was initiated with the PAF receptor antagonists (WEB2170 and BN52021). Rat lung lavages were examined after a 12-hour course of pancreatitis and no changes in PAF concentration, surfactant content, and phospholipase A2 (PLA2) activity were noted. Intravenous administration of PLA2 promoted pulmonary PAF production in experimental rats with pancreatitis but not in normal rats. This observation indicates that PLA2, which was determined to be elevated in plasma during pancreatitis, may be responsible for the accumulation of PAF in the lung. In conclusion, pancreatitis-associated lung injury appears to result from an endogenous inflammatory response in which PAF may play an important role.
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PMID:Role of platelet-activating factor in pancreatitis-associated acute lung injury in the rat. 156 55

In the present study we demonstrated that a single injection of endotoxin (lipopolysaccharides, E. Coli 0111-B4) into the superior pancreaticoduodenal artery of rabbits induced a dose-dependent acute necrotizing pancreatitis. The lesions observed by light microscopy were significant for 10 micrograms lipopolysaccharides and were maximal for 20 micrograms. After 24 h the main findings were edema, acinar cell vacuolisation, polymorphonuclear neutrophil infiltration and tissue necrosis. The pancreatic lesions developed strictly in the area supplied by the artery injected with lipopolysaccharides, without significant intestinal involvement. Since platelet-activating factor (1-O-hexadecyl-2-acetyl-sn-glycero-3- phosphocholine, PAF; 50-500 ng), a phospholipid mediator of endotoxin-induced inflammation and shock, was previously shown to cause an acute necrotizing pancreatitis in rabbits, the role of PAF in the development of acute pancreatitis induced by lipopolysaccharides was studied by evaluating: (1) the synergism between doses of lipopolysaccharides (5-10 micrograms), which produced a mild tissue injury, and doses of PAF (10 ng) not producing, per se, any significant injury, and (2) the effect of three structurally unrelated PAF receptor antagonists. The results obtained demonstrated that 10 ng of PAF significantly potentiated pancreatic tissue damage induced by 10 micrograms of lipopolysaccharides.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of platelet activating factor in acute pancreatitis induced by lipopolysaccharides in rabbits. 781 47

The effect of a potent platelet-activating factor (PAF) antagonist, BB-882, on an experimental model of acute pancreatitis induced in male Wistar rats by a technique of microvascular ischaemia was studied. A single intraperitoneal injection of BB-882 (5 mg/kg) 30 min after induction of the disease in 12 animals significantly reduced (P < 0.001) the rise in the level of serum amylase (mean 2477 (range 2100-3280) units/l) compared with that in 12 control animals (mean 3928 (range 2800-5900) units/l) and significantly improved (P < 0.001) the mean pancreatic histology score (5.0 (range 3-10) versus 12.3 (range 8-18) in controls). PAF is a biologically active ether phosphorylcholine synthesized in cell membranes and a potent inflammatory mediator. Pancreatic tissue levels of this compound are increased in experimental acute pancreatitis and pretreatment with PAF receptor antagonists can ameliorate the progression of this disease. BB-882 alters the early course of experimental pancreatitis and may have a clinical therapeutic role.
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PMID:Amelioration of experimental acute pancreatitis with a potent platelet-activating factor antagonist. 782 39

Hyperstimulation of the exocrine pancreas with cerulein causes acute pancreatitis, characterized by intensive interstitial edema, acinar vacuolization, leukocytic infiltration, and hyperamylasemia. Whereas the pathogenesis of cerulein-induced pancreatitis is not well-defined, a local inflammatory response may contribute to the full expression of acute pancreatitis. Platelet-activating factor (PAF) seems to be an important mediator of the inflammatory response. The present evidence includes: 1) pancreatic PAF levels increased in rats in which cerulein-induced pancreatitis was initiated, concomitant with an increase in calcium concentrations in the pancreatic tissue; 2) treatment of rats exposed to cerulein with WEB2170, a PAF receptor antagonist, was shown to reduce inflammatory injury, as demonstrated by decreases in pancreatic weight, Evan's blue extravasation, and myeloperoxidase activity and an improvement in pancreatic histology. In an idealized in vitro experiment mimicking cerulein-induced acute pancreatitis, in which pancreatic acini were employed, cerulein induced amylase release, an increase in [Ca2+]i, and an increase in PAF synthesis. Whereas amylase release was induced by low concentrations of cerulein (10(-11) mol/L), relatively high concentrations of cerulein (10(-9) mol/L) were required for the observed increases in PAF synthesis and the [Ca2+]i, indicating that these two responses may not occur under physiological conditions. The present study suggests that the pancreatic accumulation of PAF coupled with Ca2+ overload are important biochemical components of the pathophysiology of cerulein-induced acute pancreatitis. In fact, PAF production may serve as a primary mediator of inflammation observed during pancreatic hyperstimulation. This is an important observation that will allow a more detailed characterization of the molecular basis of cerulein-induced acute pancreatitis.
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PMID:Platelet-activating factor: a mediator of pancreatic inflammation during cerulein hyperstimulation. 849 49

The inhibitory effects of YM264, a selective platelet activating factor (PAF) receptor antagonist, and 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-( 3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, on mortality, and pancreatic, hepatic, renal and pulmonary dysfunction were evaluated in a rat model of multiple organ failure (MOF) accompanying acute pancreatitis. MOF was produced by intraperitoneal injection of lipopolysaccharide (LPS, 30 mg/kg) in rats with cerulein-induced pancreatitis. LPS dose-dependently increased the mortality in rats with or without pancreatitis. The threshold dose which produced death in rats without pancreatitis was 30 mg/kg. This same dose evoked death in more than 40% of rats with pancreatitis. Time-course changes in serum enzyme and organ myeloperoxidase (MPO) levels were first examined in rats with induced MOF, and the results were compared with those in rats treated with only LPS or cerulein. Pancreatic weight, and serum amylase and lipase levels significantly increased in rats with cerulein-induced pancreatitis despite the presence or absence of LPS, but recovery of these pancreatic dysfunctions was slower in the group given LPS. However, serum GOT, GPT, BUN and creatinine levels were significantly elevated only in MOF rats. In the MOF rats, the MPO level in the lung was significantly elevated and arterial oxygen pressure was decreased, indicating that infiltration of neutrophils into the lung might be involved in pulmonary dysfunction. However, the MPO levels in the pancreas and kidney in the MOF rats were not remarkably different from those in normal rats. The inhibitory effects of YM264 and compound 1 on mortality and organ dysfunction were examined in this MOF model. The 24-h survival rate for rats prophylactically and therapeutically treated with an intravenous infusion of YM264 at 0.1 mg/kg h was significantly higher than that of controls. The 24-h survival rate for rats treated prophylactically by intravenous infusion of 2 mg/kg h of compound 1 was significantly higher than that of control, whereas a beneficial dose of compound 1 was 5 mg/kg h in therapeutically treated rats. Prophylactic treatment with YM264 (0.1 mg/kg h) and compound 1 (2 mg/kg h) ameliorated organ dysfunction in rats with MOF. In conclusion, pancreatic, hepatic, renal and pulmonary dysfunctions are observed in this rat MOF model. The PAF receptor antagonist and neutrophil elastase inhibitor reduce the mortality rate in rats with MOF due to their inhibitory effects on organ dysfunction, indicating that PAF and neutrophil elastase may play important roles in the development of MOF. These results in the present model are largely consistent with those in patients with MOF, indicating that this model is suited for MOF in humans and may be used as a model to test new therapeutic approaches.
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PMID:Protective effects of a PAF receptor antagonist and a neutrophil elastase inhibitor on multiple organ failure induced by cerulein plus lipopolysaccharide in rats. 975 12

17 Beagle's dogs were divided randomly into tree groups: pancreatitis group (PG, n = 6), pan+BN52021 group (BNG, n = 6), control group (CG, n = 5). The acute pancreatitic model of PG and BNG was established by injecting sodium taurocholate and trypsin into the main pancreatic duct. Animals of BNG were injected PAF receptor antagonist BN52021 (5 ml/kg) intravenously 5 minutes and 3 hours respectively after acute pancreatitis induction. Blood amylase activity was determined by Winslow's method. PAF in blood and pancreatic tissue was determined by the platelet accumulation method. Blood amylase activity of PG increased by 466.7 +/- 111.6 than the baseline at 8 hours and increased significantly than that of BNG and CG (P < 0.05). Blood PAF level of PG increased from 30 minutes to 11.81 +/- 0.78 ng/ml at 8 hours. BN52021 inhibited very significantly the increase of PAF level (P < 0.01). PAF level in pancreatic tissue of PG was significantly higher than that of BNG and CG (P < 0.01). PAF may play an important role in early acute pancreatitis.
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PMID:[The role of platelet activating factor in pathogenesis of acute pancreatitis in dogs]. 1037 89

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator that belongs to a family of biologically active, structurally related alkyl phosphoglycerides with diverse pathological and physiological effects. This bioactive phospholipid mediates processes as diverse as wound healing, physiological inflammation, angiogenesis, apoptosis, reproduction and long-term potentiation. PAF acts by binding to a specific G protein-coupled receptor to activate multiple intracellular signaling pathways. Since most cells both synthesize and release PAF and express PAF receptors, PAF has potent biological actions in a broad range of cell types and tissues. Inappropriate activation of this signaling pathway is associated with many diseases in which inflammation is thought to be one of the underlying features. Acute pancreatitis (AP) is a common inflammatory disease. The onset of AP is pancreatic autodigestion mediated by abnormal activation of pancreatic enzyme caused by multiple agents, which subsequently induce pancreatic and systemic inflammatory reactions. A number of experimental pancreatitis and clinical trials indicate that PAF does play a critical role in the pathogenesis of AP. Administration of PAF receptor antagonist can significantly reduce local and systemic events that occur in AP. This review focuses on the aspects that are more relevant to the pathogenesis of AP.
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PMID:Role of platelet-activating factor in the pathogenesis of acute pancreatitis. 1648 65