AIM:To establish a one-stage model of experimental acute necrotizing pancreatitis(ANP)in rats characterized by the simplicity of performance and a high degree of repeatability.METHODS:ANP modeling in rats was performe...AIM:To establish a one-stage model of experimental acute necrotizing pancreatitis(ANP)in rats characterized by the simplicity of performance and a high degree of repeatability.METHODS:ANP modeling in rats was performed based on modification of the ligation model as follows:synthetic material ligature using an atraumatic needle was performed to capture pancreatic gland ducts and marginal duodenum vessels.Ligature tips were exteriorized to the abdominal wall,and the ligature was skinned over to avoid catching intestine loops.Pancreatic macroscopic appearance and histological changes were observed.Blood biochemical and hemostatic indicators were also determined.RESULTS:Laboratory analysis of rats with experimental ANP showed a pattern of disturbances similar to that observed during pancreatic necrosis in humans as soon as the first day.General blood analysis revealed enhanced leukocytosis and alterations in leukogram characteristics,indicating acute inflammation.Serum levels of amylase,aspartate aminotransferase and creatinine significantly increased(P<0.05).Hemostatic indicators showed alterations indicating formation of disseminated intravascular coagulation,and signs of endotoxicosis were observed.These typical pancreatic necrosis patterns of disturbances were validated by the results of histological investigation.CONCLUSION:Histological changes and laboratory indicators confirm the development of a suitable model of ANP.展开更多
AIM: To study the influence and mechanisms of dexamethasone on mesenteric lymph node of rats with severe acute pancreatitis (SAP). METHODS: The SAP rats were assigned to model, treated or sham-operated groups. The mor...AIM: To study the influence and mechanisms of dexamethasone on mesenteric lymph node of rats with severe acute pancreatitis (SAP). METHODS: The SAP rats were assigned to model, treated or sham-operated groups. The mortality, pathological changes of mesenteric lymph nodes, expression levels of NF-kB, P-selectin, Bax, Bcl-2 and caspase-3 protein and changes in apoptotic indexes in lymph nodes were observed at 3, 6 and 12 h after operation. The blood levels of endotoxin, superoxide dismutase (SOD), malondialdehyde (MDA), and endothelin-1 (ET-1) in blood were determined. RESULTS: SOD content, expression of Bax protein and apoptotic index were significantly higher in the treated group than in the model group at different time points (P < 0.05 or P < 0.01). Other blood-detecting indexes and histopathological scores of mesenteric lymphnodes were lower in the treated than in the model group (P < 0.05, P < 0.01 or P < 0.01). NF-kB protein expression was negative in all groups. Comparing P-selectin and caspase-3 expression levels among all three groups, there was no marked difference between the model and treated group. CONCLUSION: Dexamethasone can protect mesen-teric lymph nodes. The mechanism may be by reducing the content of inflammatory mediators in the blood and inducing lymphocyte apoptosis.展开更多
AIM:In previous experiments we have demonstrated that by administering low doses of cholecystokinin-octapeptide (CCK-8),the process of regeneration following L-arginine (Arg)-induced pancreatitis is accelerated.In rat...AIM:In previous experiments we have demonstrated that by administering low doses of cholecystokinin-octapeptide (CCK-8),the process of regeneration following L-arginine (Arg)-induced pancreatitis is accelerated.In rats that were also diabetic(induced by streptozotocin,STZ),pancreatic regeneration was not observed.The aim of this study was to deduce whether the administration of exogenous insulin could in fact restore the hypertrophic effect of CCK-8 in diabetic-pancreatitic rats. METHODS:Male Wistar rats were used for the experiments. Diabetes mellitus was induced by administering 60mg/kg body mass of STZ intraperitoneally(i.p.),then,on d 8, pancreatitis was induced by 200mg/100 g body mass Arg i.p.twice at an interval of 1 h.The animals were injected subcutaneously twice daily(at 7 a.m.and 7 p.m.)with 1 μg/kg of CCK-8 and/or 2 IU mixed insulin(300g/L short- action and 700g/L intermediate-action insulin) for 14 d after pancreatitis induction.Following this the animals were killed and the serum amylase,glucose and insulin levels as well as the plasma glucagon levels,the pancreatic mass/body mass ratio(pm/bm),the pancreatic contents of DNA,protein,amylase,lipase and trypsinogen were measured.Pancreatic tissue samples were examined by light microscopy on paraffin-embedded sections. RESULTS:In the diabetic-pancreatitic rats treatment with insulin and CCK-8 significantly elevated pw/bm and the pancreatic contents of protein,amylase and lipase vs the rats receiving only CCK-8 treatment.CCK-8 administered in combination with insulin also elevated the number of acinar cells with mitotic activities,whereas CCK-8 alone had no effect on laboratory parameters or the mitotic activities in diabetic-pancreatitic rats. CONCLUSION:Despite the hypertrophic effect of CCK-8 being absent following acute pancreatitis in diabetic-rats, the simultaneous administration of exogenous insulin restored this effect.Our results clearly demonstrate that insulin is necessary for the hypertrophic effect of low-doses of CCK-8 following acute pancreatitis.展开更多
The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (...The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against Post Endoscopic retrograde cholangiopancreatography Pancreatitis (PEP). The protease inhibitor Gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL) is a nitrogen oxide (NO) donor, which relaxes the sphincter of Oddi. Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted. Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials. The non-steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results. Antibodies against tumor necrosis factor-alpha (TNF-α) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta- lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted.展开更多
AIM: To examine the role of p38 during acute experimental cerulein pancreatitis. METHODS: Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347) and/or a specific p38 inhibitor (SB203580) a...AIM: To examine the role of p38 during acute experimental cerulein pancreatitis. METHODS: Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347) and/or a specific p38 inhibitor (SB203580) and pancreatic stress kinase activity was determined. Parameters to assess pancreatitis included trypsin, amylase, lipase, pancreatic weight and histology. RESULTS: JNK inhibition with CEP1347 ameliorated pancreatitis, reducing pancreatic edema. In contrast, p38 inhibition with SB203580 aggravated pancreatitis with higher trypsin levels and, with induction of acinar necrosis not normally found after cerulein hyperstimulation. Simultaneous treatment with both CEP1347 and SB203580 mutually abolished the effects of either compound on cerulein pancreatitis. CONCLUSION: Stress kinases modulate pancreatitis differentially. JNK seems to promote pancreatitis development, possibly by supporting inflammatory reactions such as edema formation while its inhibition ameliorates pancreatitis. In contrast, p38 may help reduce organ destruction while inhibition of p38 during induction of cerulein pancreatitis leads to the occurrence of acinar necrosis.展开更多
OBJECTIVE: To explore the effect and the mechanism of Chaiqinchengqi decoction(CQCQD) on the apoptosis-necrosis switch of pancreatic acinar cells in acute necrotizing pancreatitis(ANP) in rats.METHODS: Sixty Sprague-D...OBJECTIVE: To explore the effect and the mechanism of Chaiqinchengqi decoction(CQCQD) on the apoptosis-necrosis switch of pancreatic acinar cells in acute necrotizing pancreatitis(ANP) in rats.METHODS: Sixty Sprague-Dawley rats were randomized into the control group, the ANP group and the CQCQD group. The acute pancreatitis(AP)model was induced by intraperitoneal injections of4 g/kg 8% L-Arginine(PH 7.0) twice with a 1 h interval. Rats in the CQCQD group were intragastrically administered CQCQD(20 mL/kg every 2 h, 3 times,then 20 mL/kg every 6 h, 3 times). Rats were killed at the 6 and 24 h after the induction of AP.The pancreatic tissues were collected for pathology and to isolate pancreatic acinar cells and mitochondria.RESULTS: CQCQD significantly ameliorated the severity of ANP by reducing the pancreatic histopathology score, indicated by lactate dehydrogenase levels at the 6 and 24 h. The CQCQD group promoted the apoptosis of pancreatic acinar cells by raising the apoptosis index compared with the ANP group and the control group. Mitochondrial cytochrome c at the 6 and 24 h in the ANP group were lower than that in the control group or the CQCQD group(0.67±0.13 vs 1.54±0.03 vs 0.81±0.09; 0.71±0.08 vs 1.55±0.09 vs 0.89±0.16, P<0.01). The cytochrome c levels in the cytoplasm at the 6 and 2 h in the CQCQD group were higher than in the control group(1.36±0.15 vs 0.67±0.04, 1.46±0.08 vs 0.59±0.09, P<0.01), or the ANP group(0.96±0.13, P>0.05;0.97±0.09, P<0.05). CQCQD increased caspase-3 activity over the ANP group at the 6 h.CONCLUSION: CQCQD can induce apoptosis and relieve the necrosis of pancreatic acinar cells via promoting the release of mitochondrial cytochrome c and increasing pancreatic caspase-3 activity in ANP rats.展开更多
Acute necrotising pancreatitis is characterized by inflammatory and necrotic events, which followthe initial intra-acinar injury involving enzyme activation, and disruption of the acinar cytoskeleton. At present, apo...Acute necrotising pancreatitis is characterized by inflammatory and necrotic events, which followthe initial intra-acinar injury involving enzyme activation, and disruption of the acinar cytoskeleton. At present, apoptosis has become a hot topic in many kinds of disease. Bax and Bcl-2 are the important control gene during cell apoptosis. 2 Previous study has shown that interleukin 10 （IL-10） is a kind of important antiinflammatory cytokine and plays a role of selfdefense mechanism,展开更多
基金Supported by a Special Research Grant for interdisciplinary projects between the Institute of Immunology and Physiology and the Institute of Organic Synthesis,the Ural Branch of Russian Academy of Sciences(2009-2012)
文摘AIM:To establish a one-stage model of experimental acute necrotizing pancreatitis(ANP)in rats characterized by the simplicity of performance and a high degree of repeatability.METHODS:ANP modeling in rats was performed based on modification of the ligation model as follows:synthetic material ligature using an atraumatic needle was performed to capture pancreatic gland ducts and marginal duodenum vessels.Ligature tips were exteriorized to the abdominal wall,and the ligature was skinned over to avoid catching intestine loops.Pancreatic macroscopic appearance and histological changes were observed.Blood biochemical and hemostatic indicators were also determined.RESULTS:Laboratory analysis of rats with experimental ANP showed a pattern of disturbances similar to that observed during pancreatic necrosis in humans as soon as the first day.General blood analysis revealed enhanced leukocytosis and alterations in leukogram characteristics,indicating acute inflammation.Serum levels of amylase,aspartate aminotransferase and creatinine significantly increased(P<0.05).Hemostatic indicators showed alterations indicating formation of disseminated intravascular coagulation,and signs of endotoxicosis were observed.These typical pancreatic necrosis patterns of disturbances were validated by the results of histological investigation.CONCLUSION:Histological changes and laboratory indicators confirm the development of a suitable model of ANP.
基金Technological Foundation Project of Traditional Chinese Medicine Science of Zhejiang Province, No. 2003C130 and No. 2004C142Foundation Project for Medical Science and Technology of Zhejiang Province, No. 2003B134+5 种基金Grave Foundation Project for Technological and Development of Hangzhou, No. 2003123B19Intensive Foundation Project for Technology of Hangzhou No. 2004Z006Foundation Project for Medical Science and Technology of Hangzhou No. 2003A004Foundation Project for Technology of Hangzhou, No. 2005224
文摘AIM: To study the influence and mechanisms of dexamethasone on mesenteric lymph node of rats with severe acute pancreatitis (SAP). METHODS: The SAP rats were assigned to model, treated or sham-operated groups. The mortality, pathological changes of mesenteric lymph nodes, expression levels of NF-kB, P-selectin, Bax, Bcl-2 and caspase-3 protein and changes in apoptotic indexes in lymph nodes were observed at 3, 6 and 12 h after operation. The blood levels of endotoxin, superoxide dismutase (SOD), malondialdehyde (MDA), and endothelin-1 (ET-1) in blood were determined. RESULTS: SOD content, expression of Bax protein and apoptotic index were significantly higher in the treated group than in the model group at different time points (P < 0.05 or P < 0.01). Other blood-detecting indexes and histopathological scores of mesenteric lymphnodes were lower in the treated than in the model group (P < 0.05, P < 0.01 or P < 0.01). NF-kB protein expression was negative in all groups. Comparing P-selectin and caspase-3 expression levels among all three groups, there was no marked difference between the model and treated group. CONCLUSION: Dexamethasone can protect mesen-teric lymph nodes. The mechanism may be by reducing the content of inflammatory mediators in the blood and inducing lymphocyte apoptosis.
基金Supported by The Wellcome Trust Grant No.022618,and by the Hungarian Scientific Research Fund D42188,T43066 and T042589
文摘AIM:In previous experiments we have demonstrated that by administering low doses of cholecystokinin-octapeptide (CCK-8),the process of regeneration following L-arginine (Arg)-induced pancreatitis is accelerated.In rats that were also diabetic(induced by streptozotocin,STZ),pancreatic regeneration was not observed.The aim of this study was to deduce whether the administration of exogenous insulin could in fact restore the hypertrophic effect of CCK-8 in diabetic-pancreatitic rats. METHODS:Male Wistar rats were used for the experiments. Diabetes mellitus was induced by administering 60mg/kg body mass of STZ intraperitoneally(i.p.),then,on d 8, pancreatitis was induced by 200mg/100 g body mass Arg i.p.twice at an interval of 1 h.The animals were injected subcutaneously twice daily(at 7 a.m.and 7 p.m.)with 1 μg/kg of CCK-8 and/or 2 IU mixed insulin(300g/L short- action and 700g/L intermediate-action insulin) for 14 d after pancreatitis induction.Following this the animals were killed and the serum amylase,glucose and insulin levels as well as the plasma glucagon levels,the pancreatic mass/body mass ratio(pm/bm),the pancreatic contents of DNA,protein,amylase,lipase and trypsinogen were measured.Pancreatic tissue samples were examined by light microscopy on paraffin-embedded sections. RESULTS:In the diabetic-pancreatitic rats treatment with insulin and CCK-8 significantly elevated pw/bm and the pancreatic contents of protein,amylase and lipase vs the rats receiving only CCK-8 treatment.CCK-8 administered in combination with insulin also elevated the number of acinar cells with mitotic activities,whereas CCK-8 alone had no effect on laboratory parameters or the mitotic activities in diabetic-pancreatitic rats. CONCLUSION:Despite the hypertrophic effect of CCK-8 being absent following acute pancreatitis in diabetic-rats, the simultaneous administration of exogenous insulin restored this effect.Our results clearly demonstrate that insulin is necessary for the hypertrophic effect of low-doses of CCK-8 following acute pancreatitis.
文摘The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against Post Endoscopic retrograde cholangiopancreatography Pancreatitis (PEP). The protease inhibitor Gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL) is a nitrogen oxide (NO) donor, which relaxes the sphincter of Oddi. Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted. Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials. The non-steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results. Antibodies against tumor necrosis factor-alpha (TNF-α) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta- lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted.
文摘AIM: To examine the role of p38 during acute experimental cerulein pancreatitis. METHODS: Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347) and/or a specific p38 inhibitor (SB203580) and pancreatic stress kinase activity was determined. Parameters to assess pancreatitis included trypsin, amylase, lipase, pancreatic weight and histology. RESULTS: JNK inhibition with CEP1347 ameliorated pancreatitis, reducing pancreatic edema. In contrast, p38 inhibition with SB203580 aggravated pancreatitis with higher trypsin levels and, with induction of acinar necrosis not normally found after cerulein hyperstimulation. Simultaneous treatment with both CEP1347 and SB203580 mutually abolished the effects of either compound on cerulein pancreatitis. CONCLUSION: Stress kinases modulate pancreatitis differentially. JNK seems to promote pancreatitis development, possibly by supporting inflammatory reactions such as edema formation while its inhibition ameliorates pancreatitis. In contrast, p38 may help reduce organ destruction while inhibition of p38 during induction of cerulein pancreatitis leads to the occurrence of acinar necrosis.
基金Supported by National Natural Science Foundation of China (No.81072910)Science and Technology Support Program of Sichuan (No.2011SZ0291)
文摘OBJECTIVE: To explore the effect and the mechanism of Chaiqinchengqi decoction(CQCQD) on the apoptosis-necrosis switch of pancreatic acinar cells in acute necrotizing pancreatitis(ANP) in rats.METHODS: Sixty Sprague-Dawley rats were randomized into the control group, the ANP group and the CQCQD group. The acute pancreatitis(AP)model was induced by intraperitoneal injections of4 g/kg 8% L-Arginine(PH 7.0) twice with a 1 h interval. Rats in the CQCQD group were intragastrically administered CQCQD(20 mL/kg every 2 h, 3 times,then 20 mL/kg every 6 h, 3 times). Rats were killed at the 6 and 24 h after the induction of AP.The pancreatic tissues were collected for pathology and to isolate pancreatic acinar cells and mitochondria.RESULTS: CQCQD significantly ameliorated the severity of ANP by reducing the pancreatic histopathology score, indicated by lactate dehydrogenase levels at the 6 and 24 h. The CQCQD group promoted the apoptosis of pancreatic acinar cells by raising the apoptosis index compared with the ANP group and the control group. Mitochondrial cytochrome c at the 6 and 24 h in the ANP group were lower than that in the control group or the CQCQD group(0.67±0.13 vs 1.54±0.03 vs 0.81±0.09; 0.71±0.08 vs 1.55±0.09 vs 0.89±0.16, P<0.01). The cytochrome c levels in the cytoplasm at the 6 and 2 h in the CQCQD group were higher than in the control group(1.36±0.15 vs 0.67±0.04, 1.46±0.08 vs 0.59±0.09, P<0.01), or the ANP group(0.96±0.13, P>0.05;0.97±0.09, P<0.05). CQCQD increased caspase-3 activity over the ANP group at the 6 h.CONCLUSION: CQCQD can induce apoptosis and relieve the necrosis of pancreatic acinar cells via promoting the release of mitochondrial cytochrome c and increasing pancreatic caspase-3 activity in ANP rats.
文摘Acute necrotising pancreatitis is characterized by inflammatory and necrotic events, which followthe initial intra-acinar injury involving enzyme activation, and disruption of the acinar cytoskeleton. At present, apoptosis has become a hot topic in many kinds of disease. Bax and Bcl-2 are the important control gene during cell apoptosis. 2 Previous study has shown that interleukin 10 （IL-10） is a kind of important antiinflammatory cytokine and plays a role of selfdefense mechanism,
