AIM:To investigate the effects of long term pretreatment with low-,medium-and high-dose aspirin(acetylsalicylic acid,ASA) on a model of acute pancreatitis(AP) induced in rats.METHODS:Forty male Wistar rats were used.T...AIM:To investigate the effects of long term pretreatment with low-,medium-and high-dose aspirin(acetylsalicylic acid,ASA) on a model of acute pancreatitis(AP) induced in rats.METHODS:Forty male Wistar rats were used.Three experimental groups,each consisting of eight animals,received low-(5 mg/kg per day),medium-(150 mg/kg per day) and high-dose(350 mg/kg per day) ASA in supplemented pellet chow for 100 d.Eight animals,serving as the AP-control group,and another eight,serving as reference value(RV) group,were fed with standard pellet chow for the same period.After pretreatment,AP was induced in the experimental animals by intraperitoneal administration of cerulein(2 × 50 μg/kg),while the RV group received saline in the same way.Twelve hours after the second injection,the animals were sacrificed.Pancreatic tissue and plasma samples were collected.One part of the collected pancreatic tissues was used for histopathological evaluation,and the remaining portion was homogenized.Cytokine levels [tumor necrosis factor,interleukin(IL)1β,IL-6],hemogram parameters,biochemical parameters(amylase and lipase),nuclear factor-κB,aspirin triggered lipoxins and parameters related to the antioxidant system(malondialdehyde,nitric oxide,hemeoxygenase-1,catalase and superoxide dismutase) were measured.RESULTS:Cerulein administration induced mild pancreatitis,characterized by interstitial edema(total histopathological score of 5.88 ± 0.44vs 0.25 ± 0.16,P < 0.001).Subsequent pancreatic tissue damage resulted in an increase in amylase(2829.71 ± 772.48 vs 984.57 ± 49.22 U/L,P = 0.001) and lipase(110.14 ± 75.84 U/L vs 4.71 ± 0.78 U/L,P < 0.001) in plasma,and leucocytes(6.89 ± 0.48 vs 4.36 ± 0.23,P = 0.001) in peripheral blood.Cytokines,IL-1β(18.81 ± 2.55 pg/μg vs 6.65 ± 0.24 pg/μg,P = 0.002) and IL-6(14.62 ± 1.98 pg/μg vs 9.09 ± 1.36 pg/μg,P = 0.04) in pancreatic tissue also increased.Aspirin pretreatment reduced the increase in the aforementioned parameters to a certain degree and partially improved the histopathological alterations caused by cerulein.No evidence of side effects related to chronic ASA administration(e.g.,inflammation or bleeding) was observed in the gastrointestinal tract in macroscopic and histopathological examination.CONCLUSION:Long term ASA pretreatment could prevent and/or ameliorate certain hematological,serological and histological alterations caused by ceruleininduced AP.展开更多
Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory ce...Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.展开更多
AIM： To observe the expressions of early growth response factor-1 （Egr-1） and tissue factor （TF） in rats with cerulein-induced acute pancreatitis and to explore its significance. METHODS： A large dose of cerulei...AIM： To observe the expressions of early growth response factor-1 （Egr-1） and tissue factor （TF） in rats with cerulein-induced acute pancreatitis and to explore its significance. METHODS： A large dose of cerulein was used to create the experimental acute pancreatitis model in rats. The changes of Egr-1 mRNA and protein in rats were observed during 30 min to 4 h after the treatment and immunohistochemical method was used to observe the localized expression of Egr-1 in tissues. In addition to the mRNA expression of Egr-1 target gene, TF was also observed. A blank control group, and a bombesinadministered group were used for comparison. RESULTS： Alter the stimulation of a large dose of cerulein, the rats showed typical inflammatory changes of acute pancreatitis. Thirty minutes alter the stimulation, the mRNA expression of Egr-1 in the pancreatic tissue reached its peak and then declined, while the expression of Egr-1 protein reached its peak 2 h after the stimulation. Histologically, 2 h after the stimulation, almost all pancreatic acinar cells had the expression of Egr-1 protein, which was focused in the nuclei. The mRNA expression of TF occurred 1 h after the stimulation and gradually increased within 4 h. However, a large dose of bombesin only stimulated the pancreatic tissue to produce a little mRNA expression of Egr-1 and no mRNA expression of Egr-1 protein and TF. CONCLUSION： Egr-1 as a pro-inflammatory transcription factor may play an important role in the pathogenesis of acute pancreatitis by modulating the expression of TF.展开更多
AIM： To investigate the effect of Garden/a fasm/noides （GJ） on cerulein-induced acute pancreatitis （AP） in mice. METHODS： C57BL/6 mice weighing 18-20 g were divided into three groups. （1） Normal salinetreated ...AIM： To investigate the effect of Garden/a fasm/noides （GJ） on cerulein-induced acute pancreatitis （AP） in mice. METHODS： C57BL/6 mice weighing 18-20 g were divided into three groups. （1） Normal salinetreated group, （2） treatment with GJ at a dose of 0.1 g/kg, （3） treatment with GJ at a dose of 1 g/kg. GJ was administered orally （n = 6 per group） for 1 wk. Three hours later, the mice were given anintraperitoneal injection of cerulein （50 μg/kg）, a stable cholecystokinin （CCK） analogue, every hour for a total of 6h as described previously. The mice were sacrificed at 6 h after completion of cerulein injections. Blood samples were obtained to determine serum amylase, lipase and cytokine levels. The pancreas was rapidly removed for morphologic examination and scoring. A portion of pancreas was stored at -70℃ and prepared for the measurement of tissue myeloperoxidase （MPO） activity, an indicator of neutrophil sequestration, and for reverse-transcriptase PCR （RT-PCR） and real-time PCR measurements. RESULTS： Treatment with G.1 decreased significantly the severity of pancreatitis and pancreatitis-associated lung injury. Treatment with G.1 attenuated the severity of AP compared with saline-treated mice, as shown by reduction in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and mRNA expression of multiple inflammatory mediators. CONCLUSION： These results suggest that GJ attenuated the severity of AP as well as pancreatitisassociated lung injury.展开更多
AIM: To evaluate the therapeutic role of caffeic acid phenethyl ester (CAPE) in a rat model of ceruleaninduced acute pancreatitis (AP).METHODS: Seventy male Wistar albino rats were divided into seven groups. Acute ede...AIM: To evaluate the therapeutic role of caffeic acid phenethyl ester (CAPE) in a rat model of ceruleaninduced acute pancreatitis (AP).METHODS: Seventy male Wistar albino rats were divided into seven groups. Acute edematous pancreatitis was induced by subcutaneous cerulein injection (20 μg/kg) four times at 1-h intervals. CAPE (30 mg/kg) was given by subcutaneous injection at the beginning (CAPE 1 group) and 12 h after the last cerulein injection (CAPE 2 group). Serum amylase, lipase, white blood cell count, and tumor necrosis factor (TNF)-α levels were measured, and pancreatic histopathology was assessed. RESULTS: In the AP group, amylase and lipase levels were found to be elevated and the histopathological evaluation showed massive edema and inflammation of the pancreas, with less fatty necrosis when compared with sham and control groups. Amylase and lipase levels and edema formation decreased signif icantly in the CAPE therapy groups (P < 0001); especially in the CAPE 2 group, edema was improved nearly completely (P = 0001). Inflammation and fatty necrosis were partially recovered by CAPE treatment. The pathologicalresults and amylase level in the placebo groups were similar to those in the AP group. White blood cell count and TNF-α concentration was nearly the same in the CAPE and placebo groups.CONCLUSION: CAPE may be useful agent in treatment of AP but more experimental and clinical studies are needed to support our observation of benef icial effects of CAPE before clinical usage of this agent.展开更多
AIM: To investigate the changes of platelet endothelial cell adhesion molecule-1 (PECAM-1) expression on polymorphonuclear leukocytes (PMNs) in peripheral circulation and pancreatic microcirculation in cerulein-induce...AIM: To investigate the changes of platelet endothelial cell adhesion molecule-1 (PECAM-1) expression on polymorphonuclear leukocytes (PMNs) in peripheral circulation and pancreatic microcirculation in cerulein-induced acute edematous pancreatitis (AEP).METHODS: Fifty Wistar rats were randomly divided into control group (n=10) and AEP group (n=40). A model of AEP was established by subcutaneous injection of cerulein 5.5 and 7.5 μg/kg at 0 and 1 h after the beginning of experiment respectively. PECAM-1 expression on PMNs from splenic vein and inferior vena cava was determined by RT-PCR at mRNA level and determined by flow cytometry at protein level.RESULTS: In experimental rats, an increased PECAM-1mRNA expression was seen from 4 to 8 h of AEP in peripheral circulation (0.77±0.25%, 0.76±0.28%, 0.89±0.30%,1.00±0.21% ), while in pancreatic microcirculation,expression decreased from 2 h and reached the lowest level at 6 h of AEP (0.78±0.29%, 0.75±0.26%, 0.62±0.28%,0.66±0.20%). There were significant differences at 8-h time point of AEP between peripheral circulation and pancreatic microcirculation (1.00±0.21% vs0.66±0.20%, P＜0.05).Meanwhile,the difference at protein level was also found.CONCLUSION: A reverse expression of PECAM-1 on PMNs was found between peripheral circulation and pancreatic microcirculation, suggesting that inhibition of PECAM-1expression may improve the pathological change of AEP.展开更多
BACKGROUND： Oxidative stress is recognized as a pivotal effector of several pathogenic processes, including acute pancreatitis. Reactive oxygen species not just cause damage on the main cellular components, but also ...BACKGROUND： Oxidative stress is recognized as a pivotal effector of several pathogenic processes, including acute pancreatitis. Reactive oxygen species not just cause damage on the main cellular components, but also influence the expression of antioxidant system genes. Antioxidant molecules, such as melatonin, could be good candidates for the treatment of this multidimensional disease. The present study was to evaluate the chemopreventive effect of melatonin in a rat model of ceruleininduced acute pancreatitis.METHODS： Four subcutaneous injections of cerulein（20 μg/kg body weight） were given to Wistar rats at two hours intervals;melatonin was injected intraperitoneally（25 mg/kg body weight）30 minutes before each injection of cerulein. Lipid peroxidation,protein oxidation（carbonyl groups）, total antioxidant status,and glutathione peroxidase activity were determined in pancreatic tissue using commercial kits.RESULTS： The chemopreventive administration of melatonin caused a reduction in lipid peroxidation and protein oxidation due to injections of cerulein. Additionally, melatonin treatment was also able to revert glutathione peroxidase activity and total antioxidant status near to control levels, suggesting that melatonin could prevent from oxidative phenomena in the pancreas, such as lipid peroxidation and protein oxidation,and could stimulate, directly or indirectly, the expression of antioxidant enzymes.CONCLUSION： Melatonin, a polyvalent antioxidant, protected the pancreatic damage via the decrease of oxidative stress andincrease of the activities of antioxidant enzymes in ceruleininduced acute pancreatitis.展开更多
Pancreatitis is a common,life-threatening inflammatory disease of the exocrine pancreas.Its pathogenesis remains obscure,and no specific or effective treatment is available.Gallstones and alcohol excess are major etio...Pancreatitis is a common,life-threatening inflammatory disease of the exocrine pancreas.Its pathogenesis remains obscure,and no specific or effective treatment is available.Gallstones and alcohol excess are major etiologies of pancreatitis;in a small portion of patients the disease is hereditary.Pancreatitis is believed to be initiated by injured acinar cells(the main exocrine pancreas cell type),leading to parenchymal necrosis and local and systemic inflammation.The primary function of these cells is to produce,store,and secrete a variety of enzymes that break down all categories of nutrients.Most digestive enzymes,including all proteases,are secreted by acinar cells as inactive proforms(zymogens)and in physiological conditions are only activated when reaching the intestine.The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens.It was proposed that pancreatitis results from proteolytic autodigestion of the gland,mediated by premature/inappropriate trypsinogen activation within acinar cells.The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis,and in human disease.On the basis of these observations,it has been considered the central pathogenic mechanism of pancreatitis-a concept with a century-old history.This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis,particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis;analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its’damaging effects;discusses the gaps in our knowledge,potential therapeutic approaches,and directions for future research.We conclude that trypsin is not the culprit in the disease pathogenesis but,at most,a mediator of some pancreatitis responses.Therefore,the search for effective therapies should focus on approaches to prevent or normalize other intra-acinar pathologic processes,such as defective autophagy leading to parenchymal cell death and unrelenting inflammation.展开更多
BACKGROUND Acute pancreatitis(AP),the initially triggered inflammatory process in the pancreas,can be life-threatening.It has been reported that 15-lipoxygenase may promote the removal of damaged intracellular compone...BACKGROUND Acute pancreatitis(AP),the initially triggered inflammatory process in the pancreas,can be life-threatening.It has been reported that 15-lipoxygenase may promote the removal of damaged intracellular components,maintain intracellular homeostasis,and promote apoptosis by upregulating the activity of caspases.Despite an increased understanding of the lipoxygenase pathway in inflammation and immune diseases,the role of the Alox15 gene product in modulating the inflammatory changes during AP is not well defined.AIM To investigate the effect of Alox15 expression in cerulein-induced AP in rats.METHODS Model rats were transfected with Alox15 by injecting a recombinant lentivirus vector encoding Alox15 into the left gastric artery before inducing AP.The expression of Alox15 was then assessed at the mRNA and protein levels.RESULTS Our in vivo results showed that serum amylase activity and pancreatic tissue water content were significantly reduced in Alox15-transfected rats.Further,the mRNA expression levels of tumor necrosis factor alpha,interleukin(IL)-1β,IL-6,and monocyte chemoattractant protein-1,as well as the protein expression of nuclear factor kappa B in pancreatic tissue were reduced.Additionally,we observed an upregulation of cleaved caspase-3 that implies an induction of apoptosis in pancreatic cells.The transfection of Alox15 resulted in a lower number of autophagic vacuoles in AP.CONCLUSION Our findings demonstrate a regulatory role of Alox15 in apoptosis and autophagy,making it a potential therapeutic target for AP.展开更多
基金Supported by The Istanbul University Department of Scientific Research Projects,Grant No. 3101
文摘AIM:To investigate the effects of long term pretreatment with low-,medium-and high-dose aspirin(acetylsalicylic acid,ASA) on a model of acute pancreatitis(AP) induced in rats.METHODS:Forty male Wistar rats were used.Three experimental groups,each consisting of eight animals,received low-(5 mg/kg per day),medium-(150 mg/kg per day) and high-dose(350 mg/kg per day) ASA in supplemented pellet chow for 100 d.Eight animals,serving as the AP-control group,and another eight,serving as reference value(RV) group,were fed with standard pellet chow for the same period.After pretreatment,AP was induced in the experimental animals by intraperitoneal administration of cerulein(2 × 50 μg/kg),while the RV group received saline in the same way.Twelve hours after the second injection,the animals were sacrificed.Pancreatic tissue and plasma samples were collected.One part of the collected pancreatic tissues was used for histopathological evaluation,and the remaining portion was homogenized.Cytokine levels [tumor necrosis factor,interleukin(IL)1β,IL-6],hemogram parameters,biochemical parameters(amylase and lipase),nuclear factor-κB,aspirin triggered lipoxins and parameters related to the antioxidant system(malondialdehyde,nitric oxide,hemeoxygenase-1,catalase and superoxide dismutase) were measured.RESULTS:Cerulein administration induced mild pancreatitis,characterized by interstitial edema(total histopathological score of 5.88 ± 0.44vs 0.25 ± 0.16,P < 0.001).Subsequent pancreatic tissue damage resulted in an increase in amylase(2829.71 ± 772.48 vs 984.57 ± 49.22 U/L,P = 0.001) and lipase(110.14 ± 75.84 U/L vs 4.71 ± 0.78 U/L,P < 0.001) in plasma,and leucocytes(6.89 ± 0.48 vs 4.36 ± 0.23,P = 0.001) in peripheral blood.Cytokines,IL-1β(18.81 ± 2.55 pg/μg vs 6.65 ± 0.24 pg/μg,P = 0.002) and IL-6(14.62 ± 1.98 pg/μg vs 9.09 ± 1.36 pg/μg,P = 0.04) in pancreatic tissue also increased.Aspirin pretreatment reduced the increase in the aforementioned parameters to a certain degree and partially improved the histopathological alterations caused by cerulein.No evidence of side effects related to chronic ASA administration(e.g.,inflammation or bleeding) was observed in the gastrointestinal tract in macroscopic and histopathological examination.CONCLUSION:Long term ASA pretreatment could prevent and/or ameliorate certain hematological,serological and histological alterations caused by ceruleininduced AP.
基金Supported by National Research Foundation of Korea grant funded by the Korea government No.2007-0056092
文摘Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.
基金Supported by the National Natural Science Foundation of China,No. 30370648
文摘AIM： To observe the expressions of early growth response factor-1 （Egr-1） and tissue factor （TF） in rats with cerulein-induced acute pancreatitis and to explore its significance. METHODS： A large dose of cerulein was used to create the experimental acute pancreatitis model in rats. The changes of Egr-1 mRNA and protein in rats were observed during 30 min to 4 h after the treatment and immunohistochemical method was used to observe the localized expression of Egr-1 in tissues. In addition to the mRNA expression of Egr-1 target gene, TF was also observed. A blank control group, and a bombesinadministered group were used for comparison. RESULTS： Alter the stimulation of a large dose of cerulein, the rats showed typical inflammatory changes of acute pancreatitis. Thirty minutes alter the stimulation, the mRNA expression of Egr-1 in the pancreatic tissue reached its peak and then declined, while the expression of Egr-1 protein reached its peak 2 h after the stimulation. Histologically, 2 h after the stimulation, almost all pancreatic acinar cells had the expression of Egr-1 protein, which was focused in the nuclei. The mRNA expression of TF occurred 1 h after the stimulation and gradually increased within 4 h. However, a large dose of bombesin only stimulated the pancreatic tissue to produce a little mRNA expression of Egr-1 and no mRNA expression of Egr-1 protein and TF. CONCLUSION： Egr-1 as a pro-inflammatory transcription factor may play an important role in the pathogenesis of acute pancreatitis by modulating the expression of TF.
基金The Ministry of Science & Technology (MoST)/Korea Science & Engineering Foundation (KOSEF) through the Vestibulocochlear Research Center (VCRC) at Wonkwang University (R13-2002-055-00000-0)
文摘AIM： To investigate the effect of Garden/a fasm/noides （GJ） on cerulein-induced acute pancreatitis （AP） in mice. METHODS： C57BL/6 mice weighing 18-20 g were divided into three groups. （1） Normal salinetreated group, （2） treatment with GJ at a dose of 0.1 g/kg, （3） treatment with GJ at a dose of 1 g/kg. GJ was administered orally （n = 6 per group） for 1 wk. Three hours later, the mice were given anintraperitoneal injection of cerulein （50 μg/kg）, a stable cholecystokinin （CCK） analogue, every hour for a total of 6h as described previously. The mice were sacrificed at 6 h after completion of cerulein injections. Blood samples were obtained to determine serum amylase, lipase and cytokine levels. The pancreas was rapidly removed for morphologic examination and scoring. A portion of pancreas was stored at -70℃ and prepared for the measurement of tissue myeloperoxidase （MPO） activity, an indicator of neutrophil sequestration, and for reverse-transcriptase PCR （RT-PCR） and real-time PCR measurements. RESULTS： Treatment with G.1 decreased significantly the severity of pancreatitis and pancreatitis-associated lung injury. Treatment with G.1 attenuated the severity of AP compared with saline-treated mice, as shown by reduction in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and mRNA expression of multiple inflammatory mediators. CONCLUSION： These results suggest that GJ attenuated the severity of AP as well as pancreatitisassociated lung injury.
文摘AIM: To evaluate the therapeutic role of caffeic acid phenethyl ester (CAPE) in a rat model of ceruleaninduced acute pancreatitis (AP).METHODS: Seventy male Wistar albino rats were divided into seven groups. Acute edematous pancreatitis was induced by subcutaneous cerulein injection (20 μg/kg) four times at 1-h intervals. CAPE (30 mg/kg) was given by subcutaneous injection at the beginning (CAPE 1 group) and 12 h after the last cerulein injection (CAPE 2 group). Serum amylase, lipase, white blood cell count, and tumor necrosis factor (TNF)-α levels were measured, and pancreatic histopathology was assessed. RESULTS: In the AP group, amylase and lipase levels were found to be elevated and the histopathological evaluation showed massive edema and inflammation of the pancreas, with less fatty necrosis when compared with sham and control groups. Amylase and lipase levels and edema formation decreased signif icantly in the CAPE therapy groups (P < 0001); especially in the CAPE 2 group, edema was improved nearly completely (P = 0001). Inflammation and fatty necrosis were partially recovered by CAPE treatment. The pathologicalresults and amylase level in the placebo groups were similar to those in the AP group. White blood cell count and TNF-α concentration was nearly the same in the CAPE and placebo groups.CONCLUSION: CAPE may be useful agent in treatment of AP but more experimental and clinical studies are needed to support our observation of benef icial effects of CAPE before clinical usage of this agent.
基金Supported by National Natural Science Foundation of China, No.39925032
文摘AIM: To investigate the changes of platelet endothelial cell adhesion molecule-1 (PECAM-1) expression on polymorphonuclear leukocytes (PMNs) in peripheral circulation and pancreatic microcirculation in cerulein-induced acute edematous pancreatitis (AEP).METHODS: Fifty Wistar rats were randomly divided into control group (n=10) and AEP group (n=40). A model of AEP was established by subcutaneous injection of cerulein 5.5 and 7.5 μg/kg at 0 and 1 h after the beginning of experiment respectively. PECAM-1 expression on PMNs from splenic vein and inferior vena cava was determined by RT-PCR at mRNA level and determined by flow cytometry at protein level.RESULTS: In experimental rats, an increased PECAM-1mRNA expression was seen from 4 to 8 h of AEP in peripheral circulation (0.77±0.25%, 0.76±0.28%, 0.89±0.30%,1.00±0.21% ), while in pancreatic microcirculation,expression decreased from 2 h and reached the lowest level at 6 h of AEP (0.78±0.29%, 0.75±0.26%, 0.62±0.28%,0.66±0.20%). There were significant differences at 8-h time point of AEP between peripheral circulation and pancreatic microcirculation (1.00±0.21% vs0.66±0.20%, P＜0.05).Meanwhile,the difference at protein level was also found.CONCLUSION: A reverse expression of PECAM-1 on PMNs was found between peripheral circulation and pancreatic microcirculation, suggesting that inhibition of PECAM-1expression may improve the pathological change of AEP.
基金supported by grants from MICINNFEDER(BFU2010-15049)Gobierno de Extremadura(Re:GRU10003)Plan of Recruitment and Training of Human Resources on Research of University of Extremadura(1076)
文摘BACKGROUND： Oxidative stress is recognized as a pivotal effector of several pathogenic processes, including acute pancreatitis. Reactive oxygen species not just cause damage on the main cellular components, but also influence the expression of antioxidant system genes. Antioxidant molecules, such as melatonin, could be good candidates for the treatment of this multidimensional disease. The present study was to evaluate the chemopreventive effect of melatonin in a rat model of ceruleininduced acute pancreatitis.METHODS： Four subcutaneous injections of cerulein（20 μg/kg body weight） were given to Wistar rats at two hours intervals;melatonin was injected intraperitoneally（25 mg/kg body weight）30 minutes before each injection of cerulein. Lipid peroxidation,protein oxidation（carbonyl groups）, total antioxidant status,and glutathione peroxidase activity were determined in pancreatic tissue using commercial kits.RESULTS： The chemopreventive administration of melatonin caused a reduction in lipid peroxidation and protein oxidation due to injections of cerulein. Additionally, melatonin treatment was also able to revert glutathione peroxidase activity and total antioxidant status near to control levels, suggesting that melatonin could prevent from oxidative phenomena in the pancreas, such as lipid peroxidation and protein oxidation,and could stimulate, directly or indirectly, the expression of antioxidant enzymes.CONCLUSION： Melatonin, a polyvalent antioxidant, protected the pancreatic damage via the decrease of oxidative stress andincrease of the activities of antioxidant enzymes in ceruleininduced acute pancreatitis.
文摘Pancreatitis is a common,life-threatening inflammatory disease of the exocrine pancreas.Its pathogenesis remains obscure,and no specific or effective treatment is available.Gallstones and alcohol excess are major etiologies of pancreatitis;in a small portion of patients the disease is hereditary.Pancreatitis is believed to be initiated by injured acinar cells(the main exocrine pancreas cell type),leading to parenchymal necrosis and local and systemic inflammation.The primary function of these cells is to produce,store,and secrete a variety of enzymes that break down all categories of nutrients.Most digestive enzymes,including all proteases,are secreted by acinar cells as inactive proforms(zymogens)and in physiological conditions are only activated when reaching the intestine.The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens.It was proposed that pancreatitis results from proteolytic autodigestion of the gland,mediated by premature/inappropriate trypsinogen activation within acinar cells.The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis,and in human disease.On the basis of these observations,it has been considered the central pathogenic mechanism of pancreatitis-a concept with a century-old history.This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis,particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis;analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its’damaging effects;discusses the gaps in our knowledge,potential therapeutic approaches,and directions for future research.We conclude that trypsin is not the culprit in the disease pathogenesis but,at most,a mediator of some pancreatitis responses.Therefore,the search for effective therapies should focus on approaches to prevent or normalize other intra-acinar pathologic processes,such as defective autophagy leading to parenchymal cell death and unrelenting inflammation.
基金National Health Commission Research Fund,No.WKJ-ZJ-2342National Natural Science Foundation of China,No.81900583Science and Technology Plan Project of Wenzhou,No.Y20180103.
文摘BACKGROUND Acute pancreatitis(AP),the initially triggered inflammatory process in the pancreas,can be life-threatening.It has been reported that 15-lipoxygenase may promote the removal of damaged intracellular components,maintain intracellular homeostasis,and promote apoptosis by upregulating the activity of caspases.Despite an increased understanding of the lipoxygenase pathway in inflammation and immune diseases,the role of the Alox15 gene product in modulating the inflammatory changes during AP is not well defined.AIM To investigate the effect of Alox15 expression in cerulein-induced AP in rats.METHODS Model rats were transfected with Alox15 by injecting a recombinant lentivirus vector encoding Alox15 into the left gastric artery before inducing AP.The expression of Alox15 was then assessed at the mRNA and protein levels.RESULTS Our in vivo results showed that serum amylase activity and pancreatic tissue water content were significantly reduced in Alox15-transfected rats.Further,the mRNA expression levels of tumor necrosis factor alpha,interleukin(IL)-1β,IL-6,and monocyte chemoattractant protein-1,as well as the protein expression of nuclear factor kappa B in pancreatic tissue were reduced.Additionally,we observed an upregulation of cleaved caspase-3 that implies an induction of apoptosis in pancreatic cells.The transfection of Alox15 resulted in a lower number of autophagic vacuoles in AP.CONCLUSION Our findings demonstrate a regulatory role of Alox15 in apoptosis and autophagy,making it a potential therapeutic target for AP.
