环氧化酶-2对急性胰腺炎大鼠腺泡细胞凋亡的影响及其作用机制的研究
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摘要
目的:探讨环氧化酶-2(cyclooxygenase-2,Cox-2)对大鼠急性胰腺炎(acute pancreatitis,AP)时腺泡细胞凋亡的影响及其可能机制。
方法:健康清洁级SD大鼠30只,随机分为A组(假手术组)10只、B组(AEP组)10只、C组(AHNP组)10只。对逆行胰胆管穿刺注射法加以改进,分别采用0.5%及5%的牛磺胆酸钠诱导大鼠急性水肿性胰腺炎(acute edematous pancreatitis,AEP)与急性出血坏死性胰腺炎(acute hemorrhagic necrotic pancreatitis,AHNP)。三组大鼠均于术后12小时再次剖腹。肉眼观察胰腺大体病理学改变并评分。观察腹水颜色,收集腹水并计量。抽取下腔静脉血检测血清淀粉酶活性。收集胰腺组织,制作石蜡标本切片观察:予苏木素-伊红(HE)染色,显微镜下观察并评分;采用DNA原位末端标记法(TUNEL法)检测胰腺腺泡细胞的凋亡情况并计算凋亡指数(apoptotic index,AI);采用免疫组织化学SABC法检测Cox-2与Bcl-2、Bax蛋白的表达情况并进行半定量分析。
结果:
1三组大鼠术后12小时血清淀粉酶的活性分别为:A组:1479.10±111.73U/L、B组:4569.70±423.90U/L、C组:7116.90±363.83U/L;其中A组 2三组大鼠术后12小时胰腺组织的大体病理学评分分别为:A组:0.30±0.48、B组:3.98±0.51、C组:8.35±0.52;其中A组 3三组大鼠术后12小时胰腺腺泡细胞的AI分别为:A组:0.34±0.13%、B组:3.84±0.52%、C组:2.12±0.66%;其中A组C组(P<0.01)。B、C组大鼠腺泡细胞的AI与胰腺组织大体病理学评分(B组:r=-0.761 P<0.05;C组:r=-0.780 P<0.01)以及镜下病理学评分(B组:r=-0.763 P<0.05;C组:r=-0.664 P<0.05)均呈显著负相关关系。
4三组大鼠术后12小时腺泡细胞中Cox-2的阳性表达率分别为:A组:0%、B组:40%、C组:90%;其中A组C组(χ2=4.96 P<0.05)。
5术后12小时B、C组大鼠腺泡细胞中Cox-2的表达与腺泡细胞的AI均呈显著负相关关系(B组:rs=-0.874 P<0.01;C组:rs=-0.890 P<0.01)。
6术后12小时B、C组大鼠腺泡细胞中Cox-2的表达与Bcl-2的表达均呈显著正相关关系(B组:rs=0.791 P<0.01;C组:rs=0.700 P<0.05);而与Bax的表达均呈显著负相关关系(B组:rs=-0.687 P<0.05;C组:rs=-0.724 P<0.05)。
结论:
1大鼠AP时存在着胰腺腺泡细胞的凋亡,并与胰腺病变的严重程度呈负相关关系,提示其为AP时机体的一种自我保护机制。
2大鼠AP时存在着Cox-2的过度表达,并与胰腺病变的严重程度关系密切,提示Cox-2在AP发生发展的过程中发挥着重要的作用。
3大鼠AP时存在着Bcl-2与Bax的表达,二者在不同个体间的差异性表达与胰腺病变的严重程度关系密切,提示其共同参与了AP时腺泡细胞凋亡的调控。
4大鼠AP时Cox-2的过度表达与腺泡细胞的凋亡程度呈负相关关系,与Bcl-2的表达呈正相关关系,与Bax的表达呈负相关关系;提示AP时Cox-2的过度表达可能通过上调Bcl-2、下调Bax的表达,抑制腺泡细胞的凋亡,从而加重胰腺病变的严重程度。
Objective To investigate the effects of cycloxyenase-2(COX-2) on apoptosis of acinar cells in rats with experimental acute pancreatitis(AP) and explore the possible mechanisms.
Methods Thirty Sprague-Dawley(SD) rats were randomly divided into three groups: group A(shame operation group), group B(AEP group) and group C(AHNP group) each with ten in group. AP model was induced by modified method: acute edematous pancreatitis(AEP) and acute hemorrhagic necrotizing pancreatitis(AHNP) were induced by injection of 0.5% or 5% sodium deoxycholate through retrogradely common biliopancreatic ducts via papilla duodeni with epidural catheter, closed puncture hole with medical sealant glue. Rats were anatomized after 12 hours of injection. Ascites and blood samples were obtained. The pancreatic tissues were harvested for assessing the histopatholonical change, general and histological changes of pancreas was evaluated by the corresponding score system. The apoptosis of acinar cells was measured by TUNEL staining, and the expression of Cox-2, Bcl-2, Bax were determined by immunohistochemical technique.
Results
1 The serum amylase activity in group A, group B and group C were 1479.10±111.73U/L, 4569.70±423.90U/L, 7116.90±363.83U/L; And A 2 The severity of pancreas general changes appraised by the Hughes's score system in each group were 0.30±0.48, 3.98±0.51, 8.35±0.52; And A 3 The apoptotic index of acinar cells in each group were 0.34±0.13%, 3.84±0.52%, 2.12±0.66%; And AC(P<0.01). In group B and group C, apoptotic index were negatively correlated with general score(B: r=-0.761 P<0.05; C: r=-0.780 P<0.01) and histological score(B: r=-0.763 P<0.05; C: r=-0.664 P<0.05).
4 The positive rate of Cox-2 in each group were 0%, 40%, 90%; and AC(χ2=4.96 P<0.05).
5 In group B and group C, the expressions of Cox-2 were negatively correlated with the apoptotic index of acinar cells(B: rs=-0.874 P<0.01; C: rs=-0.890 P<0.01).
6 In group B and group C, the expressions of Cox-2 were positively correlated with the expressions of Bcl-2(B: rs=0.791 P<0.01; C: rs=0.700 P<0.05); However, negatively correlated with the expressions of Bax(B: rs=-0.687 P<0.05; C: rs=-0.724 P<0.05).
Conclusion
1 The apoptosis of acinar cells was observed in rats with AP, and negatively correlated with disease severity of pancreatic tissues, which indicating as a self-protection mechanism of individuals with AP.
2 The over expression of Cox-2 was observed in rats with AP, and closely related to disease severity of pancreatic tissues, which indicating Cox-2 play an important role in AP developing proceedure.
3 The expression of Bcl-2 and Bax were observed in rats with AP, differential expression of them in different individuals closely related to disease severity of pancreatic tissues, which indicating Bcl-2 and Bax were involved with the regulation of the acinar cells apoptosis.
4 The over expression of Cox-2 in rats with AP were negatively correlated with the apoptosis of acinar cells, positively correlated with the expressions of Bcl-2, and negatively correlated with the expressions of Bax; Cox-2 may up-regulate the expressions of Bcl-2, down-regulate the expressions of Bax, which inhibiting the apoptosis of acinar cells and deteriorate pancreatic disease.
方法:健康清洁级SD大鼠30只,随机分为A组(假手术组)10只、B组(AEP组)10只、C组(AHNP组)10只。对逆行胰胆管穿刺注射法加以改进,分别采用0.5%及5%的牛磺胆酸钠诱导大鼠急性水肿性胰腺炎(acute edematous pancreatitis,AEP)与急性出血坏死性胰腺炎(acute hemorrhagic necrotic pancreatitis,AHNP)。三组大鼠均于术后12小时再次剖腹。肉眼观察胰腺大体病理学改变并评分。观察腹水颜色,收集腹水并计量。抽取下腔静脉血检测血清淀粉酶活性。收集胰腺组织,制作石蜡标本切片观察:予苏木素-伊红(HE)染色,显微镜下观察并评分;采用DNA原位末端标记法(TUNEL法)检测胰腺腺泡细胞的凋亡情况并计算凋亡指数(apoptotic index,AI);采用免疫组织化学SABC法检测Cox-2与Bcl-2、Bax蛋白的表达情况并进行半定量分析。
结果:
1三组大鼠术后12小时血清淀粉酶的活性分别为:A组:1479.10±111.73U/L、B组:4569.70±423.90U/L、C组:7116.90±363.83U/L;其中A组
4三组大鼠术后12小时腺泡细胞中Cox-2的阳性表达率分别为:A组:0%、B组:40%、C组:90%;其中A组
5术后12小时B、C组大鼠腺泡细胞中Cox-2的表达与腺泡细胞的AI均呈显著负相关关系(B组:rs=-0.874 P<0.01;C组:rs=-0.890 P<0.01)。
6术后12小时B、C组大鼠腺泡细胞中Cox-2的表达与Bcl-2的表达均呈显著正相关关系(B组:rs=0.791 P<0.01;C组:rs=0.700 P<0.05);而与Bax的表达均呈显著负相关关系(B组:rs=-0.687 P<0.05;C组:rs=-0.724 P<0.05)。
结论:
1大鼠AP时存在着胰腺腺泡细胞的凋亡,并与胰腺病变的严重程度呈负相关关系,提示其为AP时机体的一种自我保护机制。
2大鼠AP时存在着Cox-2的过度表达,并与胰腺病变的严重程度关系密切,提示Cox-2在AP发生发展的过程中发挥着重要的作用。
3大鼠AP时存在着Bcl-2与Bax的表达,二者在不同个体间的差异性表达与胰腺病变的严重程度关系密切,提示其共同参与了AP时腺泡细胞凋亡的调控。
4大鼠AP时Cox-2的过度表达与腺泡细胞的凋亡程度呈负相关关系,与Bcl-2的表达呈正相关关系,与Bax的表达呈负相关关系;提示AP时Cox-2的过度表达可能通过上调Bcl-2、下调Bax的表达,抑制腺泡细胞的凋亡,从而加重胰腺病变的严重程度。
Objective To investigate the effects of cycloxyenase-2(COX-2) on apoptosis of acinar cells in rats with experimental acute pancreatitis(AP) and explore the possible mechanisms.
Methods Thirty Sprague-Dawley(SD) rats were randomly divided into three groups: group A(shame operation group), group B(AEP group) and group C(AHNP group) each with ten in group. AP model was induced by modified method: acute edematous pancreatitis(AEP) and acute hemorrhagic necrotizing pancreatitis(AHNP) were induced by injection of 0.5% or 5% sodium deoxycholate through retrogradely common biliopancreatic ducts via papilla duodeni with epidural catheter, closed puncture hole with medical sealant glue. Rats were anatomized after 12 hours of injection. Ascites and blood samples were obtained. The pancreatic tissues were harvested for assessing the histopatholonical change, general and histological changes of pancreas was evaluated by the corresponding score system. The apoptosis of acinar cells was measured by TUNEL staining, and the expression of Cox-2, Bcl-2, Bax were determined by immunohistochemical technique.
Results
1 The serum amylase activity in group A, group B and group C were 1479.10±111.73U/L, 4569.70±423.90U/L, 7116.90±363.83U/L; And A
4 The positive rate of Cox-2 in each group were 0%, 40%, 90%; and A
5 In group B and group C, the expressions of Cox-2 were negatively correlated with the apoptotic index of acinar cells(B: rs=-0.874 P<0.01; C: rs=-0.890 P<0.01).
6 In group B and group C, the expressions of Cox-2 were positively correlated with the expressions of Bcl-2(B: rs=0.791 P<0.01; C: rs=0.700 P<0.05); However, negatively correlated with the expressions of Bax(B: rs=-0.687 P<0.05; C: rs=-0.724 P<0.05).
Conclusion
1 The apoptosis of acinar cells was observed in rats with AP, and negatively correlated with disease severity of pancreatic tissues, which indicating as a self-protection mechanism of individuals with AP.
2 The over expression of Cox-2 was observed in rats with AP, and closely related to disease severity of pancreatic tissues, which indicating Cox-2 play an important role in AP developing proceedure.
3 The expression of Bcl-2 and Bax were observed in rats with AP, differential expression of them in different individuals closely related to disease severity of pancreatic tissues, which indicating Bcl-2 and Bax were involved with the regulation of the acinar cells apoptosis.
4 The over expression of Cox-2 in rats with AP were negatively correlated with the apoptosis of acinar cells, positively correlated with the expressions of Bcl-2, and negatively correlated with the expressions of Bax; Cox-2 may up-regulate the expressions of Bcl-2, down-regulate the expressions of Bax, which inhibiting the apoptosis of acinar cells and deteriorate pancreatic disease.
引文
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4 Kaiser AM, Saluja AK, Lu L, et al. Effects of cycloheximide on pancreatic endonuclease activity, apoptosis, and severity of acute pancreatitis. Am J Physiol, 1996,271(3 Pt 1):C982-93.
5 Bhatia M, Wallig MA, Hofbauer B, et al. Induction of apoptosis in pancreatic acinar cells reduces the severity of acute pancreatitis. Biochem Biophys Res Commun, 1998,246(2):476-83.
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