TGF-β_1和MMP_2对大鼠胰腺坏死后的再生作用研究
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摘要
目的
急性胰腺炎是指胰腺及其周围组织被胰腺分泌的消化酶自身消化的化学性炎症。按病理组织学与临床表现，分为急性水肿型胰腺炎与急性出血坏死型胰腺炎两种。急性出血坏死性胰腺炎病情发展迅猛，死亡率高，其发病机理尚未完全阐明。近年来有关细胞因子在急性胰腺炎发病中的作用已受到重视，有研究认为血液中细胞因子浓度与急性胰腺炎病理类型有关，但尚未取得一致意见。大剂量注射精氨酸可以损害胰腺造成胰腺坏死，本实验应用这一原理制成急性胰腺炎实验动物模型，分别观察大鼠腹腔注射L-精氨酸后1天、3天、7天、10天、14天胰腺病理改变，依据转化生长因子-β_1(TGF-β_1)和基质金属蛋白酶-2(MMP_2)在细胞生长和组织改建中的作用，运用免疫组化方法检测这两个因子在各个时期的免疫反应性，明确它们在急性坏死性胰腺炎后再生作用的角色，进一步验证它们的生物学特性，对急性胰腺炎特别是坏死后再生有更深入的认识，更好地服务于临床。
方法
选用Wistar雄性大白鼠，体重在180—220克60只，随机分组，每组10只，以500mg／100g体重注射精氨酸后1天、3天、7天、10天、14天分别断头处死大鼠，取胰腺标本用10％福尔马林固定，石蜡包埋制成蜡块。免疫组化按常规SP方法进行，载玻片经多聚赖氨酸处理，EDTA抗原热修复后，进行免疫组化染色。
结果
一、TGF-β_1的免疫组织化学染色在注射精氨酸后1天开始增加，3天后明显增加，到第7天达到最大，以后随着坏死胰腺细胞的再生，TGF-β_1的免疫组织化学染色又开始下降，至注射后14天，已降至和正常对照组相似。
二、MM几的免疫组织化学染色在正常对照组及注射精氨酸后各个时期
均有表达，在正常对照组表现为高表达，注射后1天组，表达开始下降，随后
有所上升，至注射后7天组达到最大，之后又开始下降，至注射后14天组，
胰腺组织完全再生后表达又有所升高。
三、将各组数值与正常对照组进行卡方检验，注射后3、7天TGF一p:P
<0.05，注射后1天MM几P<0.05，差异有显著性，有统计学意义。
讨论
虽然急性出血坏死性胰腺炎病情严重，一旦主要致病因素解除，胰腺的
结构和功能常可以完全恢复正常。TGF一日，是一类具有多种生物学活性的
细胞生长因子，具有诱导细胞转化、分化和抑制细胞增殖等多种功能，它的
抑制细胞增殖功能现被引人肿瘤学的研究。TGF一p;不仅是ECM在胰腺
重塑的调节物，与急性胰腺炎发病有关，而且在出血坏死性胰腺炎时，胰性
腹水中TGF一日1可诱导肝细胞凋亡。TGF一p，是由两条多肤链组成的蛋白
质，是一个多功能的细胞因子家族，共有5个亚型并已克隆化，TGF一p，可
以存在于所有的组织中，但在骨、肺、肾及胎盘组织中比较丰富，主要来源于
淋巴细胞、血小板、单核细胞/巨嗜细胞。TGF一p;能调节细胞发挥多种功
能，是细胞生长的双向调节剂，调节细胞生长、分化、基质产生和凋亡，在胚
胎生长发育过程中，对模型形成和组织特异性分化起重要作用，与成人组织
修复和免疫系统调节过程有关，调控细胞外基质(ECM)的合成和降解，刺
激ECM的合成，抑制ECM的降解，抑制细胞外蛋白水解酶的活性，该物质
能导致组织损害。受损胰腺的再生作用是由ECM合成和降解之间的平衡
决定的，胶原对组织损害愈合有支撑作用，纤维连接蛋白形成一个支架以致
细胞迁移到损害部位可以固定，TGF一p;参与愈合过程，引导单核细胞和成
纤维细胞的迁移，增加ECM的合成和分泌，抑制ECM的降解，它对损害组
织的修复是通过对ECM的作用介导的，而ECM有利于胰腺再生。
MMP.是一类含有锌原子的、以ECM为主要底物的活性依赖于钙离子
的蛋白酶总称，可以降解ECM中的主要生物大分子，被认为是组织损伤后
重建的主要酶系，对胶原的沉积和组织改建起着重要作用。MMP.同种型有
底物特异性，例如，MMP，是间质胶原酶的代表酶，主要降解I型和l型胶
原，MM几是W型胶原酶的代表酶，又称明胶酶A，主要作用于W型胶原和纤
维连接蛋白，也可分解V、VII、X胶原及变性的I型胶原，IV型胶原是构成基
底膜的主要成分，MMPs在再生过程中被表达和激活，激活的MMPs类型因器
官的不同而不同，例如，回肠、结肠表达MMP，，2，，而不是MM几，在皮肤损伤
修复中，MMPI，2，。和MM几被表达。MMPZ在精氨酸诱导的大鼠胰腺炎再生
中防止大量ECM沉积中扮演重要角色。然而，MMP。在急性坏死性胰腺炎
后再生过程中的角色还没有完全阐明。
尽管精氨酸诱导的急性胰腺炎是一种严重的坏死性胰腺炎，胰腺细胞
再生，胰腺结构在2一3周后几乎完全恢复，然而坏死后再生机制还不清楚。
总之，TGF一p:和MM几通过介导ECM和胶原蛋白对胰腺再生起重要作用，
应用这一原理，更好地了解胰腺坏死及其再生机理，减小胰腺炎所致的死亡
率，对临床治疗急性胰腺炎有广阔的前景。
结论
一、TGF一p，在大鼠胰腺坏死组织中升高，提示其可能参与胰腺炎的修
复过程。
二、MMPZ在大鼠胰腺坏死组织中降低，有利于组织的重建。
三、TGF一pl和MMPZ在胰腺坏死再生过程中可能起一定的作用。
Objective
Acute pancreatitis (AP) is a self - digested chemical inflammation by auto -secretted digestive enzymes. From pathohistology and clinical manifestation, it is divided into two types; acute edematous pancreatitis and acute hemonecro-tizing pancreatitis. Acute hemoneerotizing pancreatitis develops rapidly and has a high mortality, its development mechanics have not yet been completely elucidated . A research considered the level of cytokines in blood was correlated with pathological type of acute pancreatitis, but not confirmed. Large dosage injection of L - arginine may injure pancreas and lead to necrosis, we can develop an animal model of acute pancreatitis in this study based on this principle, notice the pathological changes of 1d 3d 7d 10d 14d in rats after injecting arginine. Based on the effect of transforming growth factor - β1 and Matrix Metalloprotein-ase - 2 in cellular growth and tissue remodelling. Detest the immunoreactivity of two cytokines of all periods through immunohistochemistry, determine
the role of regeneration after acute necrotizing pancreatitis, confirms the biological properties of two cytokines, these will help us to grasp the principle of acute pancreatitis, especially the regeneration after acute necrotizing pancreatitis, helpful to clinical services.
Methods
Sixty male Wistar rats , weighing 180 -220g, randomly grouped, 10 in one group. Killed by decapitated in all periods after injecting arginine, removed
each pancreas and fixed overnight in 10% formalin, embedded in paraffin, and deparaffinized by the standard procedure. Immunohistochemistry is completed by routine SP methods. Slides are processed with polyamine, and the process is completed after hot repairement of antigen with EDTA.
Results
1. Immunohistochemical staining of TGF - β1 began to increase on day 1 after injecting arginine , obvious on day 3, and reached a peak value on day 7. later, began to decrease gradually with the regeneration of necrotizing pancreatic cells, on day 14, similar to the level of control group.
2. Immunohistochemical staining of MMP2 is expressed in all groups, higher in control group, and began to decrease on day 1 after injecting arginine. later began to rise, reached a peak level on day 7, later to decrease, on day 14, to a higher level after regeneration completely.
3. Use x2 test of two samples, all values are contrasted with the value of control group, on day 3,7 after injecting arginine, TGF - β1 p < 0. 05, on day 1 after injecting arginine, MMP2 p < 0.05 , the variances are obvious, and have statistic significances.
4. Others p > 0. 05, the variances are not obvious, no statistic significances.
Discusion
Although acute hemonecrotizing pancreatitis is more severe, once the primary causes or factors are eliminated, the structure and functions of the exocrine pancreas are often followed by full recovery. TGF-β1, is known as a group of cellular growth factors with many biological properties, such as inducing transforming , differentiating and inhibiting the proliferation of cells, it' s inhibiting the proliferation of cells is used to the research of tumors. TGF-β1 is not only the ECM modulator of pancreatic remodelling, but also correlated with the acute pancreatitis. Moreover, in hemonecrotizing pancreatitis, TGF - β1 may induce
hepatocytes to atrophy in pancreatic ascites. TGF - β1 is a protein made of two polypeptide chains, a multifunctional cytokine group , having 5 subtypes and have been cloned, TGF - β1 may lie in all tissues, abundant in bone, lung, kidney and placenta, mainly originated in lymphatic cells, thrombocytes, mono-cytes/ Macrophages. TGF - p, can modulate cells to complete many functions, a bidual modulator of cellular growth, modulate the growth and differentiation of cells, induce matrix to appear and atrophy. In the course of the development of embryo, TGF - β1 play an important role in the formation of model and specific differentiation of tissue. In adults, it is concerned with the repairement o
急性胰腺炎是指胰腺及其周围组织被胰腺分泌的消化酶自身消化的化学性炎症。按病理组织学与临床表现，分为急性水肿型胰腺炎与急性出血坏死型胰腺炎两种。急性出血坏死性胰腺炎病情发展迅猛，死亡率高，其发病机理尚未完全阐明。近年来有关细胞因子在急性胰腺炎发病中的作用已受到重视，有研究认为血液中细胞因子浓度与急性胰腺炎病理类型有关，但尚未取得一致意见。大剂量注射精氨酸可以损害胰腺造成胰腺坏死，本实验应用这一原理制成急性胰腺炎实验动物模型，分别观察大鼠腹腔注射L-精氨酸后1天、3天、7天、10天、14天胰腺病理改变，依据转化生长因子-β_1(TGF-β_1)和基质金属蛋白酶-2(MMP_2)在细胞生长和组织改建中的作用，运用免疫组化方法检测这两个因子在各个时期的免疫反应性，明确它们在急性坏死性胰腺炎后再生作用的角色，进一步验证它们的生物学特性，对急性胰腺炎特别是坏死后再生有更深入的认识，更好地服务于临床。
方法
选用Wistar雄性大白鼠，体重在180—220克60只，随机分组，每组10只，以500mg／100g体重注射精氨酸后1天、3天、7天、10天、14天分别断头处死大鼠，取胰腺标本用10％福尔马林固定，石蜡包埋制成蜡块。免疫组化按常规SP方法进行，载玻片经多聚赖氨酸处理，EDTA抗原热修复后，进行免疫组化染色。
结果
一、TGF-β_1的免疫组织化学染色在注射精氨酸后1天开始增加，3天后明显增加，到第7天达到最大，以后随着坏死胰腺细胞的再生，TGF-β_1的免疫组织化学染色又开始下降，至注射后14天，已降至和正常对照组相似。
二、MM几的免疫组织化学染色在正常对照组及注射精氨酸后各个时期
均有表达，在正常对照组表现为高表达，注射后1天组，表达开始下降，随后
有所上升，至注射后7天组达到最大，之后又开始下降，至注射后14天组，
胰腺组织完全再生后表达又有所升高。
三、将各组数值与正常对照组进行卡方检验，注射后3、7天TGF一p:P
<0.05，注射后1天MM几P<0.05，差异有显著性，有统计学意义。
讨论
虽然急性出血坏死性胰腺炎病情严重，一旦主要致病因素解除，胰腺的
结构和功能常可以完全恢复正常。TGF一日，是一类具有多种生物学活性的
细胞生长因子，具有诱导细胞转化、分化和抑制细胞增殖等多种功能，它的
抑制细胞增殖功能现被引人肿瘤学的研究。TGF一p;不仅是ECM在胰腺
重塑的调节物，与急性胰腺炎发病有关，而且在出血坏死性胰腺炎时，胰性
腹水中TGF一日1可诱导肝细胞凋亡。TGF一p，是由两条多肤链组成的蛋白
质，是一个多功能的细胞因子家族，共有5个亚型并已克隆化，TGF一p，可
以存在于所有的组织中，但在骨、肺、肾及胎盘组织中比较丰富，主要来源于
淋巴细胞、血小板、单核细胞/巨嗜细胞。TGF一p;能调节细胞发挥多种功
能，是细胞生长的双向调节剂，调节细胞生长、分化、基质产生和凋亡，在胚
胎生长发育过程中，对模型形成和组织特异性分化起重要作用，与成人组织
修复和免疫系统调节过程有关，调控细胞外基质(ECM)的合成和降解，刺
激ECM的合成，抑制ECM的降解，抑制细胞外蛋白水解酶的活性，该物质
能导致组织损害。受损胰腺的再生作用是由ECM合成和降解之间的平衡
决定的，胶原对组织损害愈合有支撑作用，纤维连接蛋白形成一个支架以致
细胞迁移到损害部位可以固定，TGF一p;参与愈合过程，引导单核细胞和成
纤维细胞的迁移，增加ECM的合成和分泌，抑制ECM的降解，它对损害组
织的修复是通过对ECM的作用介导的，而ECM有利于胰腺再生。
MMP.是一类含有锌原子的、以ECM为主要底物的活性依赖于钙离子
的蛋白酶总称，可以降解ECM中的主要生物大分子，被认为是组织损伤后
重建的主要酶系，对胶原的沉积和组织改建起着重要作用。MMP.同种型有
底物特异性，例如，MMP，是间质胶原酶的代表酶，主要降解I型和l型胶
原，MM几是W型胶原酶的代表酶，又称明胶酶A，主要作用于W型胶原和纤
维连接蛋白，也可分解V、VII、X胶原及变性的I型胶原，IV型胶原是构成基
底膜的主要成分，MMPs在再生过程中被表达和激活，激活的MMPs类型因器
官的不同而不同，例如，回肠、结肠表达MMP，，2，，而不是MM几，在皮肤损伤
修复中，MMPI，2，。和MM几被表达。MMPZ在精氨酸诱导的大鼠胰腺炎再生
中防止大量ECM沉积中扮演重要角色。然而，MMP。在急性坏死性胰腺炎
后再生过程中的角色还没有完全阐明。
尽管精氨酸诱导的急性胰腺炎是一种严重的坏死性胰腺炎，胰腺细胞
再生，胰腺结构在2一3周后几乎完全恢复，然而坏死后再生机制还不清楚。
总之，TGF一p:和MM几通过介导ECM和胶原蛋白对胰腺再生起重要作用，
应用这一原理，更好地了解胰腺坏死及其再生机理，减小胰腺炎所致的死亡
率，对临床治疗急性胰腺炎有广阔的前景。
结论
一、TGF一p，在大鼠胰腺坏死组织中升高，提示其可能参与胰腺炎的修
复过程。
二、MMPZ在大鼠胰腺坏死组织中降低，有利于组织的重建。
三、TGF一pl和MMPZ在胰腺坏死再生过程中可能起一定的作用。
Objective
Acute pancreatitis (AP) is a self - digested chemical inflammation by auto -secretted digestive enzymes. From pathohistology and clinical manifestation, it is divided into two types; acute edematous pancreatitis and acute hemonecro-tizing pancreatitis. Acute hemoneerotizing pancreatitis develops rapidly and has a high mortality, its development mechanics have not yet been completely elucidated . A research considered the level of cytokines in blood was correlated with pathological type of acute pancreatitis, but not confirmed. Large dosage injection of L - arginine may injure pancreas and lead to necrosis, we can develop an animal model of acute pancreatitis in this study based on this principle, notice the pathological changes of 1d 3d 7d 10d 14d in rats after injecting arginine. Based on the effect of transforming growth factor - β1 and Matrix Metalloprotein-ase - 2 in cellular growth and tissue remodelling. Detest the immunoreactivity of two cytokines of all periods through immunohistochemistry, determine
the role of regeneration after acute necrotizing pancreatitis, confirms the biological properties of two cytokines, these will help us to grasp the principle of acute pancreatitis, especially the regeneration after acute necrotizing pancreatitis, helpful to clinical services.
Methods
Sixty male Wistar rats , weighing 180 -220g, randomly grouped, 10 in one group. Killed by decapitated in all periods after injecting arginine, removed
each pancreas and fixed overnight in 10% formalin, embedded in paraffin, and deparaffinized by the standard procedure. Immunohistochemistry is completed by routine SP methods. Slides are processed with polyamine, and the process is completed after hot repairement of antigen with EDTA.
Results
1. Immunohistochemical staining of TGF - β1 began to increase on day 1 after injecting arginine , obvious on day 3, and reached a peak value on day 7. later, began to decrease gradually with the regeneration of necrotizing pancreatic cells, on day 14, similar to the level of control group.
2. Immunohistochemical staining of MMP2 is expressed in all groups, higher in control group, and began to decrease on day 1 after injecting arginine. later began to rise, reached a peak level on day 7, later to decrease, on day 14, to a higher level after regeneration completely.
3. Use x2 test of two samples, all values are contrasted with the value of control group, on day 3,7 after injecting arginine, TGF - β1 p < 0. 05, on day 1 after injecting arginine, MMP2 p < 0.05 , the variances are obvious, and have statistic significances.
4. Others p > 0. 05, the variances are not obvious, no statistic significances.
Discusion
Although acute hemonecrotizing pancreatitis is more severe, once the primary causes or factors are eliminated, the structure and functions of the exocrine pancreas are often followed by full recovery. TGF-β1, is known as a group of cellular growth factors with many biological properties, such as inducing transforming , differentiating and inhibiting the proliferation of cells, it' s inhibiting the proliferation of cells is used to the research of tumors. TGF-β1 is not only the ECM modulator of pancreatic remodelling, but also correlated with the acute pancreatitis. Moreover, in hemonecrotizing pancreatitis, TGF - β1 may induce
hepatocytes to atrophy in pancreatic ascites. TGF - β1 is a protein made of two polypeptide chains, a multifunctional cytokine group , having 5 subtypes and have been cloned, TGF - β1 may lie in all tissues, abundant in bone, lung, kidney and placenta, mainly originated in lymphatic cells, thrombocytes, mono-cytes/ Macrophages. TGF - p, can modulate cells to complete many functions, a bidual modulator of cellular growth, modulate the growth and differentiation of cells, induce matrix to appear and atrophy. In the course of the development of embryo, TGF - β1 play an important role in the formation of model and specific differentiation of tissue. In adults, it is concerned with the repairement o
引文
1．陈灏珠．《内科学》第四版．人民卫生出版社 426．
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14．洪照友，俞金龙，张云生，高毅．基质金属蛋白酶-9，CD34的表达与肝癌侵袭转移的关系．世界华人消化杂志 2001；9：170-174．
15. Murphy G, Stanton H. Mechanisms for pro matrix metalloproteinaseactivation[J]. APMIS, 1999,107(3):38-44.
16. Muller- Pillasch F, Gress TM, Yamaguchi H,et al. The influence of transforming growth factor - β_1 on the expression of genes coding for matrix metalloproteinases and tissue inhibitors of metalloproteinases during regeneration from cerulein - induced pancreatitis. Pancreas 1997; 15:168-75.
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18. Tani S, Itoh H, et al. New model of acute necrotizing pancreatitis induced by excessive doses of arginine in rats. Dig Dis Sci 1990; 35:367-74. Int J Cancer 2002;97:425-431.