GLP-2对小鼠胃肠粘膜作用及其受体分布的初步研究
摘要
胃肠道是消化吸收营养物质的主要场所,各种应激损伤对机体胃肠道正常黏膜组织结构造成破坏,从而降低胃肠道对营养物质的消化和吸收。目前的研究资料表明,多肽类生长因子如表皮生长因子、转化生长因子、胰岛素样生长因子-I等参与了肠上皮生长调控,并对肠黏膜损伤后的再生修复有促进作用,但其作用缺乏特异性,常会引起机体的不良反应。近10年来有关胰高血糖素样肽-2(glucagon like peptide 2,GLP-2)与肠上皮生长调控关系的研究日益增多。众多学者认为GLP-2有明显促进肠道对营养物质的吸收作用,且具有特异性。GLP-2通过与其受体(GLP-2R)结合而实现其生物学作用,但作用机制目前尚不十分清楚。推测GLP-2对肠道的作用是通过特异性GLP-2R所介导的cAMP依赖性信号转导途径而实现。另外也有研究表明有磷脂酰肌醇3-激酶(PI3-K)和丝裂原活化蛋白激酶途径的参与。GLP-2通过直接促进肠上皮细胞的增殖、抑制其凋亡,或通过分布于肠内其他部位的GLP-2R间接促进正常小肠的生长和病理肠黏膜的恢复。
目的:观察GLP-2对小鼠胃肠道黏膜的作用效果;检测GLP-2R在小鼠不同脏器的分布和表达。
方法:选用5-6周龄的雄性健康BALB/C小鼠,体重17-20g。随机分为2组。对照组8只,处理组9只。GLP-2处理组:每天按250μg/kg腹腔注射GLP-2液两次,连续三天。实验对照组:每天等量腹腔注射生理盐水两次,连续三天。三天后,处死小鼠,每组抽取样本用于形态学观察。将组织切片进行HE染色,观察小鼠胃肠黏膜的组织学变化,用免疫组化方法检测GLP-2R在胃肠组织的表达和分布。
结果:
1、小鼠GLP-2处理后,胃黏膜上皮增厚,胃小凹加深。
2、GLP-2处理组小肠不同肠段黏膜的绒毛高度较对照组明显增加(P<0.05);绒毛增高,隐窝加深;结肠黏膜上皮增厚。
3、GLP-2R在小鼠胃肠道各部位均有表达,而肝、肺、肾与膀胱显阴性。
4、GLP-2处理组与对照组比较GLP-2R表达无差异(P﹥0.05)。
结论:
1、GLP-2能刺激胃黏膜与结肠黏膜上皮增厚,增加小肠不同肠段黏膜的绒毛高度。
2、小鼠的胃、十二指肠、空肠、回肠与结肠均有GLP-2R的表达,肝、肺、肾与膀胱无GLP-2R的表达。
3、小鼠经GLP-2处理后,其胃肠道的受体表达不受影响。
Gastrointestinal tract is the main place of digesting and absorbing nutritive materials in living organisms. Various stresses are apt to destroy the normal mucosa tissue structure of gastrointestinal tract and decrease the ability of absorbing and digesting nutritive materials. Previous studies showed that polypeptides growth factors, such as epidermal growth factor, transforming growth factor, insulin-like growth factor-1, took part in regulation of growth of intestinal epithelium and promoted regeneration and reparation of intestinal mucosa, but their clinical applications were limited due to the lack of tissue specificity and possible adverse reaction brought. Glucagon like peptide 2 (GLP-2) was discovered laterly, it could obviously and specifically promote intestinal tract to absorb nutritive materials, and more studies on the relations between GLP-2 and growth regulation of intestinal epithelium were reported in the recent decade.
Moreover, it has been reported that GLP-2 promoted the development of normal small intestine and recovering of pathological intestinal mucosa. GLP-2 stimulates generation and restraints its apoptosis by GLP-2R distributing in the enterocyte, and also plays the recuperative role of protecting intestinal cells and promoting intestinal function by GLP-2R distributing in the other parts of intestine. GLP-2 implements its biological effect by combining with GLP2 receptor (GLP-2R). GLP-2R-mediated cAMP-dependent signal transduction and phosphatidyl inositol 3-kinase (PI3-K) and mitogen-activated protein kinase ( MAPK ) presumbly are involved in the various effects of GLP2. However, the mechanism remains unclear. In this study, we try to observe the proliferative effect of GLP2 and GLP2R expression in gastrointestinal tract.
Objectives:
The effect of GLP-2 on gastrointestinal mucosa is observed and expression and distribution of GLP-2R are examined in the different parts of different organs in mice.
Methods:
Male and healthy BALB/C mice (5-6 weeks old) weighing 17-20g are used. The mice are divided into control group (n=8) and GLP-2 treated group (n=9) randomly. GLP-2 treated group mice are given GLP-2 (250μg/kg) intraperitoneal injection twice per day for three days. Control group mice are given physiological saline intraperitoneal injection twice per day for three days. Three days later, mice are sacrificed and samples are taken in each group for morphological observations. The histological changes of gastrointestinal mucosa in mice are observed by dyeing with hematoxylin and eosin staining.The expression and distribution of GLP-2R in gastrointestinal tissue are detected by Immunohistochemistry.
Results:
1. After treating with GLP-2, the muscosa epithelium of stomach thickens and gastric pit deepens in mice.
2. Mucosal villus in different section of small intestine grow obviously higher in GLP-2 treated group compared with control group (P<0.05); Villus in small intestinal segment grows higher, crypt deepens, and colon mucosa epithelium thickens.
3. GLP-2R is widely expressed in each part of gastrointestinal tract in mice. The expression of GLP-2R is not observed in liver, lung, kidney and bladder.
4. No difference was observed in the expression of GLP-2R between GLP-2 treated group and control group(P﹥0.05).
Conclusions:
1. GLP-2 is able to stimulate gastric mucosa and colon epithelium mucosa to grow and increase mucosal villus height in different section of small intestine.
2. GLP-2R is widely expressed gastric, duodenal, jejunum, ileum and colon in mice, the expression of GL P-2R in liver,lung, kidney and bladder was not observed.
3. There is no difference for GLP-2R expression in the gastrointestinal tract in the mice between the normal group and GLP-2 treated group.
目的:观察GLP-2对小鼠胃肠道黏膜的作用效果;检测GLP-2R在小鼠不同脏器的分布和表达。
方法:选用5-6周龄的雄性健康BALB/C小鼠,体重17-20g。随机分为2组。对照组8只,处理组9只。GLP-2处理组:每天按250μg/kg腹腔注射GLP-2液两次,连续三天。实验对照组:每天等量腹腔注射生理盐水两次,连续三天。三天后,处死小鼠,每组抽取样本用于形态学观察。将组织切片进行HE染色,观察小鼠胃肠黏膜的组织学变化,用免疫组化方法检测GLP-2R在胃肠组织的表达和分布。
结果:
1、小鼠GLP-2处理后,胃黏膜上皮增厚,胃小凹加深。
2、GLP-2处理组小肠不同肠段黏膜的绒毛高度较对照组明显增加(P<0.05);绒毛增高,隐窝加深;结肠黏膜上皮增厚。
3、GLP-2R在小鼠胃肠道各部位均有表达,而肝、肺、肾与膀胱显阴性。
4、GLP-2处理组与对照组比较GLP-2R表达无差异(P﹥0.05)。
结论:
1、GLP-2能刺激胃黏膜与结肠黏膜上皮增厚,增加小肠不同肠段黏膜的绒毛高度。
2、小鼠的胃、十二指肠、空肠、回肠与结肠均有GLP-2R的表达,肝、肺、肾与膀胱无GLP-2R的表达。
3、小鼠经GLP-2处理后,其胃肠道的受体表达不受影响。
Gastrointestinal tract is the main place of digesting and absorbing nutritive materials in living organisms. Various stresses are apt to destroy the normal mucosa tissue structure of gastrointestinal tract and decrease the ability of absorbing and digesting nutritive materials. Previous studies showed that polypeptides growth factors, such as epidermal growth factor, transforming growth factor, insulin-like growth factor-1, took part in regulation of growth of intestinal epithelium and promoted regeneration and reparation of intestinal mucosa, but their clinical applications were limited due to the lack of tissue specificity and possible adverse reaction brought. Glucagon like peptide 2 (GLP-2) was discovered laterly, it could obviously and specifically promote intestinal tract to absorb nutritive materials, and more studies on the relations between GLP-2 and growth regulation of intestinal epithelium were reported in the recent decade.
Moreover, it has been reported that GLP-2 promoted the development of normal small intestine and recovering of pathological intestinal mucosa. GLP-2 stimulates generation and restraints its apoptosis by GLP-2R distributing in the enterocyte, and also plays the recuperative role of protecting intestinal cells and promoting intestinal function by GLP-2R distributing in the other parts of intestine. GLP-2 implements its biological effect by combining with GLP2 receptor (GLP-2R). GLP-2R-mediated cAMP-dependent signal transduction and phosphatidyl inositol 3-kinase (PI3-K) and mitogen-activated protein kinase ( MAPK ) presumbly are involved in the various effects of GLP2. However, the mechanism remains unclear. In this study, we try to observe the proliferative effect of GLP2 and GLP2R expression in gastrointestinal tract.
Objectives:
The effect of GLP-2 on gastrointestinal mucosa is observed and expression and distribution of GLP-2R are examined in the different parts of different organs in mice.
Methods:
Male and healthy BALB/C mice (5-6 weeks old) weighing 17-20g are used. The mice are divided into control group (n=8) and GLP-2 treated group (n=9) randomly. GLP-2 treated group mice are given GLP-2 (250μg/kg) intraperitoneal injection twice per day for three days. Control group mice are given physiological saline intraperitoneal injection twice per day for three days. Three days later, mice are sacrificed and samples are taken in each group for morphological observations. The histological changes of gastrointestinal mucosa in mice are observed by dyeing with hematoxylin and eosin staining.The expression and distribution of GLP-2R in gastrointestinal tissue are detected by Immunohistochemistry.
Results:
1. After treating with GLP-2, the muscosa epithelium of stomach thickens and gastric pit deepens in mice.
2. Mucosal villus in different section of small intestine grow obviously higher in GLP-2 treated group compared with control group (P<0.05); Villus in small intestinal segment grows higher, crypt deepens, and colon mucosa epithelium thickens.
3. GLP-2R is widely expressed in each part of gastrointestinal tract in mice. The expression of GLP-2R is not observed in liver, lung, kidney and bladder.
4. No difference was observed in the expression of GLP-2R between GLP-2 treated group and control group(P﹥0.05).
Conclusions:
1. GLP-2 is able to stimulate gastric mucosa and colon epithelium mucosa to grow and increase mucosal villus height in different section of small intestine.
2. GLP-2R is widely expressed gastric, duodenal, jejunum, ileum and colon in mice, the expression of GL P-2R in liver,lung, kidney and bladder was not observed.
3. There is no difference for GLP-2R expression in the gastrointestinal tract in the mice between the normal group and GLP-2 treated group.
引文
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13. Siglet D L,Bawazir O,Martin G R,et a1.Glucagon-like peptide-2 induces a specific pattern of adaptation in remnant jejunum.Dig Dis Sci,2006,51(9):1557-1566
14.赵希敏,刘霞. GLP-2对大鼠颅脑外伤后肠黏膜免疫功能的影响.医学信息:手术学分册,2008,21(5):434-436
15.陈振勇,冯贤松,杨鹏. GLP-2对实验性梗阻性黄疸小肠上皮细胞紧密连接的调控.中国普通外科杂志,2008,17(8):760-763
16.李杭,吴国豪,陈吉.肠道缺血再灌注后GLP-2对黏膜增殖的影响.浙江医学,2007,29(11):1161-1189
17.关莉莉,宫德正,田楠.胰高血糖素样肽-2对小鼠小肠缺血/再灌注损伤的保护作用.中国应用生理学杂志,2005,21(2):192-194
18.朱亮,宫德正,邹原.胰高血糖素样肽2对移植小肠结构和功能恢复的作用.中国组织工程研究与临床康复,2008,12(18):3401-3405
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21. Bjerknes M,Cheng H.Modulation of specific intestinal epithelial progenitors by enteric neurons.Proc Natl Acad SCi USA,2001,98(22): l2497-12502
22. Yusta B, Boushey R P and Drueker D J,The slucagon-like peptide-2 receptor mediates direct inhibition of celular apoptosis via a cAMP-dependent protein kinase-independent pathway.J Biol Chem,2000,275(45):35345-35352
23. Estall JL, Drucker DJ. Tales beyond the crypt: glucagon-like peptide-2 and cytoprotection in the intestinal mucosa. Endocrinology,2005,146(1):19-21
24. Sigalet DL, Wallace LE, Holst JJ, et a1.Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2. Am J Physiol Gastrointest Liver Physiol,2007,293(1): G211 - G221
25. Estall JL, Drucker DJ. Dual regulation of cell proliferation and survival via activation of glucagon-like peptide-2 receptor signaling. J Nutr , 2003 ,133(11):3708-3711
26. DubéPE, Brubaker PL. Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators. Am J Physiol Endocrinol Metab,2007,293(2):E460-465
27. Guan X, Karpen HE, Stephens J, et a1.GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow. Gastroenterology,2006,130(1):150-164
28. Nelson DW, Sharp JW, Brownfield MS, et a1.Localization and activation of GLP-2 receptors on vagal afferents in the rat. Endocrinology,2007,148(5):1954-1962
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31. Sandgren K, Lin Z, Svenningsen AF, et a1.Vasoactive intestinal peptide and nitric oxide promote survival of adult rat myenteric neurons in culture. J Neurosci Res,2003,72(5): 595–602
32. Ekelund M, Ekblad E. Intestinal adaptation in atrophic rat ileum is accompanied by supersensitivity to vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide and nitric oxide. Scand J Gastroenterol,2001,36(3): 251–257
33. Orskov C, Hartmann B, Poulsen SS, et a1.GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors. Regul Pept,2005,124(1-3): 105–112
34. Ramsanahie A, Duxbury MS, Grikscheit TC, et a1.Effect of GLP-2 on mucosal morphology and SGLT1 expression in tissue-engineered neointestine. Am J Physiol Gastrointest Liver Physiol,2003,285(6): G1345–G1352
35. Dube PE, Forse CL, Bahrami J, et a1.The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice. Gastroenterology,2006,131(2):589-605
36. Bennett WR, Crew TE, Slack JM, et a1. Structural-proliferative units and organ growth: Effects of insulin-like growth factor 2 on the growth of colon and skin. Development,2003,130(6): 1079–1088
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3. Yusta B,Huang L,Munroe D,et a1.Enteroendocrine localization of GLP-2 receptor expression in humans and rodents.Gastroenterology,2000,ll9(3):744-755
4. Yusta B, Boushey R P and Drueker D J,The slucagon-like peptide-2receptor mediates direct inhibition of celular apoptosis via a cAMP-dependent protein kinase-independent pathway.J Biol Chem,2000,275(45):35345-35352
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8. Pedersen N B,Hjollund K R,Johnsen A H,et a1.Porcine Glucagon-like peptide-2:Structure, signaling, metabolism and ef-fects.Regul Pept,2008,146(1-3):310-320
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12. Zhang W,Zhu W M,Zhang J,et a1.Protective effects of glucagon-like peptide 2 on intestinal ischemia-reperfusion rats.Microsurgery,2008,28(4):285-290
13. Siglet D L,Bawazir O,Martin G R,et a1.Glucagon-like peptide-2 induces a specific pattern of adaptation in remnant jejunum.Dig Dis Sci,2006,51(9):1557-1566
14.赵希敏,刘霞. GLP-2对大鼠颅脑外伤后肠黏膜免疫功能的影响.医学信息:手术学分册,2008,21(5):434-436
15.陈振勇,冯贤松,杨鹏. GLP-2对实验性梗阻性黄疸小肠上皮细胞紧密连接的调控.中国普通外科杂志,2008,17(8):760-763
16.李杭,吴国豪,陈吉.肠道缺血再灌注后GLP-2对黏膜增殖的影响.浙江医学,2007,29(11):1161-1189
17.关莉莉,宫德正,田楠.胰高血糖素样肽-2对小鼠小肠缺血/再灌注损伤的保护作用.中国应用生理学杂志,2005,21(2):192-194
18.朱亮,宫德正,邹原.胰高血糖素样肽2对移植小肠结构和功能恢复的作用.中国组织工程研究与临床康复,2008,12(18):3401-3405
19. Lovshin J, Yusta B, Iliopoulos I,et a1. Ontogeny of the glucagon-like peptide-2 receptor axis in the developing rat intestine. Endocrinology,2000,141(11): 4194-4201
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21. Bjerknes M,Cheng H.Modulation of specific intestinal epithelial progenitors by enteric neurons.Proc Natl Acad SCi USA,2001,98(22): l2497-12502
22. Yusta B, Boushey R P and Drueker D J,The slucagon-like peptide-2 receptor mediates direct inhibition of celular apoptosis via a cAMP-dependent protein kinase-independent pathway.J Biol Chem,2000,275(45):35345-35352
23. Estall JL, Drucker DJ. Tales beyond the crypt: glucagon-like peptide-2 and cytoprotection in the intestinal mucosa. Endocrinology,2005,146(1):19-21
24. Sigalet DL, Wallace LE, Holst JJ, et a1.Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2. Am J Physiol Gastrointest Liver Physiol,2007,293(1): G211 - G221
25. Estall JL, Drucker DJ. Dual regulation of cell proliferation and survival via activation of glucagon-like peptide-2 receptor signaling. J Nutr , 2003 ,133(11):3708-3711
26. DubéPE, Brubaker PL. Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators. Am J Physiol Endocrinol Metab,2007,293(2):E460-465
27. Guan X, Karpen HE, Stephens J, et a1.GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow. Gastroenterology,2006,130(1):150-164
28. Nelson DW, Sharp JW, Brownfield MS, et a1.Localization and activation of GLP-2 receptors on vagal afferents in the rat. Endocrinology,2007,148(5):1954-1962
29. Niinikoski H, Stoll B, Guan X, et a1. Onset of small intestinal atrophy is associated with reduced intestinal blood flow in TPN-fed neonatal piglets. J Nutr,2004,134(6): 1467–1474
30. Guan X, Stoll B, Lu X, et a1.GLP-2-mediated up-regulation of intestinal blood flow and glucose uptake is nitric oxide-dependent in TPN-fed piglets. Gastroenterology,2003,125(1):136-47
31. Sandgren K, Lin Z, Svenningsen AF, et a1.Vasoactive intestinal peptide and nitric oxide promote survival of adult rat myenteric neurons in culture. J Neurosci Res,2003,72(5): 595–602
32. Ekelund M, Ekblad E. Intestinal adaptation in atrophic rat ileum is accompanied by supersensitivity to vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide and nitric oxide. Scand J Gastroenterol,2001,36(3): 251–257
33. Orskov C, Hartmann B, Poulsen SS, et a1.GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors. Regul Pept,2005,124(1-3): 105–112
34. Ramsanahie A, Duxbury MS, Grikscheit TC, et a1.Effect of GLP-2 on mucosal morphology and SGLT1 expression in tissue-engineered neointestine. Am J Physiol Gastrointest Liver Physiol,2003,285(6): G1345–G1352
35. Dube PE, Forse CL, Bahrami J, et a1.The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice. Gastroenterology,2006,131(2):589-605
36. Bennett WR, Crew TE, Slack JM, et a1. Structural-proliferative units and organ growth: Effects of insulin-like growth factor 2 on the growth of colon and skin. Development,2003,130(6): 1079–1088