血管紧张素转换酶调控SBS大鼠肠上皮细胞凋亡的机制
|
摘要
短肠综合征(Short Bowel Syndrome, SBS)是由于不同原因造成小肠吸收面积减少而引起的一个临床症候群,主要表现为腹泻和严重的营养障碍[1]。SBS造成了一系列的肠道代偿过程[2-4],主要包括肠道粘膜吸收面积的增加(结构性代偿)和增加肠道粘膜对营养物的吸收(功能性代偿),这种代偿作用是SBS患者得以康复的基础和保证,如何改善剩余肠段的适应性代偿包括结构性和功能性代偿是防止肠功能衰竭的关键。适应性增生的过程不仅包括肠上皮细胞的增殖,还包括了肠切除后肠上皮细胞凋亡的增加[10, 11],凋亡和增殖这两种相反的代偿过程,共同参与了肠粘膜的结构重塑。如何促进肠切除术后肠上皮细胞的增殖,抑制肠上皮的凋亡对于促进SBS小肠的适应性代偿,提高小肠功能,促进患者机体康复至关重要。
有研究发现,血管紧张素转换酶(Angiotensin converting enzyme, ACE)在肺上皮细胞和心肌细胞的凋亡中起着重要的作用,在肠道非血管区也发现了ACE的表达,通过SBS动物模型和ACE基因敲除小鼠SBS模型的研究证实,肠道表达的ACE与肠切除术后的肠粘膜适应性代偿关系密切,ACE可能通过促进上皮凋亡在上皮重塑中发挥一定的负向调控作用,抑制ACE功能可能在肠切除术后肠粘膜适应性代偿中发挥积极地作用。我们通过建立大鼠SBS模型,利用ACE抑制剂(ACEI)依那普利(enalaprilat),研究ACEI是否对肠切除术后的肠粘膜的代偿具有促进作用。
方法:
1、雄性SD成年大鼠18只随机分三组:(1)Sham组(n=6),行小肠离断吻合术;(2)SBS组(n=6),切除大约75%中段小肠并行小肠端端吻合术;(3)ACEI组(n=6),切除大约75%中段小肠并行小肠端端吻合术,术后采用灌胃法注入ACEI 2mg?kg-1?d-1。记录大鼠术后体重变化,术后10天取材,测量大鼠小肠绒毛高度、隐窝深度和粘膜层厚度的组织学变化,TUNEL法检测肠上皮细胞凋亡情况。
2、取材后,免疫组化和激光共聚焦测定大鼠肠粘膜ACE表达的变化,RT-PCR法检测肠粘膜ACE mRNA表达变化,了解ACEI作用后对肠粘膜ACE mRNA表达的影响。
3、免疫组化和激光共聚焦法测定大鼠肠粘膜血管紧张素II受体AT1R、AT2R表达的变化,分别用RT-PCR、Real time PCR法检测肠粘膜AT1R、AT2R mRNA表达的改变。
结果:
1、术后ACEI组体重恢复速度快于SBS组[(7.51±2.28)% vs. (1.54±3.05)%,P﹤0.05],但二者都低于对照组[(18.79±2.53)%,P﹤0.01]。
2、手术组粘膜绒毛较对照组明显增生肥大,绒毛高度和隐窝深度(总高度)增加约50%[(778±30μm) vs. (502±40μm), P﹤0.01],给予ACEI后,肠粘膜厚度较SBS组增高更明显[(870±29μm),P﹤0.05]。
3、肠切除术后肠上皮细胞凋亡显著增加[(5.46±0.95)% vs. (1.01±0.49)%, P﹤0.05],而给予ACEI后肠上皮细胞凋亡明显减少[(2.39±0.70)%, P﹤0.05]。
4、SBS组ACE mRNA表达较对照组明显增高[(0.24±0.07)% vs. (0.42±0.11)%, (P﹤0.05)],给予ACEI后ACE水平进一步增高[(0.54±0.12)%, (P﹤0.05)]。
5、SBS组AT1R表达下调,但AT2R变化并不明显,ACEI摄入后AT1R、AT2R表达均升高。
结论:
肠切除后ACE的升高与上皮细胞凋亡相关的粘膜结构性代偿密切相关,ACEI的应用可以抑制肠上皮细胞凋亡,促进肠粘膜适应性代偿;ANGII受体可能是ACE调控肠上皮细胞凋亡的重要环节。
Background: Short bowel syndrome is a clinical syndrome due to different causes reduced intestinal absorption area, mainly diarrhea and severe nutritional disorder. After massive small bowel resection (SBR), the residual intestine undergoes a series of adaptive processes resulting in a significant increase in intestinal absorptive surface area. In addition to an increase in functional absorption, adaptation also consists of an increase in villus length and crypt depth, and an increased number of microvilli. This compensatory role is to rehabilitate patients with short bowel syndrome in the foundation and guarantee for how to improve the adaptability of the remaining bowel compensation, including structural and functional compensation is the key to prevention of intestinal failure. This adaptation requires a remodeling of the crypt-villus complex and includes significant increases in both epithelial cell (EC) proliferation as well as EC apoptosis, and both of these two opposing processes participate in the remodeling of the intestinal mucosa. To promote intestinal epithelial cell proliferation and inhibit apoptosis is critical to promote the rehabilitation of patients undergoes SBR.
Angiotensin converting enzyme (ACE) has been previously detected in the mucosal epithelium in human, rat, as well as mouse intestine. Because ACE has been shown to promote apoptosis in various tissues. SBS was associated with an increase ACE expression. ACE appears to be associated with an up-regulation of intestinal EC apoptosis. The inhibition of ACE can promote the mucosal adaptation after intestinal resection. In this study, we investigate the effects of ACEI (ACE inhibitor, enalaprilat) on the bowel adaptation in a massive intestinal resection rat model and the pathway by which ACE modulates EC apoptosis.
Methods: Sprague-Dawley rat were used, and were divided into three groups: 1) Sham group, received a ileum transection (n=6); 2) SBS group, received a 75% mid-intestinal resection (n=6); 3) ACEI group, received a 75% mid-intestinal resection, and lavage with ACE inhibitor (ACEI, enalaprilat, 2mg?kg-1?d-1)(n=6). All rats were provided with ordinary rat chow ad libitum after surgery. Recording body weight changes in rats everyday. Sampling was done 10 days after resection. Measuring intestinal villus height, crypt depth and mucosal thickness of histological changes, TUNEL assay was used to detect EC apoptosis. ACE、angiotensin II (ANGII) receptor type 1 (AT1R)、receptor type 2(AT2R) expression were detected with RT-PCR and immunofluorescent confocal microscopy.
Results:
1、After massive bowel resection,the body weight recovery in ACEI group is faster than that in SBS group [(7.51±2.28) % vs. (1.54±3.05)%, P﹤0.05], but both are lower than the control group [(18.79±2.53)%,P﹤0.01] 10 days after surgery.
2、Massive bowel resection led to significant intestinal hypertrophy. There was an increase in both villus height and crypt depth (total height) in the SBS group. Total height was increased about 50% compared with the sham group [(778±30μm) vs. (502±40μm), P﹤0.01], and the SBS+ACEI group was about 14% higher than the SBS group[(870±29μm), P﹤0.05].
3、Bowel resection led to an increase in intestinal EC apoptosis [(5.46±0.95)% vs. (1.01±0.49)%, P﹤0.05]. And the addition of ACEI to SBS rat resulted in a significant decline in EC apoptosis [(2.39±0.70)%, P﹤0.05].
4、The expression of ACE mRNA was significantly elevated after SBS creation [(0.24±0.07)% vs. (0.42±0.11)%, (P﹤0.05)] and ACEI administration further increased mucosal ACE expression [(0.54±0.12)%, (P﹤0.05)].
5、After massive bowel resection, AT1R expression showed a significant decline,but there is no significant difference in AT2R expression was found between untreated Sham and SBS groups. And ACEI administration increased both AT1R and AT2R expression to SBS levels significantly.
Conclusion: These results offer further insight into the role of ACE on intestinal mucosal remolding after massive bowel resection. ANGII receptor may be of very importance for ACE in the modulation of intestinal adaptation.
有研究发现,血管紧张素转换酶(Angiotensin converting enzyme, ACE)在肺上皮细胞和心肌细胞的凋亡中起着重要的作用,在肠道非血管区也发现了ACE的表达,通过SBS动物模型和ACE基因敲除小鼠SBS模型的研究证实,肠道表达的ACE与肠切除术后的肠粘膜适应性代偿关系密切,ACE可能通过促进上皮凋亡在上皮重塑中发挥一定的负向调控作用,抑制ACE功能可能在肠切除术后肠粘膜适应性代偿中发挥积极地作用。我们通过建立大鼠SBS模型,利用ACE抑制剂(ACEI)依那普利(enalaprilat),研究ACEI是否对肠切除术后的肠粘膜的代偿具有促进作用。
方法:
1、雄性SD成年大鼠18只随机分三组:(1)Sham组(n=6),行小肠离断吻合术;(2)SBS组(n=6),切除大约75%中段小肠并行小肠端端吻合术;(3)ACEI组(n=6),切除大约75%中段小肠并行小肠端端吻合术,术后采用灌胃法注入ACEI 2mg?kg-1?d-1。记录大鼠术后体重变化,术后10天取材,测量大鼠小肠绒毛高度、隐窝深度和粘膜层厚度的组织学变化,TUNEL法检测肠上皮细胞凋亡情况。
2、取材后,免疫组化和激光共聚焦测定大鼠肠粘膜ACE表达的变化,RT-PCR法检测肠粘膜ACE mRNA表达变化,了解ACEI作用后对肠粘膜ACE mRNA表达的影响。
3、免疫组化和激光共聚焦法测定大鼠肠粘膜血管紧张素II受体AT1R、AT2R表达的变化,分别用RT-PCR、Real time PCR法检测肠粘膜AT1R、AT2R mRNA表达的改变。
结果:
1、术后ACEI组体重恢复速度快于SBS组[(7.51±2.28)% vs. (1.54±3.05)%,P﹤0.05],但二者都低于对照组[(18.79±2.53)%,P﹤0.01]。
2、手术组粘膜绒毛较对照组明显增生肥大,绒毛高度和隐窝深度(总高度)增加约50%[(778±30μm) vs. (502±40μm), P﹤0.01],给予ACEI后,肠粘膜厚度较SBS组增高更明显[(870±29μm),P﹤0.05]。
3、肠切除术后肠上皮细胞凋亡显著增加[(5.46±0.95)% vs. (1.01±0.49)%, P﹤0.05],而给予ACEI后肠上皮细胞凋亡明显减少[(2.39±0.70)%, P﹤0.05]。
4、SBS组ACE mRNA表达较对照组明显增高[(0.24±0.07)% vs. (0.42±0.11)%, (P﹤0.05)],给予ACEI后ACE水平进一步增高[(0.54±0.12)%, (P﹤0.05)]。
5、SBS组AT1R表达下调,但AT2R变化并不明显,ACEI摄入后AT1R、AT2R表达均升高。
结论:
肠切除后ACE的升高与上皮细胞凋亡相关的粘膜结构性代偿密切相关,ACEI的应用可以抑制肠上皮细胞凋亡,促进肠粘膜适应性代偿;ANGII受体可能是ACE调控肠上皮细胞凋亡的重要环节。
Background: Short bowel syndrome is a clinical syndrome due to different causes reduced intestinal absorption area, mainly diarrhea and severe nutritional disorder. After massive small bowel resection (SBR), the residual intestine undergoes a series of adaptive processes resulting in a significant increase in intestinal absorptive surface area. In addition to an increase in functional absorption, adaptation also consists of an increase in villus length and crypt depth, and an increased number of microvilli. This compensatory role is to rehabilitate patients with short bowel syndrome in the foundation and guarantee for how to improve the adaptability of the remaining bowel compensation, including structural and functional compensation is the key to prevention of intestinal failure. This adaptation requires a remodeling of the crypt-villus complex and includes significant increases in both epithelial cell (EC) proliferation as well as EC apoptosis, and both of these two opposing processes participate in the remodeling of the intestinal mucosa. To promote intestinal epithelial cell proliferation and inhibit apoptosis is critical to promote the rehabilitation of patients undergoes SBR.
Angiotensin converting enzyme (ACE) has been previously detected in the mucosal epithelium in human, rat, as well as mouse intestine. Because ACE has been shown to promote apoptosis in various tissues. SBS was associated with an increase ACE expression. ACE appears to be associated with an up-regulation of intestinal EC apoptosis. The inhibition of ACE can promote the mucosal adaptation after intestinal resection. In this study, we investigate the effects of ACEI (ACE inhibitor, enalaprilat) on the bowel adaptation in a massive intestinal resection rat model and the pathway by which ACE modulates EC apoptosis.
Methods: Sprague-Dawley rat were used, and were divided into three groups: 1) Sham group, received a ileum transection (n=6); 2) SBS group, received a 75% mid-intestinal resection (n=6); 3) ACEI group, received a 75% mid-intestinal resection, and lavage with ACE inhibitor (ACEI, enalaprilat, 2mg?kg-1?d-1)(n=6). All rats were provided with ordinary rat chow ad libitum after surgery. Recording body weight changes in rats everyday. Sampling was done 10 days after resection. Measuring intestinal villus height, crypt depth and mucosal thickness of histological changes, TUNEL assay was used to detect EC apoptosis. ACE、angiotensin II (ANGII) receptor type 1 (AT1R)、receptor type 2(AT2R) expression were detected with RT-PCR and immunofluorescent confocal microscopy.
Results:
1、After massive bowel resection,the body weight recovery in ACEI group is faster than that in SBS group [(7.51±2.28) % vs. (1.54±3.05)%, P﹤0.05], but both are lower than the control group [(18.79±2.53)%,P﹤0.01] 10 days after surgery.
2、Massive bowel resection led to significant intestinal hypertrophy. There was an increase in both villus height and crypt depth (total height) in the SBS group. Total height was increased about 50% compared with the sham group [(778±30μm) vs. (502±40μm), P﹤0.01], and the SBS+ACEI group was about 14% higher than the SBS group[(870±29μm), P﹤0.05].
3、Bowel resection led to an increase in intestinal EC apoptosis [(5.46±0.95)% vs. (1.01±0.49)%, P﹤0.05]. And the addition of ACEI to SBS rat resulted in a significant decline in EC apoptosis [(2.39±0.70)%, P﹤0.05].
4、The expression of ACE mRNA was significantly elevated after SBS creation [(0.24±0.07)% vs. (0.42±0.11)%, (P﹤0.05)] and ACEI administration further increased mucosal ACE expression [(0.54±0.12)%, (P﹤0.05)].
5、After massive bowel resection, AT1R expression showed a significant decline,but there is no significant difference in AT2R expression was found between untreated Sham and SBS groups. And ACEI administration increased both AT1R and AT2R expression to SBS levels significantly.
Conclusion: These results offer further insight into the role of ACE on intestinal mucosal remolding after massive bowel resection. ANGII receptor may be of very importance for ACE in the modulation of intestinal adaptation.
引文
1. Nightingale J, Woodward JM. Guidelines for management of patients with a short bowel. Gut 2006; 55 Suppl 4:1-12.
2. Ray EC, Avissar NE, Sax HC. Growth factor regulation of enterocyte nutrient transport during intestinal adaptation. Am J Surg 2002; 183: 361–371.
3. Westergaard H. Short bowel syndrome. Seminars in Gastrointestinal Disease 2002; 13: 210–220.
4. Vanderhoof JA, Langnas AN, Pinch LW, et al. Short bowel syndrome. J Pediatr Gastroenterol Nutr 1992; 14: 359–370.
5. Byrne TA, Wilmore DW, Iyer K, et al. Growth hormone, glutamine, and an op timal diet reduces parenteral nutrition in patientswith short bowel syndrome: a p rospective, randomized, p lacebo - controlled, double - blind clinical trial[ J ]. Ann Surg 2005; 242 (5) : 655-661.
6. Haxhija EQ, Yang H, Spencer AU, et al. Influence of the site of small bowel resection on intestinal epithelial cell apoptosis. Pediatr Surg Int 2006; 22: 37–42.
7. Stern LE, Huang F, Kemp CJ, et al. Bax is required for increased enterocyte apoptosis after massive small bowel resection. Surgery 2000; 128: 165–170.
8. Wildhaber BE, Yang H, Coran AG, et al. Gene alteration of intestinal intraepithelial lymphocytes in response to massive small bowel resection. Pediatr Surg Int 2003; 19: 310–315.
9. Wildhaber BE, Yang H, Haxhija EQ, et al. Intestinal intraepithelial lymphocyte derived angiotensin converting enzyme modulates epithelial cell apoptosis. Apoptosis 2005;10: 1305–1315.
10. Yang H, Jorgen Larsson, Johan Permert, et al. Bolus ornithine and arginine-ketoglutarate supplementation in distal intestine after 65% resection in rats. Nutrition Research 2000; 20(12): 1807-1816.
11.朱华,高虹,黄澜等。清洁级SD大鼠标准生物学指标的建立。医学动物防制,2005;21(9): 629-633。
12. Sundaram A, Koutkia P, Apovian CM. Nutritional management of short bowel syndrome in adults, J Clin Gastroenterol 2002; 34(3):207-220.
13. Welters CFM, Piersma FE, Hockenbery DM, et al. The role of apoptosis during intestinal adaptation after small bowel resection. J Pediatr Surg 2000; 35: 20–24.
14. Erwin CR, Falcone Jr RA, Stern LE, et al. Analysis of intestinal adaptation gene expression by cDNA expression arrays. J. Parenter. Enteral Nutr 2000; 24: 311–316.
15. Helmrath MA, Erwin CR, Shin CE, et al. Enterocyte apoptosis is increased following small bowel resection. J. Gastrointest. Surg 1998; 2: 44–49.
16. Sigalet DL, Bawazir O, Martin GR, et al. Glucagon-like peptide-2 induces a specific pattern of adaptation in remnant jejunum. Dig Dis Sci 2006; 51(9):1557-1566.
17. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev 2006; 86(3):747-803.
18. Wong TP, Debnam ES, Leung PS. Involvement of an enterocyte renin-angiotensin system in the local control of SGLT1-dependent glucose uptake across the rat small intestinal brush border membrane. J Physiol 2007; 584(Pt 2):613-623.
19. Li X, Rayford H, Uhal BD. Essential roles for angiotensin receptor AT1a in bleomycin-induced apoptosis and lung fibrosis in mice. Am J Pathol 2003; 163: 2523–2530.
20. Sabri A, Levy B, Poitevin P, et al. Differential roles of AT1 and AT2 receptor subtypes in vascular trophic and phenotypic changes in response to stimulation with angiotensin II. Arterioscler Thromb Vasc Biol 1997; 17: 257–264.
21. Suzuki J, Iwai M, Nakagami H, et al. Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation. Circulation 2002; 106: 847–852.
22. Alcantara CS, Jin XH, Brito GA, et al. Angiotensin II subtype 1 receptor blockade inhibits Clostridium difficile toxin A-induced intestinal secretion in a rabbit model. J Infect Dis 2005; 191(12):2090-2096.
1. Nightingale J, Woodward JM. Guidelines for management of patients with a short bowel. Gut 2006; 55 Suppl 4:1-12.
2. John KD, Rosemary JY, Jon AV, et al. Intestinal rehabilitation and the short bowel syndrome: part 1.Am J Gastroenterology 2004; 99(6):1386 -1395.
3.吴肇汉。重视短肠综合征的预防与治疗。中国实用外科杂志2005;11( 25):643-644。
4. Haxhija EQ, Yang H, Spencer AU, et al. Influence of the site of small bowel resection on intestinal epithelial cell apoptosis. Pediatr Surg Int 2006; 22: 37–42.
5. Messing. B, Pigot. F, Bongire. M. et al. Intestinal absorption of free oral hyperalimentation in the very short bowel syndrome. Gastroenterology 1991; 100: 1502.
6. Vanderhoof JA, Langnas LN. Short bowel syndrome in children and adults.Gastroenterology 1997; 113(5):1767-1778.
7. Strum A,Layer D , Goebell H, et al . Short bowel syndrome:an update on the therapeutic approach. Scand J Gastroenterol 1997; 32(4):289-296.
8. Byrne TA, Wilmore DW, Iyer K, et al. Growth hormone, glutamine, and an op timal diet reduces parenteral nutrition in patientswith short bowel syndrome: a prospective, randomized, placebo-controlled, double-blind clinical trial[J]. Ann Surg 2005; 242(5): 655-661.
9. Mardini HE;de Villiers WJ. Teduglutide in intestinal adaptation and repair: light at the end of the tunnel. Expert Opin Investig Drugs 2008; 17(6): 945-951.
10. De Francesco A, Malfi G, Delsedime L, et al. De Francesco A, Malfi G, Delsedime L, et al. Histological findings regarding jejunal mucosal in short bowel syndrome. Transplant Proc 1994; 26: 1455–1456.
11. O’Keefe S, Shorter R, Bennet W, et al. O’Keefe S, Shorter R, Bennet W, et al. Villous hyperplasia is uncommon in patients with massive intestinal resection. Gastroenterology 1992; 102: A231.
12. Williamson R. Williamson R. Intestinal adaptation. structural, functional, and cytokinetic changes. N Engl J Med 1978; 298: 1393–1402.
13. Erwin CR, Falcone Jr RA, Stern LE, et al. Analysis of intestinal adaptation gene expression by cDNA expression arrays. J Parenter Enteral Nutr 2000; 24: 311–316.
14. Helmrath MA, Erwin CR, Shin CE, et al. Enterocyte apoptosis is increased following small bowel resection. J. Gastrointest. Surg 1998; 2: 44–49.
15. Igor Sukhotnik, Leonardo Siplovich, Michael M. Krausz, et al. Peptide Growth Factors and Intestinal Adaptation in Short Bowel Syndrome. IMAJ 2003; 5: 184-187.
16. Oliver BL, Sha'afi RI, Hajjar JJ. Transforming growth factor alpha and epidermal growth factor activate mitogen-activated protein kinase and its substrates in intestinal epithelial cells. Proc Soc Exp Biol Med 1995; 210: 162-170.
17. Hodin R A, Graham J R, Meng S, et al. Temporal pattern of rat small intestinal gene expression with refeeding. Am J Physiol 1994; 266: G83–G89.
18. Elizabeth M Dahly, Megan E Miller, P Kay Lund, et al. Postreceptor Resistance to Exogenous Growth Hormone Exists in the Jejunal Mucosa of Parenterally Fed Rats. J. Nutr 2004; 134: 530–537.
19. Welters CFM, Piersma FE, Hockenbery DM, et al. The role of apoptosis during intestinal adaptation after small bowel resection. J Pediatr Surg 2000; 35: 20–24.
20. Shin CE, Falcone Jr RA, Kemp CJ et al. Intestinal adaptation and enterocyte apoptosis following small bowel resection is p53 independent. Am. J. Physiol 1999; 277: G717–724.
21. Stern LE, Falcone Jr RA, Huang F, et al. Epidermal growth factor alters the bax : bcl-w ratio following massive small bowel resection. J Surg Res 2000; 91: 38–42.
22. Kavita Bisht, Karl-Heinz Wagner, Andrew C. Bulmer. Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds. Toxicology 2009; 11: 008
23. Stern LE, Huang F, Kemp CJ, et al. Bax is required for increased enterocyte apoptosis after massive small bowel resection. Surgery 2000; 128: 165–170.
24. Tang Y, Swartz-Basile DA, Swietlicki EA, et al. Tang Y, Swartz-Basile DA, Swietlicki EA, et al. Bax is required for resection-induced changes in apoptosis, proliferation, and members of the extrinsic cell death pathways. Gastroenterology 2004; 126: 220–230.
25. Weser E, Heller R, Tawil T. Stimulation of mucosal growth in rat ileum by bile and pancreatic secretions after jejunal resection. Gastroenterology 1977; 73: 524–529.
26. Coster J, McCauley R, Hall J. Glutamine: metabolism and application in nutrition support[J]. Asia Pac J Clin Nutr 2004; 13(1): 25.
27. Hua Yang, Daniel H. Teitelbaum. Novel Agents in the Treatment of Intestinal Failure: Humoral Factors. Gastroenterology 2006; 130(2 Suppl 1): S117–S121.
28. Mainoya JR. Influence of bovine growth hormone on water and NaCl absorption by the rat proximal jejunum and distal ileum. Comp Biochem Physiol 1982; 71: 477–479.
29. Gu Y, Wu ZH, Xie JX, et al. Effects of growth hormone (rhGH) and glutamine supplemented parenteral nutrition on intestinal adaptation in short bowel rats. Clin Nutr 2001; 20: 159–166.
30. Zhou X, Li YX, Li N, et al. Glutamine enhances the gut-trophic effect of growth hormone in rat after massive small bowel resection. J Surg Res 2001; 99: 47–52.
31. Sigalet DL, Martin GR, Butzner JD, et al. A pilot study of the use of epidermal growth factor in pediatric short bowel syndrome. J Pediatr Surg 2005; 40: 763–768.
32. Park JH, Vanderhoof JA. Growth hormone did not enhance mucosal hyperplasia aftersmall-bowel resection. Scand. J. Gastroenterol 1996; 31: 349–354.
33. Garcia-Sancho Tellez L Jr, Gomez de Segura IA, Vazquez I, et al. Growth hormone effects in intestinal adaptation after massive bowel resection in the suckling rat. J. Pediatr. Gastroenterol. Nutr 2001; 33: 477–482.
34. Byrne TA, Morrissey TB, Nattakom TV, et al. Growth hormone, glutamine, and a modified diet enhance nutrient absorption in patients with severe short bowel syndrome. J Parent Enteral Nutr 1995; 19: 296–302.
35. Peterson C, Carey H, Hinton P, et al. Peterson C, Carey H, Hinton P, et al. GH elevates serum IGF-1 levels but does not alter mucosal atrophy in parenterally fed rats. Am J Physiol 1997; 272: G1100–1108.
36. Lund P. Lund P. Molecular basis of intestinal adaptation. the role of the insulin-like growth factor system. Ann N Y Acad Sci 1998; 859: 18–36.
37. Nightingale J. Intestinal failure. London Greenwich Medical Media Limited 2001.
38. Chaet MS, Arya G, Ziegler MM, et al. Epidermal growth factor enhances intestinal adaptation after massive small bowel resection. J. Pediatr. Surg 1994; 29: 1035–1039.
39. Helmrath MA, Erwin CR, Warner BW. A defective EGF-receptor in waved-2 mice attenuates intestinal adaptation. J Surg Res 1997; 69: 76–80.
40. Helmrath MA, Shin CE, Fox JW, et al. Adaptation after small bowel resection is attenuated by sialoadenectomy: the role for endogenous epidermal growth factor. Surgery 1998; 124: 848–854.
41. Sullivan PB, Brueton MJ, Tabara ZB, et al. Epidermal growth factor in necrotising enteritis. Lancet 1991; 338: 53–54.
42. Jeppesen PB. Clinical significance of GLP-2 in short-bowel syndrome. J Nutr 2003; 133: 3771–3774.
43. Jeppesen PB, Hartmann B, Thulesen J, et al. Elevated plasma glucagon-like peptide 1 and 2 concentrations in ileum resected short bowel patients with a preserved colon. Gut 2000; 47: 370–376.
44. Dahly EM, Gillingham MB, Guo Z, et al. Role of luminal nutrients and endogenous GLP-2 in intestinal adaptation to mid-small bowel resection. Am J Physiol Gastrointest Liver Physiol 2003; 284: 670–682.
45. Martin GR, Wallace LE, Hartmann B et al. Nutrient-stimulated GLP-2 release and cryptcell proliferation in experimental short bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol 2005; 288: 431–438.
46. Martin GR, Wallace LE, Sigalet DL. Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol 2004; 286: 964–972.
47. Jeppesen PB, Hartmann B, Thulesen J et al. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology 2001; 120: 806–815.
48. Jeppesen PB, Sanguinetti EL, Buchman A et al. Teduglutide (ALX- 0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut 2005; 54: 1224–1231.
49. Wildhaber BE, Yang H, Coran AG, et al. Gene alteration of intestinal intraepithelial lymphocytes in response to massive small bowel resection. Pediatr Surg Int 2003; 19: 310–315.
50. Wildhaber BE, Yang H, Haxhija EQ, et al. Intestinal intraepithelial lymphocyte derived angiotensin converting enzyme modulates epithelial cell apoptosis. Apoptosis 2005; 10: 1305–1315.
51. Yang H, Daniel H. Teitelbaum. Novel Agents in the Treatment of Intestinal Failure: Humoral Factors. Gastroenterology 2006; 130(2 Suppl 1): S117–S121.
2. Ray EC, Avissar NE, Sax HC. Growth factor regulation of enterocyte nutrient transport during intestinal adaptation. Am J Surg 2002; 183: 361–371.
3. Westergaard H. Short bowel syndrome. Seminars in Gastrointestinal Disease 2002; 13: 210–220.
4. Vanderhoof JA, Langnas AN, Pinch LW, et al. Short bowel syndrome. J Pediatr Gastroenterol Nutr 1992; 14: 359–370.
5. Byrne TA, Wilmore DW, Iyer K, et al. Growth hormone, glutamine, and an op timal diet reduces parenteral nutrition in patientswith short bowel syndrome: a p rospective, randomized, p lacebo - controlled, double - blind clinical trial[ J ]. Ann Surg 2005; 242 (5) : 655-661.
6. Haxhija EQ, Yang H, Spencer AU, et al. Influence of the site of small bowel resection on intestinal epithelial cell apoptosis. Pediatr Surg Int 2006; 22: 37–42.
7. Stern LE, Huang F, Kemp CJ, et al. Bax is required for increased enterocyte apoptosis after massive small bowel resection. Surgery 2000; 128: 165–170.
8. Wildhaber BE, Yang H, Coran AG, et al. Gene alteration of intestinal intraepithelial lymphocytes in response to massive small bowel resection. Pediatr Surg Int 2003; 19: 310–315.
9. Wildhaber BE, Yang H, Haxhija EQ, et al. Intestinal intraepithelial lymphocyte derived angiotensin converting enzyme modulates epithelial cell apoptosis. Apoptosis 2005;10: 1305–1315.
10. Yang H, Jorgen Larsson, Johan Permert, et al. Bolus ornithine and arginine-ketoglutarate supplementation in distal intestine after 65% resection in rats. Nutrition Research 2000; 20(12): 1807-1816.
11.朱华,高虹,黄澜等。清洁级SD大鼠标准生物学指标的建立。医学动物防制,2005;21(9): 629-633。
12. Sundaram A, Koutkia P, Apovian CM. Nutritional management of short bowel syndrome in adults, J Clin Gastroenterol 2002; 34(3):207-220.
13. Welters CFM, Piersma FE, Hockenbery DM, et al. The role of apoptosis during intestinal adaptation after small bowel resection. J Pediatr Surg 2000; 35: 20–24.
14. Erwin CR, Falcone Jr RA, Stern LE, et al. Analysis of intestinal adaptation gene expression by cDNA expression arrays. J. Parenter. Enteral Nutr 2000; 24: 311–316.
15. Helmrath MA, Erwin CR, Shin CE, et al. Enterocyte apoptosis is increased following small bowel resection. J. Gastrointest. Surg 1998; 2: 44–49.
16. Sigalet DL, Bawazir O, Martin GR, et al. Glucagon-like peptide-2 induces a specific pattern of adaptation in remnant jejunum. Dig Dis Sci 2006; 51(9):1557-1566.
17. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev 2006; 86(3):747-803.
18. Wong TP, Debnam ES, Leung PS. Involvement of an enterocyte renin-angiotensin system in the local control of SGLT1-dependent glucose uptake across the rat small intestinal brush border membrane. J Physiol 2007; 584(Pt 2):613-623.
19. Li X, Rayford H, Uhal BD. Essential roles for angiotensin receptor AT1a in bleomycin-induced apoptosis and lung fibrosis in mice. Am J Pathol 2003; 163: 2523–2530.
20. Sabri A, Levy B, Poitevin P, et al. Differential roles of AT1 and AT2 receptor subtypes in vascular trophic and phenotypic changes in response to stimulation with angiotensin II. Arterioscler Thromb Vasc Biol 1997; 17: 257–264.
21. Suzuki J, Iwai M, Nakagami H, et al. Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation. Circulation 2002; 106: 847–852.
22. Alcantara CS, Jin XH, Brito GA, et al. Angiotensin II subtype 1 receptor blockade inhibits Clostridium difficile toxin A-induced intestinal secretion in a rabbit model. J Infect Dis 2005; 191(12):2090-2096.
1. Nightingale J, Woodward JM. Guidelines for management of patients with a short bowel. Gut 2006; 55 Suppl 4:1-12.
2. John KD, Rosemary JY, Jon AV, et al. Intestinal rehabilitation and the short bowel syndrome: part 1.Am J Gastroenterology 2004; 99(6):1386 -1395.
3.吴肇汉。重视短肠综合征的预防与治疗。中国实用外科杂志2005;11( 25):643-644。
4. Haxhija EQ, Yang H, Spencer AU, et al. Influence of the site of small bowel resection on intestinal epithelial cell apoptosis. Pediatr Surg Int 2006; 22: 37–42.
5. Messing. B, Pigot. F, Bongire. M. et al. Intestinal absorption of free oral hyperalimentation in the very short bowel syndrome. Gastroenterology 1991; 100: 1502.
6. Vanderhoof JA, Langnas LN. Short bowel syndrome in children and adults.Gastroenterology 1997; 113(5):1767-1778.
7. Strum A,Layer D , Goebell H, et al . Short bowel syndrome:an update on the therapeutic approach. Scand J Gastroenterol 1997; 32(4):289-296.
8. Byrne TA, Wilmore DW, Iyer K, et al. Growth hormone, glutamine, and an op timal diet reduces parenteral nutrition in patientswith short bowel syndrome: a prospective, randomized, placebo-controlled, double-blind clinical trial[J]. Ann Surg 2005; 242(5): 655-661.
9. Mardini HE;de Villiers WJ. Teduglutide in intestinal adaptation and repair: light at the end of the tunnel. Expert Opin Investig Drugs 2008; 17(6): 945-951.
10. De Francesco A, Malfi G, Delsedime L, et al. De Francesco A, Malfi G, Delsedime L, et al. Histological findings regarding jejunal mucosal in short bowel syndrome. Transplant Proc 1994; 26: 1455–1456.
11. O’Keefe S, Shorter R, Bennet W, et al. O’Keefe S, Shorter R, Bennet W, et al. Villous hyperplasia is uncommon in patients with massive intestinal resection. Gastroenterology 1992; 102: A231.
12. Williamson R. Williamson R. Intestinal adaptation. structural, functional, and cytokinetic changes. N Engl J Med 1978; 298: 1393–1402.
13. Erwin CR, Falcone Jr RA, Stern LE, et al. Analysis of intestinal adaptation gene expression by cDNA expression arrays. J Parenter Enteral Nutr 2000; 24: 311–316.
14. Helmrath MA, Erwin CR, Shin CE, et al. Enterocyte apoptosis is increased following small bowel resection. J. Gastrointest. Surg 1998; 2: 44–49.
15. Igor Sukhotnik, Leonardo Siplovich, Michael M. Krausz, et al. Peptide Growth Factors and Intestinal Adaptation in Short Bowel Syndrome. IMAJ 2003; 5: 184-187.
16. Oliver BL, Sha'afi RI, Hajjar JJ. Transforming growth factor alpha and epidermal growth factor activate mitogen-activated protein kinase and its substrates in intestinal epithelial cells. Proc Soc Exp Biol Med 1995; 210: 162-170.
17. Hodin R A, Graham J R, Meng S, et al. Temporal pattern of rat small intestinal gene expression with refeeding. Am J Physiol 1994; 266: G83–G89.
18. Elizabeth M Dahly, Megan E Miller, P Kay Lund, et al. Postreceptor Resistance to Exogenous Growth Hormone Exists in the Jejunal Mucosa of Parenterally Fed Rats. J. Nutr 2004; 134: 530–537.
19. Welters CFM, Piersma FE, Hockenbery DM, et al. The role of apoptosis during intestinal adaptation after small bowel resection. J Pediatr Surg 2000; 35: 20–24.
20. Shin CE, Falcone Jr RA, Kemp CJ et al. Intestinal adaptation and enterocyte apoptosis following small bowel resection is p53 independent. Am. J. Physiol 1999; 277: G717–724.
21. Stern LE, Falcone Jr RA, Huang F, et al. Epidermal growth factor alters the bax : bcl-w ratio following massive small bowel resection. J Surg Res 2000; 91: 38–42.
22. Kavita Bisht, Karl-Heinz Wagner, Andrew C. Bulmer. Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds. Toxicology 2009; 11: 008
23. Stern LE, Huang F, Kemp CJ, et al. Bax is required for increased enterocyte apoptosis after massive small bowel resection. Surgery 2000; 128: 165–170.
24. Tang Y, Swartz-Basile DA, Swietlicki EA, et al. Tang Y, Swartz-Basile DA, Swietlicki EA, et al. Bax is required for resection-induced changes in apoptosis, proliferation, and members of the extrinsic cell death pathways. Gastroenterology 2004; 126: 220–230.
25. Weser E, Heller R, Tawil T. Stimulation of mucosal growth in rat ileum by bile and pancreatic secretions after jejunal resection. Gastroenterology 1977; 73: 524–529.
26. Coster J, McCauley R, Hall J. Glutamine: metabolism and application in nutrition support[J]. Asia Pac J Clin Nutr 2004; 13(1): 25.
27. Hua Yang, Daniel H. Teitelbaum. Novel Agents in the Treatment of Intestinal Failure: Humoral Factors. Gastroenterology 2006; 130(2 Suppl 1): S117–S121.
28. Mainoya JR. Influence of bovine growth hormone on water and NaCl absorption by the rat proximal jejunum and distal ileum. Comp Biochem Physiol 1982; 71: 477–479.
29. Gu Y, Wu ZH, Xie JX, et al. Effects of growth hormone (rhGH) and glutamine supplemented parenteral nutrition on intestinal adaptation in short bowel rats. Clin Nutr 2001; 20: 159–166.
30. Zhou X, Li YX, Li N, et al. Glutamine enhances the gut-trophic effect of growth hormone in rat after massive small bowel resection. J Surg Res 2001; 99: 47–52.
31. Sigalet DL, Martin GR, Butzner JD, et al. A pilot study of the use of epidermal growth factor in pediatric short bowel syndrome. J Pediatr Surg 2005; 40: 763–768.
32. Park JH, Vanderhoof JA. Growth hormone did not enhance mucosal hyperplasia aftersmall-bowel resection. Scand. J. Gastroenterol 1996; 31: 349–354.
33. Garcia-Sancho Tellez L Jr, Gomez de Segura IA, Vazquez I, et al. Growth hormone effects in intestinal adaptation after massive bowel resection in the suckling rat. J. Pediatr. Gastroenterol. Nutr 2001; 33: 477–482.
34. Byrne TA, Morrissey TB, Nattakom TV, et al. Growth hormone, glutamine, and a modified diet enhance nutrient absorption in patients with severe short bowel syndrome. J Parent Enteral Nutr 1995; 19: 296–302.
35. Peterson C, Carey H, Hinton P, et al. Peterson C, Carey H, Hinton P, et al. GH elevates serum IGF-1 levels but does not alter mucosal atrophy in parenterally fed rats. Am J Physiol 1997; 272: G1100–1108.
36. Lund P. Lund P. Molecular basis of intestinal adaptation. the role of the insulin-like growth factor system. Ann N Y Acad Sci 1998; 859: 18–36.
37. Nightingale J. Intestinal failure. London Greenwich Medical Media Limited 2001.
38. Chaet MS, Arya G, Ziegler MM, et al. Epidermal growth factor enhances intestinal adaptation after massive small bowel resection. J. Pediatr. Surg 1994; 29: 1035–1039.
39. Helmrath MA, Erwin CR, Warner BW. A defective EGF-receptor in waved-2 mice attenuates intestinal adaptation. J Surg Res 1997; 69: 76–80.
40. Helmrath MA, Shin CE, Fox JW, et al. Adaptation after small bowel resection is attenuated by sialoadenectomy: the role for endogenous epidermal growth factor. Surgery 1998; 124: 848–854.
41. Sullivan PB, Brueton MJ, Tabara ZB, et al. Epidermal growth factor in necrotising enteritis. Lancet 1991; 338: 53–54.
42. Jeppesen PB. Clinical significance of GLP-2 in short-bowel syndrome. J Nutr 2003; 133: 3771–3774.
43. Jeppesen PB, Hartmann B, Thulesen J, et al. Elevated plasma glucagon-like peptide 1 and 2 concentrations in ileum resected short bowel patients with a preserved colon. Gut 2000; 47: 370–376.
44. Dahly EM, Gillingham MB, Guo Z, et al. Role of luminal nutrients and endogenous GLP-2 in intestinal adaptation to mid-small bowel resection. Am J Physiol Gastrointest Liver Physiol 2003; 284: 670–682.
45. Martin GR, Wallace LE, Hartmann B et al. Nutrient-stimulated GLP-2 release and cryptcell proliferation in experimental short bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol 2005; 288: 431–438.
46. Martin GR, Wallace LE, Sigalet DL. Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol 2004; 286: 964–972.
47. Jeppesen PB, Hartmann B, Thulesen J et al. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology 2001; 120: 806–815.
48. Jeppesen PB, Sanguinetti EL, Buchman A et al. Teduglutide (ALX- 0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut 2005; 54: 1224–1231.
49. Wildhaber BE, Yang H, Coran AG, et al. Gene alteration of intestinal intraepithelial lymphocytes in response to massive small bowel resection. Pediatr Surg Int 2003; 19: 310–315.
50. Wildhaber BE, Yang H, Haxhija EQ, et al. Intestinal intraepithelial lymphocyte derived angiotensin converting enzyme modulates epithelial cell apoptosis. Apoptosis 2005; 10: 1305–1315.
51. Yang H, Daniel H. Teitelbaum. Novel Agents in the Treatment of Intestinal Failure: Humoral Factors. Gastroenterology 2006; 130(2 Suppl 1): S117–S121.