小肠移植大鼠一氧化氮、诱导型一氧化氮合酶及低氧诱导因子1α表达的实验研究
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摘要
小肠是体内富含淋巴细胞的最大器官，小肠移植是治疗终末期肠功能衰竭的唯一确切的方法，可使患者从根本上摆脱肠外营养(total parenteral nutrition，TPN)的困扰，恢复正常的生活方式。但由于小肠属于有菌的高免疫源性器官而易产生强烈的排斥反应，导致小肠移植的失败。近年来随着环孢菌素A(cyclosporine A，CsA)、FK506(Tacrolimus)等免疫抑制剂相继应用于临床，各种强效抗细菌、真菌、病毒药物的应用，减少了小肠移植后的各种并发症，小肠移植物的长期存活率有了明显的提高。目前在小肠移植方面已经进行了大量的基础性研究，包括免疫、感染以及再灌注损伤等多个反面，并且取得了较大的进展。我们通过建立大鼠异位节段性小肠移植动物模型及大鼠热缺血再灌注模型，对血清中一氧化氮(nitric oxide，NO)的变化，小肠组织中一氧化氮合酶(nitric oxide synthase，NOS)、诱导型一氧化氮合酶(inducible nitric oxide synthase，iNOS)及低氧诱导因子—1α(hypoxia induced factor 1α，HIF—1α)的改变进行研究，探讨一氧化氮、一氧化氮合酶、诱导型一氧化氮合酶及低氧诱导因子1α与小肠移植过程中缺血再灌注及急性排斥反应的关系，为临床小肠移植术后的治疗提供新的思路。
常圈苹.沁气习曰砚d卜月卜勺七们食，忆
研究目的
1.熟练掌握大鼠异位节段性小肠移植动物模型的建立方法。
2.研究大鼠小肠移植术后血清中NO的浓度变化及其与急性排斥
反应的关系。
3.研究大鼠小肠移植术后小肠组织中NOS、iNOS的活性变化，
HIF一1。的表达，探讨HIF一la对小肠移植的影响及相关作用。
研究方法
实验分组:A组(对照组):正常SD大鼠;B组(热缺血组):
建立大鼠热缺血再灌注模型，夹闭肠系膜上动脉1小时后再灌注
分为O小时、1小时、2小时、6小时各亚组;C组(冷缺血组):
SD大鼠，冷缺血2.5小时;D组(同系移植组):建立大鼠异位
节段性小肠移植模型(冷缺血2.5小时)，术后常规补液，给予
抗生素;E组(同种移植组):建立大鼠异位节段性小肠移植模型
(冷缺血2.5小时)，术后常规补液，给予抗生素，同D组;F组:
建立大鼠异位节段性小肠移植模型(冷缺血2.5小时)，行同种
移植，术后常规补液，给予抗生素，并肌注环抱菌素A。D、E、F
组分别于术后第3、5、7天取材，其余各组按各时点取材。小肠
标本HE病理染色，观察组织学变化;用硝酸还原酶法检测血清
中NO浓度;用分光光度法测定移植小肠组织中NOS、iNOS的活
性变化;用免疫组织化学的方法观察小肠组织中HIF一1Q的表达。
研究结果
1.E组于术后第3、5、7天分别出现轻、中、重度排斥反应，F
组仅部分受体于术后第5、7天出现轻度急性排斥反应，D组未见
明显排斥反应的发生。
2.B组血清NO水平从0小时开始呈现递减趋势，0小时、1小时
组与A组相比显著升高，有统计学意义(P<0.01)，2小时、6
小时组与A组相比无统计学差异(P>.05);E组于第3、5、7天
血清NO水平显著升高，有统计学意义(P<0 .01)，A组、D组、F
布曰早.比气月妇吸创七拳位今卜J忆
组之间血清NO水平无统计学差异(P>0.05)。
3.E组于第3、5、7天小肠组织NOS及iNOS活性亦显著高于A、
D、F组，有统计学意义(均为P<0 .01)，A组、D组、F组小肠组
织NOS及iNOS活性之间无统计学差异(P>.05)。
4.B组热缺血再灌注后，0小时可见HIF一1Q表达呈弱阳性，1
小时、2小时、6小时表达呈阴性;C组HIF一a表达呈弱阳性;A
组、D组、F组HIF一10表达呈阴性;E组于第3、5天HIF一10表
达呈阳性，第7天HIF一10表达呈弱阳性。
结论
1.血清NO在大鼠小肠缺血再灌注中的水平变化，提示NO在小
肠移植过程中起重要作用。
2.大鼠小肠同种移植后小肠组织中NOS及iNOS的活性和血清
NO水平明显增高，但不与急性排斥反应的严重程度呈正相关的
关系。血清NO水平的检测对于小肠移植急性排斥反应的发生可
能具有早期的辅助诊断意义。
3.大鼠小肠移植过程中HIF一1a表达的变化，提示HIF一。对iNOS
有转录激活作用，NO对HIF一。有负向调节作用，有助于对小肠
移植的治疗和判断预后提供新的思路和理论依据。
The small bowel is the largest organ of lymphocyte in the body and the small bowel transplantation (SBT) is the exclusive assured method of curing the telophase function failure of small bowel. SBT can make the patients get rid of the worry of TPN and resume the natural life. But SBT will take place severe rejection inducing the failure of the operation because small bowel is the high immunocompetent bacterial organ. Following the immunosuppressant(for example: cyclosporine A and Tacrolimus) and multifarious strong drugs of anti-bacterium, anti-epiphyte and anti-virus used in clinic in the past several years, various syndrome was decreased after SBT and the long-term livability of the transplanted small bowel has been increased obviously. At present, it has taken a lot of basic study on SBT including immunity, infection, reperfusion injury and so on, and it
has obtained much progress. First, we built the model of the segmental SBT and the model of heat ischemia reperfusion of SBT in rats, then mensurated the serum level of nitric oxide(NO) , the activity of nitric oxide synthase (NOS) , the activity of inducible nitric oxide synthase (iNOS) and the changing of hypoxia induced factor 1 a(HIF-la)of small bowel tissue. We studied the relationship of NO, NOS, iNOS and HIF-la with acute graft rejection and offered a new method for the clinical therapy of small bowel transplantation. AIM
l.To master the technic to build the model of the segmental small bowel transplantation in rats.
2. To study the relationship of the serum level changing of nitric oxide with acute graft rejection after small bowel transplantation in rats.
3. To study the changing of the activity of nitric oxide synthase and inducible nitric oxide synthase and expression of hypoxia induced factor 1 a and to discuss the effect and correlative function of hypoxia induced factor 1 a in small bowel transplantation of rats.
METHOD
The experiment was shared into the following groups: group A (control group, the common SD rats);group B(heat ischemia group) :to build the model of heat ischemia of rats, nipped the superior mesentery artery for 1 hour and shared into the following subgroups according to reperfusion:0 hour,1 hour,2 hour,6 hour; group C (cold ischemia
group):cold ischemia was performed for 2.5 hour; group D (isograft group):To build the model of the segmental SBT in rats(keeping cold ischemia for 2.5 hour),to supply routine fluid replacement and antibiotic after the operation; group E(allograft group): To build the model of the segmental SBT in rats(keeping cold ischemia for 2.5 hour), to supply routine fluid replacement and antibiotic after the operation as well as group D; group F: To build the model of the segmental SBT in rats (keeping cold ischemia for 2. 5 hour), to perform allograft, to supply routine fluid replacement and antibiotic and cyclosporine A by injecting muscle after the operation. D, E and F groups were taken blood and small bowel tissue in the 3rd day, 5th day and 7th day after operation, other groups were taken blood and small bowel tissue according to the time points of themselves respectively. The specimen of small bowel tissue was stained with hematoxylin and eosin for pathological examination and we observed the changing of histopathology. The serum NO level were mensurated by the method of nitric acid deoxidization synthase. The activity of NOS and iNOS of small bowel tissue were mensurated by spectrophotometer. The expression of HIF-1a were mensurated by the method of immunohistochemistry. RESULTS
1.The pathological examination of grafts from group E showed that the degree of acute rejection was from light to weight in the 3rd day,5th day and 7th day in turn; the fraction of grafts from group F showed light degree of acute
rejection in the 5th day and 7th day after SBT; group D had not pathological evidence of acute rejection.
2. The serum NO level of group B showed the degressive direction from 0 hour ,and the serum NO level of 0 hour subgroup and 1 hour subgroup were significant different from group A(P<
常圈苹.沁气习曰砚d卜月卜勺七们食，忆
研究目的
1.熟练掌握大鼠异位节段性小肠移植动物模型的建立方法。
2.研究大鼠小肠移植术后血清中NO的浓度变化及其与急性排斥
反应的关系。
3.研究大鼠小肠移植术后小肠组织中NOS、iNOS的活性变化，
HIF一1。的表达，探讨HIF一la对小肠移植的影响及相关作用。
研究方法
实验分组:A组(对照组):正常SD大鼠;B组(热缺血组):
建立大鼠热缺血再灌注模型，夹闭肠系膜上动脉1小时后再灌注
分为O小时、1小时、2小时、6小时各亚组;C组(冷缺血组):
SD大鼠，冷缺血2.5小时;D组(同系移植组):建立大鼠异位
节段性小肠移植模型(冷缺血2.5小时)，术后常规补液，给予
抗生素;E组(同种移植组):建立大鼠异位节段性小肠移植模型
(冷缺血2.5小时)，术后常规补液，给予抗生素，同D组;F组:
建立大鼠异位节段性小肠移植模型(冷缺血2.5小时)，行同种
移植，术后常规补液，给予抗生素，并肌注环抱菌素A。D、E、F
组分别于术后第3、5、7天取材，其余各组按各时点取材。小肠
标本HE病理染色，观察组织学变化;用硝酸还原酶法检测血清
中NO浓度;用分光光度法测定移植小肠组织中NOS、iNOS的活
性变化;用免疫组织化学的方法观察小肠组织中HIF一1Q的表达。
研究结果
1.E组于术后第3、5、7天分别出现轻、中、重度排斥反应，F
组仅部分受体于术后第5、7天出现轻度急性排斥反应，D组未见
明显排斥反应的发生。
2.B组血清NO水平从0小时开始呈现递减趋势，0小时、1小时
组与A组相比显著升高，有统计学意义(P<0.01)，2小时、6
小时组与A组相比无统计学差异(P>.05);E组于第3、5、7天
血清NO水平显著升高，有统计学意义(P<0 .01)，A组、D组、F
布曰早.比气月妇吸创七拳位今卜J忆
组之间血清NO水平无统计学差异(P>0.05)。
3.E组于第3、5、7天小肠组织NOS及iNOS活性亦显著高于A、
D、F组，有统计学意义(均为P<0 .01)，A组、D组、F组小肠组
织NOS及iNOS活性之间无统计学差异(P>.05)。
4.B组热缺血再灌注后，0小时可见HIF一1Q表达呈弱阳性，1
小时、2小时、6小时表达呈阴性;C组HIF一a表达呈弱阳性;A
组、D组、F组HIF一10表达呈阴性;E组于第3、5天HIF一10表
达呈阳性，第7天HIF一10表达呈弱阳性。
结论
1.血清NO在大鼠小肠缺血再灌注中的水平变化，提示NO在小
肠移植过程中起重要作用。
2.大鼠小肠同种移植后小肠组织中NOS及iNOS的活性和血清
NO水平明显增高，但不与急性排斥反应的严重程度呈正相关的
关系。血清NO水平的检测对于小肠移植急性排斥反应的发生可
能具有早期的辅助诊断意义。
3.大鼠小肠移植过程中HIF一1a表达的变化，提示HIF一。对iNOS
有转录激活作用，NO对HIF一。有负向调节作用，有助于对小肠
移植的治疗和判断预后提供新的思路和理论依据。
The small bowel is the largest organ of lymphocyte in the body and the small bowel transplantation (SBT) is the exclusive assured method of curing the telophase function failure of small bowel. SBT can make the patients get rid of the worry of TPN and resume the natural life. But SBT will take place severe rejection inducing the failure of the operation because small bowel is the high immunocompetent bacterial organ. Following the immunosuppressant(for example: cyclosporine A and Tacrolimus) and multifarious strong drugs of anti-bacterium, anti-epiphyte and anti-virus used in clinic in the past several years, various syndrome was decreased after SBT and the long-term livability of the transplanted small bowel has been increased obviously. At present, it has taken a lot of basic study on SBT including immunity, infection, reperfusion injury and so on, and it
has obtained much progress. First, we built the model of the segmental SBT and the model of heat ischemia reperfusion of SBT in rats, then mensurated the serum level of nitric oxide(NO) , the activity of nitric oxide synthase (NOS) , the activity of inducible nitric oxide synthase (iNOS) and the changing of hypoxia induced factor 1 a(HIF-la)of small bowel tissue. We studied the relationship of NO, NOS, iNOS and HIF-la with acute graft rejection and offered a new method for the clinical therapy of small bowel transplantation. AIM
l.To master the technic to build the model of the segmental small bowel transplantation in rats.
2. To study the relationship of the serum level changing of nitric oxide with acute graft rejection after small bowel transplantation in rats.
3. To study the changing of the activity of nitric oxide synthase and inducible nitric oxide synthase and expression of hypoxia induced factor 1 a and to discuss the effect and correlative function of hypoxia induced factor 1 a in small bowel transplantation of rats.
METHOD
The experiment was shared into the following groups: group A (control group, the common SD rats);group B(heat ischemia group) :to build the model of heat ischemia of rats, nipped the superior mesentery artery for 1 hour and shared into the following subgroups according to reperfusion:0 hour,1 hour,2 hour,6 hour; group C (cold ischemia
group):cold ischemia was performed for 2.5 hour; group D (isograft group):To build the model of the segmental SBT in rats(keeping cold ischemia for 2.5 hour),to supply routine fluid replacement and antibiotic after the operation; group E(allograft group): To build the model of the segmental SBT in rats(keeping cold ischemia for 2.5 hour), to supply routine fluid replacement and antibiotic after the operation as well as group D; group F: To build the model of the segmental SBT in rats (keeping cold ischemia for 2. 5 hour), to perform allograft, to supply routine fluid replacement and antibiotic and cyclosporine A by injecting muscle after the operation. D, E and F groups were taken blood and small bowel tissue in the 3rd day, 5th day and 7th day after operation, other groups were taken blood and small bowel tissue according to the time points of themselves respectively. The specimen of small bowel tissue was stained with hematoxylin and eosin for pathological examination and we observed the changing of histopathology. The serum NO level were mensurated by the method of nitric acid deoxidization synthase. The activity of NOS and iNOS of small bowel tissue were mensurated by spectrophotometer. The expression of HIF-1a were mensurated by the method of immunohistochemistry. RESULTS
1.The pathological examination of grafts from group E showed that the degree of acute rejection was from light to weight in the 3rd day,5th day and 7th day in turn; the fraction of grafts from group F showed light degree of acute
rejection in the 5th day and 7th day after SBT; group D had not pathological evidence of acute rejection.
2. The serum NO level of group B showed the degressive direction from 0 hour ,and the serum NO level of 0 hour subgroup and 1 hour subgroup were significant different from group A(P<
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37．孙备．细胞凋亡与缺血再灌注损伤的研究进展．国外医学外科学分册，1998，25(6)：325—326．
38．高博，尹桂山．神经系统中的一氧化氦．生物化学与生物物理进展，1999，26(1)：31—34．
39．李洪鹏，吕永利．脑血管内皮细胞与衰老．解剖科学进展，1999，5(4)：317—320．
40. Plamer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature, 1998, 333:664-666.
41．史树贵．一氧化氮与细胞凋亡．国外医学：生理病理科学与临床分册，1997，17(3)：267—270．
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44. Szabolcs M, Michler RE, Yang X. Apoptosis of cardiac myocytes during cardiac allograft rejection. Relation to introduction of nitric oxide synthase. Circulation, 1996, 94(5):1665-1679.
45. Nathan C, Xie QW. Nitric oxide synthase:Roles, tolls, and controls. Cell, 1994,78(3):915-926.
46. Liaduet L, Garcia-Soriano F, Szabo C. Biology of nitric oxide
signaling. Crit Care Med, 2000,28(2):37-47.
47. Moncada S, Higgs EA. Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEBJ, 1995,9(12): 1319-1324.
48. Knowles RG, Salter M, Brooks SL. Anti—inflammatory. glucocorticoids inhibit the induction by endotoxin of nitric oxide synthase in the lung, liver and aorta of the rat. Biochem Biophys Res Commun, 1990,172(3): 1042-1048.
49. Davies S. Insect Biochem. Mol Biol, 2000,30:1123-1138.
50. Cho HJ, Xie QW, Calaycay J,Mnmford RA, Swiderek KM, Lee TD, Nathan C. Exp Med, 1992,176:599-604.
51. Goldstein IM, Ostnald P, Roth S. Vision Res, 1996,36(18): 2979-2984.
52. Maiese K, TenBroeke M, Kue I. Neuroprotection of lubeluzole is mediated through the signal transduction pathways of nitric oxide. J Neurochem, 1997,68(2):710-714.
53. Hangai M,Yoshimura N, Hiroi K, Mandai M, Honda Y. Inducible nitric oxide synthase in retinal ischemia-reperfusion injury. Exp Eye Res, 1996,63(5):501-509.
54. Mattys P, Froyen G, Yerdot L. IFN-gamma receptor-deficient mice are hypersensitive to the anti-CD3-induced cytokine release syndrome and thymocyte apoptosis. Protective role of endogenous nitric oxide.J Immunol, 1995, 155(8):3823-3829.
55. Wink DA,Mitchell JB. Chemical biology of nitric oxide: Insights into regulatory cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radical Biol Med, 1998,25(6):434-442.
56. Grisham MB,Jourd D, Wink DA. Physiological chemistry of nitric
oxide and its metabolites:Implications in inflamation. Am J Physiol, 1999, 276 (6) :G315-326.
57. Szabo C. Alterations in nitric oxide production in various forms of circulatory shock. New Horizons, 1995, 3(3):2-15.
58. Guo JP, Murohara T, Buerke M. Direct measurement of nitric oxide release from vascular endothelial cells. Appl Physiol, 1996, 81 (6): 774-786.
59. Lefer AM, Leffer D. The role of nitric oxide and cell adhesion molecules on the microcirculation in ischemia reperfusion. Cardiovasc Res, 1996, 32 (4) : 743-755.
60. Bult H, Boeckxsaens CE, Polckmans PA. Nitric oxide as an inhibitory non-adrenergic non-neurotrasmitter. Nature, 1990, 345 (6281) : 346-351.
61．蒋波，楚正绪．一氧化氮与炎症．国外医学生理、病理科学与临床分册，1998，18(1)：44～47．
62. Laszlo F, Whittle BJR. Endogenous nitric oxide in the maintenance of rat microvascular integrity asainst widespread plasma leakage following abdominal laparotomy, Br J Pharmacol, 1999,126(2):515-517.
63. Coras NK, Wakid NW. Determination of inorgantic nitrate in serum and urine by a kinetic cadmiumreduction method. Clin Chem, 1990,36(7):1440-1445.
64. Bartholomew B. A rapid method for the assay of nitrate in urine the nitrate reductase enzyme of cherichia coil. Food Chem Taxical, 1984,22(3):541-544.
65. Leone AM, Francis PL, Rhodes P. A rapid simple method for the measurement of nitrite and nitrate in plasma by high performace capillary electrophoresis. Biochem Biophys Res
Commun, 1994, 200 (6) :951-958.
66．王成彬，童红莉，沈文梅，田亚平，汪德清，蒋赐恩，谷峰．硝酸还原酶测定血清和尿中硝酸盐浓度．中华医学检验杂志，1997，20(3)：156—158．
67. Westenberger U, Thanner S, Ruf HH, Gersonde K,.Sutter G, Trentz O. Formation of radical and nitric oxide derivative of hemoglobin in rats during shock syndrome. Free Radic Res Commun, 1990,11(1-3):167-168.
68. Kharittonov SA, Yates D, Barnes PJ.Increased nitric oxide in exhaled air of normal human subjects with upper respiratory tract infection. Eur Respir J, 1995,8(2):295-297.
69．王成彬，田亚平，沈文梅，江朝光，汪德清，蒋赐恩，王彩云，格日乐．液体充气鲁米诺发光测定全血一氧化氮．中华医学检验杂志，1997，20(5)：285—287．
70. Wang GL, Jiang BH, Rue EA. Hypoxia induible factor-1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O_2 tension. Proc Natl Acad Sci USA, 1995, 92(12):5510-5514.
71. Semenza GL, Tiang BH, Leng SW. Hypoxia response elements in the aldolasea, enolase, and lacture dehydrogenase A gene promotes contain essential binding sites for hypoxia-inducible factor 1.J Biol Chem, 1996,271: 32529-32537.
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