吡格列酮对STZ诱导的糖尿病大鼠十二指肠病理及免疫炎性指标的影响
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摘要
目的：以正常大鼠及无干预治疗的STZ诱导的DM大鼠作为对照,观察不同剂量Piog对STZ诱导的DM大鼠十二指肠的病理组织学变化,IL-10和TNF-α的表达,以及T淋巴细胞数目和比值的影响,并与免疫调节剂环孢菌素A(CsA)及胰岛素干预的大鼠相作比较,了解Piog是否通过影响CD4+/CD8+T淋巴细胞比值,TNF-α与IL-10等细胞因子的表达,来预防和控制糖尿病大鼠十二指肠的器官损伤,为临床上应用Piog控制DM及其并发症提供理论依据。
方法：健康雄性SD大鼠96只,随机分为Piog小剂量干预组、Piog小剂量加INS干预组、Piog大剂量干预组、Cs A干预组、Cs A加INS干预组、INS干预组、DM无干预组和CON组等8组。除CON组外,其余均由STZ诱导造成DM模型。造模前及成模后每周检测大鼠体重,每月测定血糖,共饲养16周后处死。处死前取血清和尿检测生化指标。对各组大鼠十二指肠,采用HE染色、AB-PAS染色法观察十二指肠杯状细胞；免疫组织化学法检测各组大鼠十二指肠肌层Cajal间质细胞的表达,CD4+、CD8+T淋巴细胞的表达及TNF-α与IL-10的表达水平。
结果：1.成功建立了STZ诱导的DM大鼠模型；2. Piog能明显降低血脂和改善肾功能；3.DM组大鼠十二指肠均有不同程度的粘膜固有层充血,水肿,绒毛损伤,各PIO或CsA治疗组大鼠十二指肠病变均有不同程度减轻；4.DM组大鼠十二指肠粘膜层杯状细胞数目明显低于CON组,各PIO或CsA治疗组大鼠十二指肠粘膜层杯状细胞数目均有不同程度增加；5.DM组大鼠十二指肠肌层Cajal间质细胞的数量减少,各PIO或CsA治疗组大鼠十二指肠粘膜层杯状细胞数目均有不同程度增加；6.DM组大鼠十二指肠CD4+T淋巴细胞数量增加,CD8+T淋巴细胞数量减少,且CD4+/CD8+T淋巴细胞比值增加；各PIO或CsA治疗组CD4+T淋巴细胞数量减少,CD8+T淋巴细胞数量增加,且CD4+/CD8+T淋巴细胞比值降低。7.DM组大鼠十二指肠抑炎因子IL-10的量减少,致炎因子TNF-α的量增加；各PIO或CsA治疗组抑炎因子IL-10的量增加,致炎因子TNF-α的量减少。
结论：Piog除有INS增敏和降糖作用外,Piog能明显降低血脂和改善肾功能；糖尿病大鼠十二指肠粘膜T淋巴细胞亚群的变化和细胞因子IL-10,TNF-α的异常表达提示免疫机制和炎症反应参与了十二指肠的病理组织学损伤,引起十二指肠粘膜层杯状细胞,肌层Cajal间质细胞数目减少,导致糖尿病大鼠十二指肠动力障碍。各PIO或CsA治疗能改善十二指肠粘膜T淋巴细胞亚群的变化和细胞因子的异常表达,减轻了器官的炎症反应,增加杯状细胞和Cajal间质细胞数目。因此,Piog不但可作为一种降糖药物,而且可作为一种免疫调节剂,用于预防和控制DM的器官免疫损伤,减少功能障碍的发生。
Objective:To investigate the effection of different dosege of the Piog on the function, pathology of the duodenum of the STZ-induced DM rats, as well as the the expression of the IL-10,TNF-aand the number and ratio of T cells on the same organs. And compare its effection with the immunomodulator cyclosporin A (CsA) and the insulin (INS). To find whether Piog has the effection to prevent and ameliorate the duodenum injury of the DM which through the immunizing mechanisms that mediated by the IL-10, TNF-aand ratio between CD4+ and CD8+ T lymphocytes. And provide the theoretical evidence for the usage of the Piog in the clinical practice.
Materials and methods:Ninety-six healthy male SD rats were randomly divided into 7 DM groups and 1 healthy control group. According to the interventing mode, the DM groups were made by intravenous administration of STZ and then were divided into low dose Piog group, low dose Piog plus INS group, large dose Piog group, Cs A group, Cs A plus INS group, INS group, and DM group, respectively. The weight and blood glucose of each rat were investigated by routine test each month. After feeding 16 weeks, all rats were sacrificed. The serum was seperated and the urine was obtained to test the hepatic, renal function, triglyceride, insulin level and the urine albumin. The hematoxylin and eosin Stain, AB-PAS Stain were carried out to observe the goblet cells of the duodenum of the rats in different groups. On the same organs, the immunohistochemistry were carried out to detect the number of interstital cells of Cajal, CD4+ and CD8+T cells,deposition of the IL-10 antigen, and TNF-aantigen.
Results:1. The STZ-induced DM rat model were successfully established; 2. Piog can significantly lower blood triglyceride and improving kidney function; 3. Congestion,edema and damage to the villus were found in the duodenum of DM group, Compared with the normal and DM control group,the duodenum of the large dose Piog interventing group rat and the CsA interventing DM groups are much better. 4. The number of goblet cells in the duodenum of DM group decreased,while compared with the DM group, Piog interventing group rat and the CsA interventing DM groups, The number of goblet cells in the duodenum increased to some extent.5. The number of Cajal cells in the duodenum of DM group decreased, while compared with the DM group,the Piog interventing group rat and the CsA interventing DM groups, The number of Cajal cells in the duodenum increased to some extent.6. The number of CD4+T cells in the duodenum of DM group increased, while The number of CD8+T cells decreased,the ratio between CD4+and CD8+T lymphocytes increased, compared with the DM group,the Piog interventing group rat and the CsA interventing DM groups, The number of CD4+T cells in the duodenum of DM group decreased, while The number of CD8+T cells increased,the ratio between CD4+ and CD8+ T lymphocytes decreased.7.Decreaed IL-10 and incresed TNF-a were found in DM group, while in the Piog interventing group rat and the CsA interventing DM groups, increaed IL-10 and decresed TNF-a were found.
Conclusions:Apart from its insulin sensitization effect, Piog could also lower the blood triglyceride significantly and ameliorate the renal function of the DM rats. Diabetic rat duodenum changes in T lymphocyte subsets and inflammatory cytokines IL-10, TNF-a suggest abnormal expression of the immune system and inflammatory responses involved in the duodenum of pathological tissue damage, reduce of the number mucosal layer of goblet cells, muscularis of interstitial cells of Cajal, resulting in motor dysfunction of diabetic rat duodenum. The PIO, or CsA treatment can improve the duodenal mucosa T lymphocyte subsets and abnormal expression of cytokines, reduced organ inflammation, increased goblet cells and the number of interstitial cells of Cajal.Therefore, Piog is not only a medicine of INS sensitizer, but also is an immunomodulator for the preventing multi-organ immune damage of the DM.
方法：健康雄性SD大鼠96只,随机分为Piog小剂量干预组、Piog小剂量加INS干预组、Piog大剂量干预组、Cs A干预组、Cs A加INS干预组、INS干预组、DM无干预组和CON组等8组。除CON组外,其余均由STZ诱导造成DM模型。造模前及成模后每周检测大鼠体重,每月测定血糖,共饲养16周后处死。处死前取血清和尿检测生化指标。对各组大鼠十二指肠,采用HE染色、AB-PAS染色法观察十二指肠杯状细胞；免疫组织化学法检测各组大鼠十二指肠肌层Cajal间质细胞的表达,CD4+、CD8+T淋巴细胞的表达及TNF-α与IL-10的表达水平。
结果：1.成功建立了STZ诱导的DM大鼠模型；2. Piog能明显降低血脂和改善肾功能；3.DM组大鼠十二指肠均有不同程度的粘膜固有层充血,水肿,绒毛损伤,各PIO或CsA治疗组大鼠十二指肠病变均有不同程度减轻；4.DM组大鼠十二指肠粘膜层杯状细胞数目明显低于CON组,各PIO或CsA治疗组大鼠十二指肠粘膜层杯状细胞数目均有不同程度增加；5.DM组大鼠十二指肠肌层Cajal间质细胞的数量减少,各PIO或CsA治疗组大鼠十二指肠粘膜层杯状细胞数目均有不同程度增加；6.DM组大鼠十二指肠CD4+T淋巴细胞数量增加,CD8+T淋巴细胞数量减少,且CD4+/CD8+T淋巴细胞比值增加；各PIO或CsA治疗组CD4+T淋巴细胞数量减少,CD8+T淋巴细胞数量增加,且CD4+/CD8+T淋巴细胞比值降低。7.DM组大鼠十二指肠抑炎因子IL-10的量减少,致炎因子TNF-α的量增加；各PIO或CsA治疗组抑炎因子IL-10的量增加,致炎因子TNF-α的量减少。
结论：Piog除有INS增敏和降糖作用外,Piog能明显降低血脂和改善肾功能；糖尿病大鼠十二指肠粘膜T淋巴细胞亚群的变化和细胞因子IL-10,TNF-α的异常表达提示免疫机制和炎症反应参与了十二指肠的病理组织学损伤,引起十二指肠粘膜层杯状细胞,肌层Cajal间质细胞数目减少,导致糖尿病大鼠十二指肠动力障碍。各PIO或CsA治疗能改善十二指肠粘膜T淋巴细胞亚群的变化和细胞因子的异常表达,减轻了器官的炎症反应,增加杯状细胞和Cajal间质细胞数目。因此,Piog不但可作为一种降糖药物,而且可作为一种免疫调节剂,用于预防和控制DM的器官免疫损伤,减少功能障碍的发生。
Objective:To investigate the effection of different dosege of the Piog on the function, pathology of the duodenum of the STZ-induced DM rats, as well as the the expression of the IL-10,TNF-aand the number and ratio of T cells on the same organs. And compare its effection with the immunomodulator cyclosporin A (CsA) and the insulin (INS). To find whether Piog has the effection to prevent and ameliorate the duodenum injury of the DM which through the immunizing mechanisms that mediated by the IL-10, TNF-aand ratio between CD4+ and CD8+ T lymphocytes. And provide the theoretical evidence for the usage of the Piog in the clinical practice.
Materials and methods:Ninety-six healthy male SD rats were randomly divided into 7 DM groups and 1 healthy control group. According to the interventing mode, the DM groups were made by intravenous administration of STZ and then were divided into low dose Piog group, low dose Piog plus INS group, large dose Piog group, Cs A group, Cs A plus INS group, INS group, and DM group, respectively. The weight and blood glucose of each rat were investigated by routine test each month. After feeding 16 weeks, all rats were sacrificed. The serum was seperated and the urine was obtained to test the hepatic, renal function, triglyceride, insulin level and the urine albumin. The hematoxylin and eosin Stain, AB-PAS Stain were carried out to observe the goblet cells of the duodenum of the rats in different groups. On the same organs, the immunohistochemistry were carried out to detect the number of interstital cells of Cajal, CD4+ and CD8+T cells,deposition of the IL-10 antigen, and TNF-aantigen.
Results:1. The STZ-induced DM rat model were successfully established; 2. Piog can significantly lower blood triglyceride and improving kidney function; 3. Congestion,edema and damage to the villus were found in the duodenum of DM group, Compared with the normal and DM control group,the duodenum of the large dose Piog interventing group rat and the CsA interventing DM groups are much better. 4. The number of goblet cells in the duodenum of DM group decreased,while compared with the DM group, Piog interventing group rat and the CsA interventing DM groups, The number of goblet cells in the duodenum increased to some extent.5. The number of Cajal cells in the duodenum of DM group decreased, while compared with the DM group,the Piog interventing group rat and the CsA interventing DM groups, The number of Cajal cells in the duodenum increased to some extent.6. The number of CD4+T cells in the duodenum of DM group increased, while The number of CD8+T cells decreased,the ratio between CD4+and CD8+T lymphocytes increased, compared with the DM group,the Piog interventing group rat and the CsA interventing DM groups, The number of CD4+T cells in the duodenum of DM group decreased, while The number of CD8+T cells increased,the ratio between CD4+ and CD8+ T lymphocytes decreased.7.Decreaed IL-10 and incresed TNF-a were found in DM group, while in the Piog interventing group rat and the CsA interventing DM groups, increaed IL-10 and decresed TNF-a were found.
Conclusions:Apart from its insulin sensitization effect, Piog could also lower the blood triglyceride significantly and ameliorate the renal function of the DM rats. Diabetic rat duodenum changes in T lymphocyte subsets and inflammatory cytokines IL-10, TNF-a suggest abnormal expression of the immune system and inflammatory responses involved in the duodenum of pathological tissue damage, reduce of the number mucosal layer of goblet cells, muscularis of interstitial cells of Cajal, resulting in motor dysfunction of diabetic rat duodenum. The PIO, or CsA treatment can improve the duodenal mucosa T lymphocyte subsets and abnormal expression of cytokines, reduced organ inflammation, increased goblet cells and the number of interstitial cells of Cajal.Therefore, Piog is not only a medicine of INS sensitizer, but also is an immunomodulator for the preventing multi-organ immune damage of the DM.
引文
[1]中华医学会糖尿病分会.中国2型糖尿病防治指南(2007版)[J].中华医学杂志,2008,88(18)：145-167.
[2]翁建平.突出中国特点的2型糖尿病防治指南[J].中华内分泌代谢杂志,2009,25(1)：增录1 a3-4.
[3]Summary of Revisions for the 2008 Clinical Practice Recommendations [J]. Diabetes Care,2008,31:S3-S4.
[4]Poitout V, Robertson RP. Glucolipotoxicity:fuel excess and beta-cell dysfunction [J]. Endocr Rev.2008,29(3):351-366.
[5]陈名道.胰岛β细胞的“糖毒性”、“脂毒性”与“糖脂毒性”[J].中华内分泌代谢杂志,2009,25(1)：5-8.
[6]Poitout V, Hagman D, Stein R, Artner I, et al. Regulation of the insulin gene by glucose and fatty acids[J]. J Nutr,2006,136(4):873-876.
[7]Zeng MD. Glucotoxicity, lipotoxicity and the nonalcoholic fatty liver disease [J]. Zhonghua Gan Zang Bing Za Zhi,2005,13(2):81-82.
[8]Thomas F. Luscher, Mark A. Creager, Joshua A. Cechman, et al. Diabetes and vascular disease. Pathophysiology, clinical consequences and medical therapy: part Ⅱ [J]. Circulation,2003,108:1655-1661.
[9]Mark A. Creager, Thomas F. Luscher, Francesco Cosentino, et al. Diabetes and vascular disease. Pathophysiology, clinical consequences, and medical therapy: part Ⅰ [J]. Circulation,2003,108:1527-1532.
[10]Wassink AM, Olijhoek JK, Visseren FL. The metabolic syndrome:metabolic changes with vascular consequences [J]. Eur J Clin Invest,2007,37(1):8-17.
[11]Nghiem PP, Platt SR, Schatzberg S. The weak cat. Practical approach and common neurological differentials [J]. J Feline Med Surg,2009,11(5):373-383.
[12]Chatenoud L, Bluestone JA. CD3-specific antibodies:a portal to the treatment of autoimmunity [J]. Nat Rev Immunol,2007,7(8):622-632.
[13]Oling V, Marttila J, Knip M, et al. Circulating CD4+CD25 high regulatory T cells and natural killer T cells in children with newly diagnosed type 1 diabetes or with diabetes-associated autoantibodies [J]. Ann N Y Acad Sci,2007,1107(1): 363-372.
[14]Moriyama H, Kotani R, Katsuta A, et al. Autoreactive T cell response in CD25-negative fraction of peripheral blood mononuclear cells in established type 1 diabetes [J]. Ann N Y Acad Sci.2008,1150(12):278-281.
[15]Alizadeh Dehnavi R, Beishuizen ED, van de Ree MA, et al. The impact of metabolic syndrome and CRP on vascular phenotype in type 2 diabetes mellitus [J]. Eur J Intern Med,2008,19(2):115-121.
[16]Deedwania P, Srikanth S. Diabetes and vascular disease [J]. Expert Rev Cardiovasc Ther,2008,6(1):127-138.
[17]Aronson D. Hyperglycemia and the pathobiology of diabetic complications [J]. Adv Cardiol,2008,45:1-16.
[18]高桦,邱明才.应加强对部分2型糖尿病多器官免疫损伤的研究[J].中华医学杂志,2005,85(12)：793-795.
[19]邱明才,孟春梅.糖尿病并发症发病过程中的补体活化作用[J].中华内分泌代谢杂志,2006,22(3)：303-305.
[20]邱明才,林珊,高志红,等.有胫前黑斑的2型糖尿病患者皮肤黑斑和肾活检[J].天津医药,2004,32(5)：257-259.
[21]Zachary T. Bloomgarden. Diabetic Retinopathy [J]. Diabetes Care,2008,31 (3): 1080-1083.
[22]David A. Antonetti, Alistair J. Barber, Sarah K. Bronson, et al. Diabetic Retinopathy:Seeing Beyond Glucose-Induced Microvascular Disease [J]. Diabetes,2006,55(9):2401-2411.
[23]孟春梅,高桦,邱明才,等.链脲佐菌素诱导的糖尿病大鼠视网膜的免疫损伤[J].中华内分泌代谢杂志,2006,22(06)：588-589.
[24]李德强；环孢菌素A对STZ诱导的糖尿病大鼠肾脏自身免疫和炎症损伤的预防作用探讨[D].天津：天津医科大学,2006.
[25]崔瑾.环孢菌素A对STZ诱导的糖尿病大鼠多器官免疫损伤的治疗作用[D].天津：天津医科大学,2006.
[26]侯宁宁.链脲佐菌素诱导的糖尿病大鼠外周神经病变免疫损伤和环孢素A的抑制作用[D].天津：天津医科大学,2007.
[27]王朝迅.环孢素A抑制链脲佐菌素诱导的糖尿病大鼠大脑免疫和NF-kB通路 激活的实验研究[D].天津：天津医科大学,2007.
[28]张杰涛,邱明才.关于糖尿病的几点认识[J].医学与哲学(临床决策论坛版),2008,29(2)：18-19.
[29]Nakahara M, Isozaki K, Hirota S, et al. Deficiency of KIT-positive cells in the colon of patients with diabetes mellitus. J Gastroenterol Hepatol,2002,17(6): 666-670.
[30]Choi KM, Zhu J, Stoltz GJ, et al. Determination of gastric emptying in nonobese diabetic mice. Am J Physiol Gastrointest Liver Physiol.2007;293:G1039-45.
[31]Ward SM. Sanders KM. Physiology and pathophysiology of the interstitial cell of Cajal:from bench to bedside. Ⅰ. Functional development and plasticity of interstitial cells of Cajal networks. Am J Physiol Gastrointest Liver Physiol, 2001,281(3):G602-G611.
[32]柳利明,秦榕,黄华.糖尿病大鼠肠道Cajal间质细胞的实验研究.实用糖尿病杂志,2009,5(5)：34-35.
[33]Bensinger SJ, Tontonoz P.Integration of metabolism and inflammation by lipid-activated nuclear receptors [J]. Nature,2008,454(7203):470-477.
[34]Hotamisligil GS. Inflammation and metabolic disorders [J]. Nature,2006, 444(7121):860-867.
[35]A. Michael Lincoff, Kathy Wolski, Stephen J. Nicholls, et al. Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus:A Meta-analysis of Randomized Trials [J]. JAMA,2007,298:1180-1188.
[36]Kalaitzidis RG, Sarafidis PA, Bakris GL. Effects of thiazolidinediones beyond glycaemic control [J]. Curr Pharm Des.2009,15(5):529-536.
[37]Ceriello A. Thiazolidinediones as anti-inflammatory and anti-atherogenic agents [J]. Diabetes Metab Res Rev.2008,24(1):14-26.
[38]Reddy RC. Immunomodulatory role of PPAR-gamma in alveolar macrophages [J]. J Investig Med,2008,56(2):522-527.
[39]Wilensky RL, Hamamdzic D. The molecular basis of vulnerable plaque:potential therapeutic role for immunomodulation [J]. Curr Opin Cardiol,2007, 22(6):545-551.
[40]Szeles L, Torocsik D, Nagy L. PPARgamma in immunity and inflammation:cell types and diseases [J]. Biochim Biophys Acta,2007,1771(8):1014-1030.
[41]Saunders BM, Tran S, Ruuls S, et al. Transmembrane TNF is sufficient to initiate cell migration and granuloma formation and provide acute, but not longterm, control of Mycobacterium tuberculosis infection. J Immunol,2005,174 (8):4 852.
[42]Aggarwal BB, Shishodia S, Ashikawa K, et al. The role of TNF and its familymembers in inflammatory and cancer:lesson from gene deletion. Curr Drug Targets Inflamm Allergy,2002,1 (4):327.
[43]Lakatos PL, Miheller P. Is there an increased risk of lymphoma and malignancies under anti-TNF therapy in IBD? Curr Drug Targets.2010 Feb;11(2):179-86.
[44]Stallmach A, Hagel S, Bruns T. Adverse effects of biologics used for treating IBD. Best Pract Res Clin Gastroenterol.2010;24(2):167-82.
[45]周长玉,王江滨。调节性T细胞及其分化因子IL-10治疗炎症性肠病的研究进展。国外医学·消化系疾病分册·2004,24(6)：332-334.
[46]Dalmasso G, Cottrez F, Imbert V. Saccharomyces boulardii inhibits inflammatory bowel disease by trapping T cells in mesenteric lymph nodes. Gastroenterology. 2006;131(6):1812-25.
[47]Verschoor CP, Pant SD, You Q, et al. Polymorphisms in the gene encoding bovine interleukin-10 receptor alpha are associated with Mycobacterium avium ssp. paratuberculosis infection status. BMC Genet.2010;11(1):23.
[48]Erdman SE, Rao VP. CD4 (+) CD25 (+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice[J]. Cancer Res,2003, 63(18):6042-6050.
[49]Beatty PL, Narayanan S, Gariepy J,et al. Vaccine against MUC1 antigen expressed in inflammatory bowel disease and cancer lessens colonic inflammation and prevents progression to colitis-associated colon cancer. Cancer Prev Res (Phila Pa).2010;3(4):438-446.
[50]Okamoto S, WatanabeM, YamazakiM, et al. A synthetic mimetic of CD4 is able to suppress disease in rodentmodel of immune cells[J].Eur J Imm unol,1999,29: 355-366.
[51]Simp son SJ, Mizoguchi E, Allen D, et al. Evidence that CD4+ but not CD8+ T cells are responsible formurine interleukin-22deficient colitis [J]. Eur J Imm unol,1995,25:2618-2625.
[52]Das G, AugustineMM, Das J, et al. An important regulatory role for CD4+ CD8aa T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease [J]. PNAS,2003,100:5324-5329.
[53]McNamee EN, Wermers JD, Masterson JC,et al. Novel model of TH2-polarized chronic ileitis:the SAMP1 mouse. Inflamm Bowel Dis.2010;16(5):743-752.
[54]Monteleone G, MacDonald TT. Manipulation of cytokines in the management of patients with inflammatory bowel disease. Ann Med.2000;32(8):552-560.
[55]Asseman C, Fowler S, Powrie F. Control of experimental inflammatory bowel disease by regulatory T cells. Am J Respir Crit Care Med.2000; 162(4 Pt 2):S185-189.
[56]杜冠华,李学军,张永祥,等译.药理学实验指南新药发现和药理学评价[T].北京：科学出版社,2001.698-7121
[57]Yokoi N, Identification of a major gene respible for type 1 diabetes in the Komeda diabetes-prone rat [J]. Exp Anim,2005,54(2):111-115.
[58]Wang H, Hagenfeldt-Johansson K, Otten LA, et al. Experimental models of transcription factor-associated maturity-onset diabetes of young [J]. Diabetes, 2002,51 Suppl 3:S333-342.
[59]Pettpher CC, Ledoux SP, VA, et al. Pepair of Alkalilabile sites within the mitochondrial DNA of RINr 38 cells after exposure to the nitrosourea streptozotocin [J]. Bio Chem,1991;266:3113
[60]Choi AE, Noh HL, Kim HM,et al. Streptozotocin upregulates GAD67 expression in MIN6N8a beta cells [J]. J Autoimmu,2002,19:1-8.
[61]Paik SG, Fleischer N, Shin SI. Insulin depedent diabetes mellitus induced by subdiabetogenic doses of streptozotocin:obligatory role of cell mediated autoimmune process [J]. Proc Nat Acad Sci USA,1980,77:6129-6133.36
[62]Papaccio G, Frascatore S, Esposito V, et al. Early macrophage infiltration in mice treated with low-dose streptozonic in decreases islet superoxide dismutase levels: prevention by silica pretreatment [J]. Acta Anat (Basel),1991,142(2):141-146.
[63]Takasu N, Komiya J, Asawa T, et al. Streptozocin- and alloxan-induced H2O2 generation and DNA fragmentation in pancreatic islets. H2O2 as mediator for DNA fragmentation [J]. Diabetes,1991,40(9):1141-1145.
[64]Mauricio D, Mandrup-Palsen T. Apoptosis and the pathogenesis of IDDM:a question of life and death [J]. Diabetes,1998,47:1537.
[65]Liu K, Parterson A J, Chin E, at al. Glucose stimulates protein modifiation by O-linked GlcNAC pancreastic beta cell:Linkage of O-linked GlcNAC to beta cell death [J]. Proc Natl Acad Sci USA,2000,97(16):2820.
[66]黄波,刘学政,庞东渤.不同途经注射链脲佐菌素致大鼠糖尿病模型的研究[J].锦州医学院学报,2003,24(1)19-20.
[67]李德强.环孢素A对STZ诱导的糖尿病大鼠肾脏自身免疫和炎症损伤的预防作用探讨[D].天津：天津医科大学,2006：
[68]邹仲之.组织学与胚胎学.第5版.北京：人民卫生出版社。2001.9：160.
[69]Shatos M A, Rios J D, Horikawa Y, et aL Isolation and characterization of cultured human conjunctival goblet cells[J]. Invest Ophthalmol Vis Sci,2003。 44(6):2477-2486.
[70]巫全胜,钱宁,吴曙光.药物依赖性便秘大鼠大肠杯状细胞及5-HT变化的实验研究.实验动物科学,2008,25(3)：11-13.
[71]Johan D, Soderhohn, Yang PC, et al. Chronic sLressinduces mast cell dependent bacterial adherence and initiates mucesal inilan II rlatiOll in rat intestine[J]. Gastroenterology,2002,123:1099-1108.
[72]仝巧云,罗和生,朱宗耀.慢性应激对大鼠结肠粘蛋白muc2的表达的影响[J].中国医师杂志2005,7(5)：629-631.
[73]Herbert T ilg, Alexander R Moschen. Inflammatory Mechanisms in the Regulation of Insulin Resistance [J].Tilg and Moschen 2008,14 (3-4):222-231.
[74]Plaisancie P,Barcelo A,Moro F,et al.Effects of neurotransmitters,gut hormones,and inflammatory mediators on mucus discharge in rat colon.Am.J.Physsiol.1998,275:1073-1084.
[75]Belley A,Chadee K. Prostaglandin E2 stimulates rat and human colonic mucin exocytosis via the EP4 receptor.Gastroenterology,1999,117:1352-1362.
[76]Schrier BP, Lichtendonk WJ, Wtjes JA.The effect of N-acetyl-L-cysteine on the viscosity of ileal neoblader mucus.World J Urol.2002,20:64-67.
[77]Yin J, Chen JD. Roles of interstitial cells of Cajal in regulating gastrointestinal motility:in vitro versus in vivo studies [J]. J Cell MolMed,2008,12 (4):1118-1129.
[78]Ward SM,Sanders KM, Hirst GD.Role of interstitial cells of Cajal in neural control of gastrointestinal smooth muscles.Neurogastroenterol Motil,2004,16(1:) 112-117.
[79]刘诗.胃肠道Cajal间质细胞。临床消化病杂志,2009,21(2)：105-106
[80]李睿明,沈洪,张蓓等.Cajal间质细胞_胃肠道动力调节药作用靶点[J]。现代中西医结合杂志,2008,17(20)：3229-3232。
[81]梁国刚,李毅,齐清会。大鼠小肠神经-Cajal间质细胞-平滑肌网络的超微结构研究。大连医科大学学报,2009,31(1)：5-8
[82]Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin induced diabetes.Wang XY, Huizinga JD, Diamond J, Liu LW.Neurogastroenterol Motil. 2009;21(10):1095-e92
[83]杨琰,余跃.ICC与胃肠道炎症免疫.世界华人消化杂志 2009；17(36)：3715-3719
[84]Wu JJ, Rothman TP,Gershon MD.Development of the interstitial cell of Cajal:origin,kit dependence and neuronal and nonneuronal sources of kit ligand.J Neurosci Res,2000,59(3):384-401.
[85]Iwasaki H, Kajimura M, Osawa S, et al. A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus. J Gastroenterol.2006 Nov;41 (11):1076-87.
[86]Matsuura T, Masumoto K, Ieiri S, Nakatsuji T,et al. Morphological and physiological changes of interstitial cells of Cajal after small bowel transplantation in rats. Transpl Int 2007; 20:616-624.
[87]Lin L, Xu LM, Zhang W, et al.Roles of stem cell factor on the depletion of interstitial cells of Cajal in the colon of diabetic mice. Am J Physiol Gastrointest Liver Physiol.2010;298(2):G241-247.
[88]Horvath VJ, Vittal H, Lorincz A, et al. Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis. Gastroenterology.2006;130(3):759-70.
[89]侯宁宁,王朝迅,雒瑢等.STZ-糖尿病大鼠小肠动力与肠神经胆碱能和氮能神经元关系的研究.天津医科大学学报,2007,13(2)：165-170.
[90]Consoli A, Devangelio E, Lupus. Thiazolidinediones and inflammation [J].2005, 14(9):794-797.
[91]Horvath VJ, Vittal H, Ordog T. Reduced insulin and IGF-I signaling, not hyperglycemia, underlies the diabetes-associated depletion of interstitial cells of Cajal in the murine stomach. Diabetes 2005; 54 (5):1528-1533.
[92]Matsuyama M, Yoshimura R. A novel approach to anticancer therapies:peroxisome proliferator activator-receptor-gamma as a new target therapy in thetreatment of human urological cancer[J]. Endocr Metab Immune Disord Drug Targets. 2009,9(1):76-83.
[93]Piqueras L, Sanz MJ, et al. Activation of PPAR{beta}/{delta} inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release[J]. J Leukoc Biol.,2009. [Epub ahead of print].
[94]汪涛,秦志平,李恩.毗格列酮对糖尿病冠心病炎性因子水平的影响[J].医药论坛杂志,2008,29(8)：61-62.
[95]李淑华,付绪栋,等盐酸吡格列酮对2型糖尿病患者血清基质金属蛋白酶-9水平影响研究[J].中国全科医学,2006,9(1)：33-34.
[96]Zeender E, Maedler K,et al. Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta[J]. J Clin Endocrinol Metab.2004,89(10):5059-5066.
[97]Kim SR, Lee KS, Involvement of IL-10 in peroxisome proliferator-activated receptor gamma-mediated anti-inflammatory response in asthma[J].Mol Pharmacol,2005,68(6):1568-1575.
[98]Hetzel M, Walcher D,et al. Inhibition of MMP-9 expression by PPARgamma activators in human bronchial epithelial cells[J].Thorax.2003,58(9):778-783.
[99]Zhang WY, Schwartz EA,,etc.Pioglitazone inhibits the expression of inflammatory cytokines from both monocytes and lymphocytes in patients with impaired glucose tolerance[J]. Arterioscler Thromb Vasc Biol.2008,28(12):2312-2318.
[100]Justin I,Odegaard, Roberto R,et al.Macrophage-specific PPARy controls alternative activation and improves insulin resistance[J]. Nature.2007 June 28; 447(7148):1116-1120.
[101]Nikolaus Marx, Daniel Walcher,et al. Thiazolidinediones Reduce Endothelial Expression of Receptors for Advanced Glycation End Products[J].Diabetes,2004, 53:2662-2668.
[102]范钦明,廖崇先.过氧化物酶体增植物激活酶体(PPAR)激活剂(吡格列酮)在大鼠心脏移植中的初步研究[D].福建：福建医科大学,2003.
[103]王晓兰,吕和平,康跃军.肿瘤坏死因子α与炎症性肠病研究进展.洛阳医专学报,2002,20(3)：462-562.
[104]施颖琦.细胞因子在炎症性肠病免疫调节中的研究进展.交通医学,2009,23(3)：310-313.
[105]Ueyama H, Kiyohara T, Sawada N, et al. High Fas ligand expression on lymphocytes in lesions of ulcerative colitis.Gut,1998,43 (1):48-55.
[106]Coffey JC, Bennett MW, Wang JH, et al. Upregulation of Fas-Fas-L (CD95/CD95L)-mediated epithelial apoptosis--a putative role in pouchitis? J Surg Res,2001,98(1):27-32.
[107]Van den Brande J, Homines DW, Peppelenbosch MP. Infliximab induced T lymphocyte apoptosis in Crohn's disease. J Rheumatol Suppl,2005,74:26-30.
[108]Papa A, Mocci G, Scaldaferri F, Bonizzi M. New therapeutic approach in inflammatory bowel disease. Eur Rev Med Pharmacol Sci.2009;13 (Suppl 1):33-35.
[109]Kettritz R, ChoiM, Rolle S, et all Integrins and cytokines activate nuclear transcription factor-kappaB in human neutrophils[J].Biol Chem,2004,279 (4): 2657-2665.
[110]Ma DJ, Li SJ,etc. Temporal and spatial profiling of nuclei-associated proteins upon TNF-alpha/NF-kappaB signaling[J]. Cell Res.2009, [Epub ahead of print].
[111]DubuquoyL, Jansson EA,Deeb S, et al. Impaired exp ression of peroxisome proliferator-activated receptor gamma in ulcerative colitis[J].Astroenterology, 2003,124:1265-1276.
[112]Wang YL, Frauwirth KA, Rangwala SM, et al. Thiazolidinedione activation of peroxisome proliferator-activated recep tor gamma can enhance mitochondrial potential and p romote cell survival [J]. J Biol Chem,2002,277: 31781-31788.
[113]Lytle C, Tod T, Kathy T, et al. The peroxisome p roliferators-activated receptor gamma ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency [J]. Inflamm Bowel Dis,2005,11: 231-243.
[114]James D, Gary R, Robert B, et al. An open-label trail of the PPAR gamma ligand rosiglitazone for active ulcerative colitis[J]. Am J Gastroenterol,2001,96: 3323-3328.
[115]Ebert EC, Panja A, Das KM, et al. Patients with inflammatory bowel disease may have a transforming growth factorbeta-, interleukin (IL)-2-or IL-10-deficient state induced by intrinsic neutralizing antibodies [J]. Clin Exp Immunol,2009,155(1):65-71.
[116]Kallel L, Boubaker J, Louzir H, et al. Colonic expression of gamma-interferon and interleukin-10 in Crohn's disease and ulcerative colitis[J]. Presse Med,2005,34(1):8-12.
[117]Kidd M, Gustafsson BI, Drozdov I, et al. ILlbeta-and LPSinduced serotonin secretion is increased in EC cells derived from Crohn's disease [J]. Neurogastroenterol Motil,2009,21 (4):439-450.
[118]Rennick DM, Fort MM. Lessons from genetically engineered animal models. XII. IL-10-deficient (IL-10(-/-) mice and intestinal inflammation[J].Am J physiol Gastrointest liver physiol,2000,278(6):829-833.
[119]Frank Autschbach, Jutta Braunstein, In Situ Expression of Interleukin-10 in NoninflamedHuman Gut and in Inflammatory Bowel Disease[J]. American Journal of Pathbology,1998,153:121-130.
[120]Meresse B, Rutgeerts P, Malchow H, et al. Low ileal inter-leukin 10 concentrations are predictive of endoscopic recur-rence in patients with Crohn disease[J]. GUT,2002,50(1):25.
[121]Gasche, S Bakos, IL-10 secretion and sensitivity in normal human intestine and inflammatory bowel disease[J]. J Clin Immunol,2000,20(5):362-370.
[122]Niessner M, Volk BA. Altered Thl/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction(RT-PCR)[J]. Clin Exp Immunol, 1995,101:428-435.
[123]Autschbach F, Braunstein J, Helmke B, et al. In Situ Expression of Interleukin-10 in Noninflamed Human Gut and in Inflammatory Bowel Disease[J]. Am J Pathol,1998,153:121-130.
[124]王瑞良,苏青.RAGE及其配体的临床意义研究进展[J].国际内分泌代谢杂志,2006 26(3)：160-162.
[125]Jacob A, Wu R, ZhouM, et al. Mechanism of the anti-inflammatory effect of curcumin:PPAR-gamma activation[J].PPAR Res,2007,2007:89369.
[126]Bright JJ, Kanakasabai S, PPAR Regulation of Inflammatory Signaling in CNS Diseases[J].PPAR Res.2008;2008:658520.
[127]Hwang J, Kleinhenz DJ, Lassegue B, et al. Peroxisome Proliferators-activated recep tor-gamma ligands regulate endothelialmembrane superoxide production[J]. Am J Physiol Cell Physiol,2005,288 (4):C899-905.
[128]Henderson BC, Sen U, Reynolds C. Reversal of systemic hypertension-associated cardiac remodeling in chronic pressure overload myocardium by ciglitazone[J]. Int JBiol Sci,2007,3(6):385-392.
[129]Chung SW, Kang BY, Kim TS, et al. Inhibition of interleukin-4 production in CD4+T cells by peroxisome proliferators-activated receptor-gamma (PPAR-gamma) ligands:involvement of physical association between PPAR-gamma and the nuclear factor of activated T cells transcription factor [J]. Mol Pharmacol,2003,64(2):1169-1179.
[130]Woodland DL. Cell-mediated immunity to respiratory virus infections [J]. Curr OpinImmunol,2003,15 (4):430.
[131]Rabinnovitch A. Perspectives in diabetes:Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM:Therapeutic intervention by immunostimulation? [J]. Diabetes,1994,43:613.
[132]'De Carli Met al. Human Th1 and Th2 cells:functional properties, regulation of development and roles in autoimmunity [J]. Autoimmunity,1994,18:301
[133]Healey D, Ozegbe P, Arden S, et al. In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice [J]. J Clin Invest,1995,95:2979-2985.
[134]吴翰桂,朱诚,丁仁瑞.肠道黏膜免疫研究进展[J].免疫学杂志,2000,16(3)：235-237.
[135]Weiner HL, Friedman A, Miller A, et al. Oral tolerance:immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens [J]. Annu Rev Immunol,1994, 12:809-837.
[136]莫剑忠,袁耀宗,邹多武.消化系功能性和动力障碍性疾病[M].上海：上海科学技术出版社,2005：280-298.
[137]金杭斌,顾竹影,厉有名.神经-免疫-内分泌网络与肠易激综合征[J].国际消化病杂志,2006,26(1)：40-43.
[138]Zhao A, McDermott J, Urban JF J r, et al. Dependence of IL-4, IL-13, and nematode induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves [J]. J Immunol,2003,171 (2) 948-954.
[139]KhanW I, Collins SM. Gut motor function:immunological control in enteric infection and inflammation [J]. Clin Exp Immunol,2006,143 (3):389-397.
[140]毛咏秋,姜愚,李梅,等.289例中晚期肿瘤病人外周血T淋巴细胞表型分析[J].华西医学,2004,19(2)：185-186.
[141]Mori A, Sagara F, Shimizu S, et al Changes in peripheral lymphocyte subsets in the type 1 diabetic dogs treated with insulin injections[J]. J Vet Med Sci. 2008;70(2):185-187.
[142]Yang Z, Zhou Z, Huang G, et,al. The CD4(+) regulatory T-cells is decreased in adults with latent autoimmune diabetes[J]. Diabetes Res Clin Pract.2007; 76 (1):126-131.
[143]赵宏艳.灵芝多糖对H22荷瘤小鼠肠道黏膜免疫功能的影响[D].北京：中国中医科学院中医基础理论研究所,2008.
[144]Zhang X, Young HA. PPAR and immune system-what do we know? [J]. Int Immunopharmacol,2002,2:1029-1044.
[145]Clark RB. The role of PPARs in inflammation and immunity [J]. J Leukoc Biol,2002,71:388-400.
[146]Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity [J]. Nat Rev Imunol,2002,2:748-759.
[1]李睿明,沈洪,张蓓等.Cajal间质细胞_胃肠道动力调节药作用靶点[J]。现代中西医结合杂志,2008,17(20)：3229-3232。
[2]王伟,王景杰,黄裕新。胃肠道Cajal间质细胞的研究现状。中国中西医结合消化杂志2007,15(6)415-416
[3]陈慧群,黄裕新,2E景杰。消化道Cajal间质细胞及其受体的研究进展胃肠病学和肝病学杂志。2008,17(4)332.334
[4]Sanders KW,Koh SD,Ward SM.Interstitial cells of cajal as pacemakers in the gastrointestinal tract.Annu Reu Physiol 2006;68:307-343.
[5]Yin J, Chen JD. Roles of interstitial cells of Cajal in regulating gastrointestinalmotility:in vitro versus in vivo studies [J]. J Cell Mol Med,2008,12 (4):1118-1129.
[6]Lecoin L, Gabella G,Le Douarin N. Origin of the c-kit positive interstitial cells in the avian bowel. Development,1996; 122:725
[7]Ward SM,Sanders KM, Hirst GD.Role of interstitial cells of Cajal in neural control of gastrointestinal smooth muscles.Neurogastroenterol Motil,2004,16(1:) 112-117.
[8]刘诗.胃肠道Cajal间质细胞.临床消化病杂志,2009,21(2)：105.106
[9]Ordwang T, Hayashi Y, Gibbons SJ. Cellular pathogenesis of diabetic gastroenteropathy. Minerva Gastroenterol Dietol.2009 Sep;55(3):315-43.
[10]Nakagawa T,Misawa H,Nakajima Y,Takaki M.Absence of peristalsis in the ileum of W/W(V) mutant mice that are selectively deficient in myenteric interstitial cells of Cajal. J Smooth Muscle Res 2005;41:141-151.
[11]Park SJ,Mckay CM,Zhu Y,Huizina JD.Volume activated chloride currents in interstitial cells of cajal.Am J Physiol Gastrointest liver physiol 2005;289:G791-797.
[12]SHA L, FARRUGIA G, HARMSEN WS, et al. Membrane potential gradient is carbon monoxide-dependent in mouse and human small intestine[J]. Am J Physiol Gastrointesst Liver Physiol,2007,293:G438.
[13]梁国刚，李毅,齐清会.大鼠小肠神经-Cajal间质细胞.平滑肌网络的超微结构研究：大连医科大学学报,2009,31(1)：5-8.
[14]Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin induced diabetes.Wang XY, Huizinga JD, Diamond J, Liu LW.Neurogastroenterol Motil. 2009;21(10):1095-e92.
[15]Daniel EE. Communication between interstial cells of Cajal and gsstrointestinal mnscle. Neurogast roenterol Motil,2004,16:118-122。
[16]Salmhofer H,Neuhuber WL,Ruth P et al. Pivotal role of the interstitial cells of cajal in the nitric oxide signaling pathway of rat small intestine.Cell Tissue Res,2001,305 (3):331-340
[17]Korenaga K,Micci MA,Taglialatela G,et al.Supperession of Inos expression in rat enteric neurons by the receptor for advanced glycation end-products[J].Neurogastroenterol Motil,2006,18(5):392
[18]Epperson A, Hatton WJ, Callaghan B, et al. Molecular component s expressed in cultured and f reshly isolated interstitial cells of Cajal. Am J Physiol,2000,279: C529-539。
[19]Ward SM, Sanders KM. Interstitial cells of Cajal:p rimary targets of enteric motor innervation. Anat Rec,2001; 262 (1):125
[20]柳利明,秦榕,黄华.糖尿病大鼠肠道Cajal间质细胞的实验研究.实用糖尿病杂志2009,5(5)：34-35.
[21]Horvath VJ, Vittal H, Ordog T. Reduced insulin and IGF-I signaling, not hyperglycemia, underlies the diabetes-associated depletion of interstitial cells of Cajal in the murine stomach. Diabetes 2005; 54 (5):1528-1533.
[22]Farrugia G. Interstitial cells of Cajal in health and disease [J].NeurogastroenterolMotil,2008,20 (Suppl 1):54-63
[23]杨琰,余跃.ICC与胃肠道炎症免疫.世界华人消化杂志2009；17(36)：3715-3719
[24]Wu JJ, Rothman TP,Gershon MD.Development of the interstitial cell of Cajal:origin,kit dependence and neuronal and nonneuronal sources of kit ligand.J Neurosci Res,2000,59(3):384-401.
[25]Iwasaki H, Kajimura M, Osawa S, et al. A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus. J Gastroenterol.2006 Nov;41(11):1076-87.
[26]Matsuura T, Masumoto K, Ieiri S, Nakatsuji T,et al. Morphological and physiological changes of interstitial cells of Cajal after small bowel transplantation in rats. Transpl Int 2007; 20:616-624
[27]Lin L, Xu LM, Zhang W, et al.Roles of stem cell factor on the depletion of interstitial cells of Cajal in the colon of diabetic mice. Am J Physiol Gastrointest Liver Physiol.2010;298(2):G241-247.
[2]翁建平.突出中国特点的2型糖尿病防治指南[J].中华内分泌代谢杂志,2009,25(1)：增录1 a3-4.
[3]Summary of Revisions for the 2008 Clinical Practice Recommendations [J]. Diabetes Care,2008,31:S3-S4.
[4]Poitout V, Robertson RP. Glucolipotoxicity:fuel excess and beta-cell dysfunction [J]. Endocr Rev.2008,29(3):351-366.
[5]陈名道.胰岛β细胞的“糖毒性”、“脂毒性”与“糖脂毒性”[J].中华内分泌代谢杂志,2009,25(1)：5-8.
[6]Poitout V, Hagman D, Stein R, Artner I, et al. Regulation of the insulin gene by glucose and fatty acids[J]. J Nutr,2006,136(4):873-876.
[7]Zeng MD. Glucotoxicity, lipotoxicity and the nonalcoholic fatty liver disease [J]. Zhonghua Gan Zang Bing Za Zhi,2005,13(2):81-82.
[8]Thomas F. Luscher, Mark A. Creager, Joshua A. Cechman, et al. Diabetes and vascular disease. Pathophysiology, clinical consequences and medical therapy: part Ⅱ [J]. Circulation,2003,108:1655-1661.
[9]Mark A. Creager, Thomas F. Luscher, Francesco Cosentino, et al. Diabetes and vascular disease. Pathophysiology, clinical consequences, and medical therapy: part Ⅰ [J]. Circulation,2003,108:1527-1532.
[10]Wassink AM, Olijhoek JK, Visseren FL. The metabolic syndrome:metabolic changes with vascular consequences [J]. Eur J Clin Invest,2007,37(1):8-17.
[11]Nghiem PP, Platt SR, Schatzberg S. The weak cat. Practical approach and common neurological differentials [J]. J Feline Med Surg,2009,11(5):373-383.
[12]Chatenoud L, Bluestone JA. CD3-specific antibodies:a portal to the treatment of autoimmunity [J]. Nat Rev Immunol,2007,7(8):622-632.
[13]Oling V, Marttila J, Knip M, et al. Circulating CD4+CD25 high regulatory T cells and natural killer T cells in children with newly diagnosed type 1 diabetes or with diabetes-associated autoantibodies [J]. Ann N Y Acad Sci,2007,1107(1): 363-372.
[14]Moriyama H, Kotani R, Katsuta A, et al. Autoreactive T cell response in CD25-negative fraction of peripheral blood mononuclear cells in established type 1 diabetes [J]. Ann N Y Acad Sci.2008,1150(12):278-281.
[15]Alizadeh Dehnavi R, Beishuizen ED, van de Ree MA, et al. The impact of metabolic syndrome and CRP on vascular phenotype in type 2 diabetes mellitus [J]. Eur J Intern Med,2008,19(2):115-121.
[16]Deedwania P, Srikanth S. Diabetes and vascular disease [J]. Expert Rev Cardiovasc Ther,2008,6(1):127-138.
[17]Aronson D. Hyperglycemia and the pathobiology of diabetic complications [J]. Adv Cardiol,2008,45:1-16.
[18]高桦,邱明才.应加强对部分2型糖尿病多器官免疫损伤的研究[J].中华医学杂志,2005,85(12)：793-795.
[19]邱明才,孟春梅.糖尿病并发症发病过程中的补体活化作用[J].中华内分泌代谢杂志,2006,22(3)：303-305.
[20]邱明才,林珊,高志红,等.有胫前黑斑的2型糖尿病患者皮肤黑斑和肾活检[J].天津医药,2004,32(5)：257-259.
[21]Zachary T. Bloomgarden. Diabetic Retinopathy [J]. Diabetes Care,2008,31 (3): 1080-1083.
[22]David A. Antonetti, Alistair J. Barber, Sarah K. Bronson, et al. Diabetic Retinopathy:Seeing Beyond Glucose-Induced Microvascular Disease [J]. Diabetes,2006,55(9):2401-2411.
[23]孟春梅,高桦,邱明才,等.链脲佐菌素诱导的糖尿病大鼠视网膜的免疫损伤[J].中华内分泌代谢杂志,2006,22(06)：588-589.
[24]李德强；环孢菌素A对STZ诱导的糖尿病大鼠肾脏自身免疫和炎症损伤的预防作用探讨[D].天津：天津医科大学,2006.
[25]崔瑾.环孢菌素A对STZ诱导的糖尿病大鼠多器官免疫损伤的治疗作用[D].天津：天津医科大学,2006.
[26]侯宁宁.链脲佐菌素诱导的糖尿病大鼠外周神经病变免疫损伤和环孢素A的抑制作用[D].天津：天津医科大学,2007.
[27]王朝迅.环孢素A抑制链脲佐菌素诱导的糖尿病大鼠大脑免疫和NF-kB通路 激活的实验研究[D].天津：天津医科大学,2007.
[28]张杰涛,邱明才.关于糖尿病的几点认识[J].医学与哲学(临床决策论坛版),2008,29(2)：18-19.
[29]Nakahara M, Isozaki K, Hirota S, et al. Deficiency of KIT-positive cells in the colon of patients with diabetes mellitus. J Gastroenterol Hepatol,2002,17(6): 666-670.
[30]Choi KM, Zhu J, Stoltz GJ, et al. Determination of gastric emptying in nonobese diabetic mice. Am J Physiol Gastrointest Liver Physiol.2007;293:G1039-45.
[31]Ward SM. Sanders KM. Physiology and pathophysiology of the interstitial cell of Cajal:from bench to bedside. Ⅰ. Functional development and plasticity of interstitial cells of Cajal networks. Am J Physiol Gastrointest Liver Physiol, 2001,281(3):G602-G611.
[32]柳利明,秦榕,黄华.糖尿病大鼠肠道Cajal间质细胞的实验研究.实用糖尿病杂志,2009,5(5)：34-35.
[33]Bensinger SJ, Tontonoz P.Integration of metabolism and inflammation by lipid-activated nuclear receptors [J]. Nature,2008,454(7203):470-477.
[34]Hotamisligil GS. Inflammation and metabolic disorders [J]. Nature,2006, 444(7121):860-867.
[35]A. Michael Lincoff, Kathy Wolski, Stephen J. Nicholls, et al. Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus:A Meta-analysis of Randomized Trials [J]. JAMA,2007,298:1180-1188.
[36]Kalaitzidis RG, Sarafidis PA, Bakris GL. Effects of thiazolidinediones beyond glycaemic control [J]. Curr Pharm Des.2009,15(5):529-536.
[37]Ceriello A. Thiazolidinediones as anti-inflammatory and anti-atherogenic agents [J]. Diabetes Metab Res Rev.2008,24(1):14-26.
[38]Reddy RC. Immunomodulatory role of PPAR-gamma in alveolar macrophages [J]. J Investig Med,2008,56(2):522-527.
[39]Wilensky RL, Hamamdzic D. The molecular basis of vulnerable plaque:potential therapeutic role for immunomodulation [J]. Curr Opin Cardiol,2007, 22(6):545-551.
[40]Szeles L, Torocsik D, Nagy L. PPARgamma in immunity and inflammation:cell types and diseases [J]. Biochim Biophys Acta,2007,1771(8):1014-1030.
[41]Saunders BM, Tran S, Ruuls S, et al. Transmembrane TNF is sufficient to initiate cell migration and granuloma formation and provide acute, but not longterm, control of Mycobacterium tuberculosis infection. J Immunol,2005,174 (8):4 852.
[42]Aggarwal BB, Shishodia S, Ashikawa K, et al. The role of TNF and its familymembers in inflammatory and cancer:lesson from gene deletion. Curr Drug Targets Inflamm Allergy,2002,1 (4):327.
[43]Lakatos PL, Miheller P. Is there an increased risk of lymphoma and malignancies under anti-TNF therapy in IBD? Curr Drug Targets.2010 Feb;11(2):179-86.
[44]Stallmach A, Hagel S, Bruns T. Adverse effects of biologics used for treating IBD. Best Pract Res Clin Gastroenterol.2010;24(2):167-82.
[45]周长玉,王江滨。调节性T细胞及其分化因子IL-10治疗炎症性肠病的研究进展。国外医学·消化系疾病分册·2004,24(6)：332-334.
[46]Dalmasso G, Cottrez F, Imbert V. Saccharomyces boulardii inhibits inflammatory bowel disease by trapping T cells in mesenteric lymph nodes. Gastroenterology. 2006;131(6):1812-25.
[47]Verschoor CP, Pant SD, You Q, et al. Polymorphisms in the gene encoding bovine interleukin-10 receptor alpha are associated with Mycobacterium avium ssp. paratuberculosis infection status. BMC Genet.2010;11(1):23.
[48]Erdman SE, Rao VP. CD4 (+) CD25 (+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice[J]. Cancer Res,2003, 63(18):6042-6050.
[49]Beatty PL, Narayanan S, Gariepy J,et al. Vaccine against MUC1 antigen expressed in inflammatory bowel disease and cancer lessens colonic inflammation and prevents progression to colitis-associated colon cancer. Cancer Prev Res (Phila Pa).2010;3(4):438-446.
[50]Okamoto S, WatanabeM, YamazakiM, et al. A synthetic mimetic of CD4 is able to suppress disease in rodentmodel of immune cells[J].Eur J Imm unol,1999,29: 355-366.
[51]Simp son SJ, Mizoguchi E, Allen D, et al. Evidence that CD4+ but not CD8+ T cells are responsible formurine interleukin-22deficient colitis [J]. Eur J Imm unol,1995,25:2618-2625.
[52]Das G, AugustineMM, Das J, et al. An important regulatory role for CD4+ CD8aa T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease [J]. PNAS,2003,100:5324-5329.
[53]McNamee EN, Wermers JD, Masterson JC,et al. Novel model of TH2-polarized chronic ileitis:the SAMP1 mouse. Inflamm Bowel Dis.2010;16(5):743-752.
[54]Monteleone G, MacDonald TT. Manipulation of cytokines in the management of patients with inflammatory bowel disease. Ann Med.2000;32(8):552-560.
[55]Asseman C, Fowler S, Powrie F. Control of experimental inflammatory bowel disease by regulatory T cells. Am J Respir Crit Care Med.2000; 162(4 Pt 2):S185-189.
[56]杜冠华,李学军,张永祥,等译.药理学实验指南新药发现和药理学评价[T].北京：科学出版社,2001.698-7121
[57]Yokoi N, Identification of a major gene respible for type 1 diabetes in the Komeda diabetes-prone rat [J]. Exp Anim,2005,54(2):111-115.
[58]Wang H, Hagenfeldt-Johansson K, Otten LA, et al. Experimental models of transcription factor-associated maturity-onset diabetes of young [J]. Diabetes, 2002,51 Suppl 3:S333-342.
[59]Pettpher CC, Ledoux SP, VA, et al. Pepair of Alkalilabile sites within the mitochondrial DNA of RINr 38 cells after exposure to the nitrosourea streptozotocin [J]. Bio Chem,1991;266:3113
[60]Choi AE, Noh HL, Kim HM,et al. Streptozotocin upregulates GAD67 expression in MIN6N8a beta cells [J]. J Autoimmu,2002,19:1-8.
[61]Paik SG, Fleischer N, Shin SI. Insulin depedent diabetes mellitus induced by subdiabetogenic doses of streptozotocin:obligatory role of cell mediated autoimmune process [J]. Proc Nat Acad Sci USA,1980,77:6129-6133.36
[62]Papaccio G, Frascatore S, Esposito V, et al. Early macrophage infiltration in mice treated with low-dose streptozonic in decreases islet superoxide dismutase levels: prevention by silica pretreatment [J]. Acta Anat (Basel),1991,142(2):141-146.
[63]Takasu N, Komiya J, Asawa T, et al. Streptozocin- and alloxan-induced H2O2 generation and DNA fragmentation in pancreatic islets. H2O2 as mediator for DNA fragmentation [J]. Diabetes,1991,40(9):1141-1145.
[64]Mauricio D, Mandrup-Palsen T. Apoptosis and the pathogenesis of IDDM:a question of life and death [J]. Diabetes,1998,47:1537.
[65]Liu K, Parterson A J, Chin E, at al. Glucose stimulates protein modifiation by O-linked GlcNAC pancreastic beta cell:Linkage of O-linked GlcNAC to beta cell death [J]. Proc Natl Acad Sci USA,2000,97(16):2820.
[66]黄波,刘学政,庞东渤.不同途经注射链脲佐菌素致大鼠糖尿病模型的研究[J].锦州医学院学报,2003,24(1)19-20.
[67]李德强.环孢素A对STZ诱导的糖尿病大鼠肾脏自身免疫和炎症损伤的预防作用探讨[D].天津：天津医科大学,2006：
[68]邹仲之.组织学与胚胎学.第5版.北京：人民卫生出版社。2001.9：160.
[69]Shatos M A, Rios J D, Horikawa Y, et aL Isolation and characterization of cultured human conjunctival goblet cells[J]. Invest Ophthalmol Vis Sci,2003。 44(6):2477-2486.
[70]巫全胜,钱宁,吴曙光.药物依赖性便秘大鼠大肠杯状细胞及5-HT变化的实验研究.实验动物科学,2008,25(3)：11-13.
[71]Johan D, Soderhohn, Yang PC, et al. Chronic sLressinduces mast cell dependent bacterial adherence and initiates mucesal inilan II rlatiOll in rat intestine[J]. Gastroenterology,2002,123:1099-1108.
[72]仝巧云,罗和生,朱宗耀.慢性应激对大鼠结肠粘蛋白muc2的表达的影响[J].中国医师杂志2005,7(5)：629-631.
[73]Herbert T ilg, Alexander R Moschen. Inflammatory Mechanisms in the Regulation of Insulin Resistance [J].Tilg and Moschen 2008,14 (3-4):222-231.
[74]Plaisancie P,Barcelo A,Moro F,et al.Effects of neurotransmitters,gut hormones,and inflammatory mediators on mucus discharge in rat colon.Am.J.Physsiol.1998,275:1073-1084.
[75]Belley A,Chadee K. Prostaglandin E2 stimulates rat and human colonic mucin exocytosis via the EP4 receptor.Gastroenterology,1999,117:1352-1362.
[76]Schrier BP, Lichtendonk WJ, Wtjes JA.The effect of N-acetyl-L-cysteine on the viscosity of ileal neoblader mucus.World J Urol.2002,20:64-67.
[77]Yin J, Chen JD. Roles of interstitial cells of Cajal in regulating gastrointestinal motility:in vitro versus in vivo studies [J]. J Cell MolMed,2008,12 (4):1118-1129.
[78]Ward SM,Sanders KM, Hirst GD.Role of interstitial cells of Cajal in neural control of gastrointestinal smooth muscles.Neurogastroenterol Motil,2004,16(1:) 112-117.
[79]刘诗.胃肠道Cajal间质细胞。临床消化病杂志,2009,21(2)：105-106
[80]李睿明,沈洪,张蓓等.Cajal间质细胞_胃肠道动力调节药作用靶点[J]。现代中西医结合杂志,2008,17(20)：3229-3232。
[81]梁国刚,李毅,齐清会。大鼠小肠神经-Cajal间质细胞-平滑肌网络的超微结构研究。大连医科大学学报,2009,31(1)：5-8
[82]Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin induced diabetes.Wang XY, Huizinga JD, Diamond J, Liu LW.Neurogastroenterol Motil. 2009;21(10):1095-e92
[83]杨琰,余跃.ICC与胃肠道炎症免疫.世界华人消化杂志 2009；17(36)：3715-3719
[84]Wu JJ, Rothman TP,Gershon MD.Development of the interstitial cell of Cajal:origin,kit dependence and neuronal and nonneuronal sources of kit ligand.J Neurosci Res,2000,59(3):384-401.
[85]Iwasaki H, Kajimura M, Osawa S, et al. A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus. J Gastroenterol.2006 Nov;41 (11):1076-87.
[86]Matsuura T, Masumoto K, Ieiri S, Nakatsuji T,et al. Morphological and physiological changes of interstitial cells of Cajal after small bowel transplantation in rats. Transpl Int 2007; 20:616-624.
[87]Lin L, Xu LM, Zhang W, et al.Roles of stem cell factor on the depletion of interstitial cells of Cajal in the colon of diabetic mice. Am J Physiol Gastrointest Liver Physiol.2010;298(2):G241-247.
[88]Horvath VJ, Vittal H, Lorincz A, et al. Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis. Gastroenterology.2006;130(3):759-70.
[89]侯宁宁,王朝迅,雒瑢等.STZ-糖尿病大鼠小肠动力与肠神经胆碱能和氮能神经元关系的研究.天津医科大学学报,2007,13(2)：165-170.
[90]Consoli A, Devangelio E, Lupus. Thiazolidinediones and inflammation [J].2005, 14(9):794-797.
[91]Horvath VJ, Vittal H, Ordog T. Reduced insulin and IGF-I signaling, not hyperglycemia, underlies the diabetes-associated depletion of interstitial cells of Cajal in the murine stomach. Diabetes 2005; 54 (5):1528-1533.
[92]Matsuyama M, Yoshimura R. A novel approach to anticancer therapies:peroxisome proliferator activator-receptor-gamma as a new target therapy in thetreatment of human urological cancer[J]. Endocr Metab Immune Disord Drug Targets. 2009,9(1):76-83.
[93]Piqueras L, Sanz MJ, et al. Activation of PPAR{beta}/{delta} inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release[J]. J Leukoc Biol.,2009. [Epub ahead of print].
[94]汪涛,秦志平,李恩.毗格列酮对糖尿病冠心病炎性因子水平的影响[J].医药论坛杂志,2008,29(8)：61-62.
[95]李淑华,付绪栋,等盐酸吡格列酮对2型糖尿病患者血清基质金属蛋白酶-9水平影响研究[J].中国全科医学,2006,9(1)：33-34.
[96]Zeender E, Maedler K,et al. Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta[J]. J Clin Endocrinol Metab.2004,89(10):5059-5066.
[97]Kim SR, Lee KS, Involvement of IL-10 in peroxisome proliferator-activated receptor gamma-mediated anti-inflammatory response in asthma[J].Mol Pharmacol,2005,68(6):1568-1575.
[98]Hetzel M, Walcher D,et al. Inhibition of MMP-9 expression by PPARgamma activators in human bronchial epithelial cells[J].Thorax.2003,58(9):778-783.
[99]Zhang WY, Schwartz EA,,etc.Pioglitazone inhibits the expression of inflammatory cytokines from both monocytes and lymphocytes in patients with impaired glucose tolerance[J]. Arterioscler Thromb Vasc Biol.2008,28(12):2312-2318.
[100]Justin I,Odegaard, Roberto R,et al.Macrophage-specific PPARy controls alternative activation and improves insulin resistance[J]. Nature.2007 June 28; 447(7148):1116-1120.
[101]Nikolaus Marx, Daniel Walcher,et al. Thiazolidinediones Reduce Endothelial Expression of Receptors for Advanced Glycation End Products[J].Diabetes,2004, 53:2662-2668.
[102]范钦明,廖崇先.过氧化物酶体增植物激活酶体(PPAR)激活剂(吡格列酮)在大鼠心脏移植中的初步研究[D].福建：福建医科大学,2003.
[103]王晓兰,吕和平,康跃军.肿瘤坏死因子α与炎症性肠病研究进展.洛阳医专学报,2002,20(3)：462-562.
[104]施颖琦.细胞因子在炎症性肠病免疫调节中的研究进展.交通医学,2009,23(3)：310-313.
[105]Ueyama H, Kiyohara T, Sawada N, et al. High Fas ligand expression on lymphocytes in lesions of ulcerative colitis.Gut,1998,43 (1):48-55.
[106]Coffey JC, Bennett MW, Wang JH, et al. Upregulation of Fas-Fas-L (CD95/CD95L)-mediated epithelial apoptosis--a putative role in pouchitis? J Surg Res,2001,98(1):27-32.
[107]Van den Brande J, Homines DW, Peppelenbosch MP. Infliximab induced T lymphocyte apoptosis in Crohn's disease. J Rheumatol Suppl,2005,74:26-30.
[108]Papa A, Mocci G, Scaldaferri F, Bonizzi M. New therapeutic approach in inflammatory bowel disease. Eur Rev Med Pharmacol Sci.2009;13 (Suppl 1):33-35.
[109]Kettritz R, ChoiM, Rolle S, et all Integrins and cytokines activate nuclear transcription factor-kappaB in human neutrophils[J].Biol Chem,2004,279 (4): 2657-2665.
[110]Ma DJ, Li SJ,etc. Temporal and spatial profiling of nuclei-associated proteins upon TNF-alpha/NF-kappaB signaling[J]. Cell Res.2009, [Epub ahead of print].
[111]DubuquoyL, Jansson EA,Deeb S, et al. Impaired exp ression of peroxisome proliferator-activated receptor gamma in ulcerative colitis[J].Astroenterology, 2003,124:1265-1276.
[112]Wang YL, Frauwirth KA, Rangwala SM, et al. Thiazolidinedione activation of peroxisome proliferator-activated recep tor gamma can enhance mitochondrial potential and p romote cell survival [J]. J Biol Chem,2002,277: 31781-31788.
[113]Lytle C, Tod T, Kathy T, et al. The peroxisome p roliferators-activated receptor gamma ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency [J]. Inflamm Bowel Dis,2005,11: 231-243.
[114]James D, Gary R, Robert B, et al. An open-label trail of the PPAR gamma ligand rosiglitazone for active ulcerative colitis[J]. Am J Gastroenterol,2001,96: 3323-3328.
[115]Ebert EC, Panja A, Das KM, et al. Patients with inflammatory bowel disease may have a transforming growth factorbeta-, interleukin (IL)-2-or IL-10-deficient state induced by intrinsic neutralizing antibodies [J]. Clin Exp Immunol,2009,155(1):65-71.
[116]Kallel L, Boubaker J, Louzir H, et al. Colonic expression of gamma-interferon and interleukin-10 in Crohn's disease and ulcerative colitis[J]. Presse Med,2005,34(1):8-12.
[117]Kidd M, Gustafsson BI, Drozdov I, et al. ILlbeta-and LPSinduced serotonin secretion is increased in EC cells derived from Crohn's disease [J]. Neurogastroenterol Motil,2009,21 (4):439-450.
[118]Rennick DM, Fort MM. Lessons from genetically engineered animal models. XII. IL-10-deficient (IL-10(-/-) mice and intestinal inflammation[J].Am J physiol Gastrointest liver physiol,2000,278(6):829-833.
[119]Frank Autschbach, Jutta Braunstein, In Situ Expression of Interleukin-10 in NoninflamedHuman Gut and in Inflammatory Bowel Disease[J]. American Journal of Pathbology,1998,153:121-130.
[120]Meresse B, Rutgeerts P, Malchow H, et al. Low ileal inter-leukin 10 concentrations are predictive of endoscopic recur-rence in patients with Crohn disease[J]. GUT,2002,50(1):25.
[121]Gasche, S Bakos, IL-10 secretion and sensitivity in normal human intestine and inflammatory bowel disease[J]. J Clin Immunol,2000,20(5):362-370.
[122]Niessner M, Volk BA. Altered Thl/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction(RT-PCR)[J]. Clin Exp Immunol, 1995,101:428-435.
[123]Autschbach F, Braunstein J, Helmke B, et al. In Situ Expression of Interleukin-10 in Noninflamed Human Gut and in Inflammatory Bowel Disease[J]. Am J Pathol,1998,153:121-130.
[124]王瑞良,苏青.RAGE及其配体的临床意义研究进展[J].国际内分泌代谢杂志,2006 26(3)：160-162.
[125]Jacob A, Wu R, ZhouM, et al. Mechanism of the anti-inflammatory effect of curcumin:PPAR-gamma activation[J].PPAR Res,2007,2007:89369.
[126]Bright JJ, Kanakasabai S, PPAR Regulation of Inflammatory Signaling in CNS Diseases[J].PPAR Res.2008;2008:658520.
[127]Hwang J, Kleinhenz DJ, Lassegue B, et al. Peroxisome Proliferators-activated recep tor-gamma ligands regulate endothelialmembrane superoxide production[J]. Am J Physiol Cell Physiol,2005,288 (4):C899-905.
[128]Henderson BC, Sen U, Reynolds C. Reversal of systemic hypertension-associated cardiac remodeling in chronic pressure overload myocardium by ciglitazone[J]. Int JBiol Sci,2007,3(6):385-392.
[129]Chung SW, Kang BY, Kim TS, et al. Inhibition of interleukin-4 production in CD4+T cells by peroxisome proliferators-activated receptor-gamma (PPAR-gamma) ligands:involvement of physical association between PPAR-gamma and the nuclear factor of activated T cells transcription factor [J]. Mol Pharmacol,2003,64(2):1169-1179.
[130]Woodland DL. Cell-mediated immunity to respiratory virus infections [J]. Curr OpinImmunol,2003,15 (4):430.
[131]Rabinnovitch A. Perspectives in diabetes:Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM:Therapeutic intervention by immunostimulation? [J]. Diabetes,1994,43:613.
[132]'De Carli Met al. Human Th1 and Th2 cells:functional properties, regulation of development and roles in autoimmunity [J]. Autoimmunity,1994,18:301
[133]Healey D, Ozegbe P, Arden S, et al. In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice [J]. J Clin Invest,1995,95:2979-2985.
[134]吴翰桂,朱诚,丁仁瑞.肠道黏膜免疫研究进展[J].免疫学杂志,2000,16(3)：235-237.
[135]Weiner HL, Friedman A, Miller A, et al. Oral tolerance:immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens [J]. Annu Rev Immunol,1994, 12:809-837.
[136]莫剑忠,袁耀宗,邹多武.消化系功能性和动力障碍性疾病[M].上海：上海科学技术出版社,2005：280-298.
[137]金杭斌,顾竹影,厉有名.神经-免疫-内分泌网络与肠易激综合征[J].国际消化病杂志,2006,26(1)：40-43.
[138]Zhao A, McDermott J, Urban JF J r, et al. Dependence of IL-4, IL-13, and nematode induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves [J]. J Immunol,2003,171 (2) 948-954.
[139]KhanW I, Collins SM. Gut motor function:immunological control in enteric infection and inflammation [J]. Clin Exp Immunol,2006,143 (3):389-397.
[140]毛咏秋,姜愚,李梅,等.289例中晚期肿瘤病人外周血T淋巴细胞表型分析[J].华西医学,2004,19(2)：185-186.
[141]Mori A, Sagara F, Shimizu S, et al Changes in peripheral lymphocyte subsets in the type 1 diabetic dogs treated with insulin injections[J]. J Vet Med Sci. 2008;70(2):185-187.
[142]Yang Z, Zhou Z, Huang G, et,al. The CD4(+) regulatory T-cells is decreased in adults with latent autoimmune diabetes[J]. Diabetes Res Clin Pract.2007; 76 (1):126-131.
[143]赵宏艳.灵芝多糖对H22荷瘤小鼠肠道黏膜免疫功能的影响[D].北京：中国中医科学院中医基础理论研究所,2008.
[144]Zhang X, Young HA. PPAR and immune system-what do we know? [J]. Int Immunopharmacol,2002,2:1029-1044.
[145]Clark RB. The role of PPARs in inflammation and immunity [J]. J Leukoc Biol,2002,71:388-400.
[146]Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity [J]. Nat Rev Imunol,2002,2:748-759.
[1]李睿明,沈洪,张蓓等.Cajal间质细胞_胃肠道动力调节药作用靶点[J]。现代中西医结合杂志,2008,17(20)：3229-3232。
[2]王伟,王景杰,黄裕新。胃肠道Cajal间质细胞的研究现状。中国中西医结合消化杂志2007,15(6)415-416
[3]陈慧群,黄裕新,2E景杰。消化道Cajal间质细胞及其受体的研究进展胃肠病学和肝病学杂志。2008,17(4)332.334
[4]Sanders KW,Koh SD,Ward SM.Interstitial cells of cajal as pacemakers in the gastrointestinal tract.Annu Reu Physiol 2006;68:307-343.
[5]Yin J, Chen JD. Roles of interstitial cells of Cajal in regulating gastrointestinalmotility:in vitro versus in vivo studies [J]. J Cell Mol Med,2008,12 (4):1118-1129.
[6]Lecoin L, Gabella G,Le Douarin N. Origin of the c-kit positive interstitial cells in the avian bowel. Development,1996; 122:725
[7]Ward SM,Sanders KM, Hirst GD.Role of interstitial cells of Cajal in neural control of gastrointestinal smooth muscles.Neurogastroenterol Motil,2004,16(1:) 112-117.
[8]刘诗.胃肠道Cajal间质细胞.临床消化病杂志,2009,21(2)：105.106
[9]Ordwang T, Hayashi Y, Gibbons SJ. Cellular pathogenesis of diabetic gastroenteropathy. Minerva Gastroenterol Dietol.2009 Sep;55(3):315-43.
[10]Nakagawa T,Misawa H,Nakajima Y,Takaki M.Absence of peristalsis in the ileum of W/W(V) mutant mice that are selectively deficient in myenteric interstitial cells of Cajal. J Smooth Muscle Res 2005;41:141-151.
[11]Park SJ,Mckay CM,Zhu Y,Huizina JD.Volume activated chloride currents in interstitial cells of cajal.Am J Physiol Gastrointest liver physiol 2005;289:G791-797.
[12]SHA L, FARRUGIA G, HARMSEN WS, et al. Membrane potential gradient is carbon monoxide-dependent in mouse and human small intestine[J]. Am J Physiol Gastrointesst Liver Physiol,2007,293:G438.
[13]梁国刚，李毅,齐清会.大鼠小肠神经-Cajal间质细胞.平滑肌网络的超微结构研究：大连医科大学学报,2009,31(1)：5-8.
[14]Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin induced diabetes.Wang XY, Huizinga JD, Diamond J, Liu LW.Neurogastroenterol Motil. 2009;21(10):1095-e92.
[15]Daniel EE. Communication between interstial cells of Cajal and gsstrointestinal mnscle. Neurogast roenterol Motil,2004,16:118-122。
[16]Salmhofer H,Neuhuber WL,Ruth P et al. Pivotal role of the interstitial cells of cajal in the nitric oxide signaling pathway of rat small intestine.Cell Tissue Res,2001,305 (3):331-340
[17]Korenaga K,Micci MA,Taglialatela G,et al.Supperession of Inos expression in rat enteric neurons by the receptor for advanced glycation end-products[J].Neurogastroenterol Motil,2006,18(5):392
[18]Epperson A, Hatton WJ, Callaghan B, et al. Molecular component s expressed in cultured and f reshly isolated interstitial cells of Cajal. Am J Physiol,2000,279: C529-539。
[19]Ward SM, Sanders KM. Interstitial cells of Cajal:p rimary targets of enteric motor innervation. Anat Rec,2001; 262 (1):125
[20]柳利明,秦榕,黄华.糖尿病大鼠肠道Cajal间质细胞的实验研究.实用糖尿病杂志2009,5(5)：34-35.
[21]Horvath VJ, Vittal H, Ordog T. Reduced insulin and IGF-I signaling, not hyperglycemia, underlies the diabetes-associated depletion of interstitial cells of Cajal in the murine stomach. Diabetes 2005; 54 (5):1528-1533.
[22]Farrugia G. Interstitial cells of Cajal in health and disease [J].NeurogastroenterolMotil,2008,20 (Suppl 1):54-63
[23]杨琰,余跃.ICC与胃肠道炎症免疫.世界华人消化杂志2009；17(36)：3715-3719
[24]Wu JJ, Rothman TP,Gershon MD.Development of the interstitial cell of Cajal:origin,kit dependence and neuronal and nonneuronal sources of kit ligand.J Neurosci Res,2000,59(3):384-401.
[25]Iwasaki H, Kajimura M, Osawa S, et al. A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus. J Gastroenterol.2006 Nov;41(11):1076-87.
[26]Matsuura T, Masumoto K, Ieiri S, Nakatsuji T,et al. Morphological and physiological changes of interstitial cells of Cajal after small bowel transplantation in rats. Transpl Int 2007; 20:616-624
[27]Lin L, Xu LM, Zhang W, et al.Roles of stem cell factor on the depletion of interstitial cells of Cajal in the colon of diabetic mice. Am J Physiol Gastrointest Liver Physiol.2010;298(2):G241-247.