溃疡性结肠炎大鼠结肠粘膜肥大细胞类胰蛋白酶表达变化及其抑制剂的作用
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摘要
背景:葡聚糖硫酸钠(DSS)诱导的溃疡性结肠炎大鼠的组织学特点与人类溃疡结肠炎(Ulcerative Colitis, UC)类似。实验性溃疡性结肠炎和人溃疡性结肠炎肠粘膜内肥大细胞(Mast Cell,MC)的活性和数量显著增多,其中类胰蛋白酶(tryptase)是其活化和释放颗粒的特异性标志。
目的:测定DSS诱导的溃疡性结肠炎大鼠结肠粘膜中MC数量和tryptase表达变化、及IL-6、IL-8的含量变化,并观察类胰蛋白酶抑制剂(tryptase inhibitor, TPI)对他们的影响。
方法:40只雄性Wistar大鼠按1:3随机分为A组(空白对照组,10只)和S组(研究组,30只),A组自由饮用无菌蒸馏水7天,后续无菌蒸馏水连续灌肠7天,1次/天;S组自由饮用3%DSS溶液7天,然后再随机分为B组(模型对照组,无菌蒸馏水灌肠)、C组(NM组,10-9mol/L灌肠)、D组(5-ASA组,100mg/kg灌肠),每组10只。实验结束,对疾病活动指数(DAI)、组织学损伤指数(HI)、远端结肠组织肥大细胞(甲苯胺蓝改良染色法)和类胰蛋白酶的表达(免疫组化)进行评价,取血清测IL-6和IL-8(ELISA法)的浓度。
结果:⑴治疗第1天,A组(空白对照组)DAI评分与B组(模型对照组)、C组(NM组)、D组(5-ASA组)相比,有显著统计学意义(P<0.01);实验结束后,B组DAI、HI评分(6.50±1.43、5.10±0.74)与C组(3.40±1.26、2.30±0.67)、D组(2.60±0.97、2.00±0.82)相比明显增高(P<0.01);⑵远端结肠粘膜肥大细胞数及类胰蛋白酶表达:B组(15.30±1.89,102.87±3.39)与C组(5.40±1.43,140.27±1.65)、D组(4.40±1.51,142.95±2.62)相比,表达显著增高(P<0.01);⑶血清IL-6、IL-8浓度比较:B组(72.81±12.64,234.29±18.56)比C组(41.39±4.82,140.68±9.38)、D组(37.21±8.29,138.81±15.83)浓度显著增高(P<0.01)。以上各指标C组(NM组)与D组(5-ASA组)比较无统计学差异(P>0.05)。
结论:小剂量类胰蛋白酶抑制剂可以下调结肠粘膜肥大细胞数量、抑制肥大细胞类胰蛋白酶表达,对DSS诱导溃疡性结肠炎大鼠有治疗作用。
Background:
Dextran sulfate sodium(DSS)-induced colitis mimics human Ulcerative Colitis (UC) in histological features. The activities and number of mast cell (MC) in colonic mucosa are significantly increased both in experimental colitis and UC patients. Tryptase is considered as a unique maker of MC’s activation.
Aims:
To investigate the number of MC and the expression of MC tryptase in the colonic mucosa in rat with DSS-induced ulcerative colitis, and the effects of the tryptase inhibitor (TPI) on the colitis.
Methods:
Forty male Wistar rats were randomly divided into two groups, group A (control group,10 rats) and group S (experimental group, 30 rats). Rats in group A were free to drink distilled water for 7 days and then received an enema once a day for a continual 7 days; Rats in group S were given 3% DSS solution for 7 days and then randomly subdivided into 3 groups with an enema of three different solution once a day for a continual 7 days: Group B (distilled water), Group C ( NM, 10-9mol/L),and Group D(5-ASA, 100mg/kg). At the end of the procedure, the DAI and HI were caculated. The MC number and the expression of MC tryptase in the distal colonic mucosa were assessed by toluidine blue staining and immunohistochemistry respectively. The concentrations of IL-6 and IL-8 were assessed by ELISA.
Result:
⑴On the first day after treatment, the DAI in groupB (distilled water) was significantly higher than that in group C ( NM) and D (5-ASA) respectively(P<0.01). While on the 7th day , the scores of DAI and HI in group B (6.50±1.43,5.10±0.74) were significant different from those in group C(3.40±1.26、2.30±0.67)and in group D(2.60±0.97、2.00±0.82)(P<0.01, respectively).⑵The number of mucosa mast cell and average gray scale (AGS) of MC tryptase in group B(15.30±1.89,102.87±3.39)showed significant difference when compared with those in group C(5.40±1.43,140.27±1.65)and in group D(4.40±1.51,142.95±2.62)( P<0.01 , respectively).⑶The levels of serum IL-6 and IL-8 in group B(72.81±12.64,234.29±18.56)were significant higher than those in group C(41.39±4.82,140.68±9.38)or in group D(37.21±8.29,138.81±15.83)(P<0.01, respectively). There was no significant difference among these indexes in group C and group D (P>0.05).
Conclusions:
A small dosage of tryptase inhibitor may downregulate the mast cell number and the tryptase expression in the colonic mucosa in rats with DSS-induced ulcerative colitis, which may has a beneficial effect on this disease.
目的:测定DSS诱导的溃疡性结肠炎大鼠结肠粘膜中MC数量和tryptase表达变化、及IL-6、IL-8的含量变化,并观察类胰蛋白酶抑制剂(tryptase inhibitor, TPI)对他们的影响。
方法:40只雄性Wistar大鼠按1:3随机分为A组(空白对照组,10只)和S组(研究组,30只),A组自由饮用无菌蒸馏水7天,后续无菌蒸馏水连续灌肠7天,1次/天;S组自由饮用3%DSS溶液7天,然后再随机分为B组(模型对照组,无菌蒸馏水灌肠)、C组(NM组,10-9mol/L灌肠)、D组(5-ASA组,100mg/kg灌肠),每组10只。实验结束,对疾病活动指数(DAI)、组织学损伤指数(HI)、远端结肠组织肥大细胞(甲苯胺蓝改良染色法)和类胰蛋白酶的表达(免疫组化)进行评价,取血清测IL-6和IL-8(ELISA法)的浓度。
结果:⑴治疗第1天,A组(空白对照组)DAI评分与B组(模型对照组)、C组(NM组)、D组(5-ASA组)相比,有显著统计学意义(P<0.01);实验结束后,B组DAI、HI评分(6.50±1.43、5.10±0.74)与C组(3.40±1.26、2.30±0.67)、D组(2.60±0.97、2.00±0.82)相比明显增高(P<0.01);⑵远端结肠粘膜肥大细胞数及类胰蛋白酶表达:B组(15.30±1.89,102.87±3.39)与C组(5.40±1.43,140.27±1.65)、D组(4.40±1.51,142.95±2.62)相比,表达显著增高(P<0.01);⑶血清IL-6、IL-8浓度比较:B组(72.81±12.64,234.29±18.56)比C组(41.39±4.82,140.68±9.38)、D组(37.21±8.29,138.81±15.83)浓度显著增高(P<0.01)。以上各指标C组(NM组)与D组(5-ASA组)比较无统计学差异(P>0.05)。
结论:小剂量类胰蛋白酶抑制剂可以下调结肠粘膜肥大细胞数量、抑制肥大细胞类胰蛋白酶表达,对DSS诱导溃疡性结肠炎大鼠有治疗作用。
Background:
Dextran sulfate sodium(DSS)-induced colitis mimics human Ulcerative Colitis (UC) in histological features. The activities and number of mast cell (MC) in colonic mucosa are significantly increased both in experimental colitis and UC patients. Tryptase is considered as a unique maker of MC’s activation.
Aims:
To investigate the number of MC and the expression of MC tryptase in the colonic mucosa in rat with DSS-induced ulcerative colitis, and the effects of the tryptase inhibitor (TPI) on the colitis.
Methods:
Forty male Wistar rats were randomly divided into two groups, group A (control group,10 rats) and group S (experimental group, 30 rats). Rats in group A were free to drink distilled water for 7 days and then received an enema once a day for a continual 7 days; Rats in group S were given 3% DSS solution for 7 days and then randomly subdivided into 3 groups with an enema of three different solution once a day for a continual 7 days: Group B (distilled water), Group C ( NM, 10-9mol/L),and Group D(5-ASA, 100mg/kg). At the end of the procedure, the DAI and HI were caculated. The MC number and the expression of MC tryptase in the distal colonic mucosa were assessed by toluidine blue staining and immunohistochemistry respectively. The concentrations of IL-6 and IL-8 were assessed by ELISA.
Result:
⑴On the first day after treatment, the DAI in groupB (distilled water) was significantly higher than that in group C ( NM) and D (5-ASA) respectively(P<0.01). While on the 7th day , the scores of DAI and HI in group B (6.50±1.43,5.10±0.74) were significant different from those in group C(3.40±1.26、2.30±0.67)and in group D(2.60±0.97、2.00±0.82)(P<0.01, respectively).⑵The number of mucosa mast cell and average gray scale (AGS) of MC tryptase in group B(15.30±1.89,102.87±3.39)showed significant difference when compared with those in group C(5.40±1.43,140.27±1.65)and in group D(4.40±1.51,142.95±2.62)( P<0.01 , respectively).⑶The levels of serum IL-6 and IL-8 in group B(72.81±12.64,234.29±18.56)were significant higher than those in group C(41.39±4.82,140.68±9.38)or in group D(37.21±8.29,138.81±15.83)(P<0.01, respectively). There was no significant difference among these indexes in group C and group D (P>0.05).
Conclusions:
A small dosage of tryptase inhibitor may downregulate the mast cell number and the tryptase expression in the colonic mucosa in rats with DSS-induced ulcerative colitis, which may has a beneficial effect on this disease.
引文
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[1] Longstreth GF, Wilson A, Knight K, Wong J, et al. Irritable bowel syndrome, health care use, and costs (a U.S. managed care perspective). Am J Gastroenterol 2003;98(3):600–7. PMID: 12650794 [PubMed - indexed for MEDLINE]
[2] RitehieJ.Pain from distention of the Pelvic colon by inflating a balloon in the irritable colon syndrome.Gut,1973,14(2):125-132. PMID: 4696535 [PubMed– indexed for MEDLINE]
[3] Chang, L, Mayer EA, Johnson T, et al. Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia. Pain ,2000,84(2-3): 297-307. PMID: 10666535 [PubMed - indexed for MEDLINE]
[4] Fukudo S, Nomura T, Muranaka M, Taguchi F. Brain-gut response to stress and cholinergic stimulation in irritable bowel syndrome. A preliminary study. J Clin Gastroenterol, 1993,17(2):133–141. PMID: 8031340 [PubMed - indexed forMEDLINE]
[5]Fukudo S. Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation. J Gastroenterol ,2007, 42[Suppl XVII]:48–51. PMID 17238026 [PubMed - indexed for MEDLINE]
[6] Accarino AM, Azpiroz F, Malagelada JR. Attention and distraction: effects on gut perception. Gastroenterology,1997,113(2): 415-422. PMID: 9247458 [PubMed– indexed for MEDLINE]
[7] Bonaz B,Baciu M ,Pap illon E,et al.Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study .A m J Gastroenterol,2002,97(3): 654-661. PMID: 12749964 [PubMed - indexed for MEDLINE]
[8] Bernstein CN , F rankenstein UN , Raw stho rne P, et al. Cortical mapping of visceral pain in patients with GI disorders using functional magnetic resonance imaging . A m J Gastroenterol, 2002,97(2):319-327. PMID: 11866268 [PubMed - indexed for MEDLINE]
[9] Barbara G, De Giorgio R , Stanghellini V , et al . A role for inflammation in irritable bowel syndrome? Gut ,2002 ,51(Suppl 1):i41-44. PMID: 12077063 [PubMed - indexed for MEDLINE]
[10] Baigent SM, Lowry PJ. mRNA expression profiles for corticotrophin-releasing factor (CRF), urocortin, CRF receptors and CRFbinding protein in peripheral rat tissues . J Mol Endocrinol,2000,25(1):43–52. PMID: 10915217 [PubMed– indexed for MEDLINE]
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[16] David G.Serotonin and sensory signalling from the gastrointestinal lumen. J Physiol,2006,575 (Pt 1):1-2. PMID: 16740608 [PubMed - indexed for MEDLINE]
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[18] Tu Y, Di Leo V, Salim S, Soderholm JD, Marshall J, Irvine J. CD23/Fc epsilon RII (low affinity IgE receptor) is expressed on human epithelial cells and upregulated by IL-4 and LPS. Gastroenterology , 2001,120:A188.
[19] Barbara G,Stanghellini V,De Giorgio R,et al.Functional gastrointestinal disorders and mast cells: implications for therapy .Neurogastroenterol Motil,2006,18 (1): 6–17. PMID: 16371078 [PubMed - indexed for MEDLINE]
[20] Ahmed Kayssi,Silvia Amadesi,Francisco Bautista, et al.Bunnettand Stephen Vanner. Mechanisms of protease- activated receptor 2-evoked hyperexcitability of nociceptive neurons innervating the mouse colon .J Physiol,2007,580(3): 977-991. PMID: 17289784 [PubMed - indexed for MEDLINE]
[21] Mayer EA, Naliboff BD, Chang L, et al. Stress and the Gastrointestinal Tract: V. Stress and irritable bowel syndrome . Am J Physiol Gastrointest Liver Physiol, 2001,280(4): G519–G524. PMID: 11254476 [PubMed - indexed for MEDLINE]
[22] Andre G,Buret.How Stress Induces Intestinal Hypersensitivity .American Journal of Pathology,2006,168 (1): 3-5. PMID: 16400003 [PubMed - indexed for MEDLINE]
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