MFG-E8、NF-κBp65在溃疡性结肠炎患者肠粘膜中的表达及临床意义

发布时间：2018-06-16 11:52

本文选题：溃疡性结肠炎 + 乳汁球微粒表皮生长因子8　；参考：《川北医学院》2016年硕士论文

【摘要】：研究背景:溃疡性结肠炎(ulcerative colitis,UC)是一种非特异性慢性肠道炎症性疾病,该病主要累及直肠和结肠粘膜及粘膜下层。临床主要表现为腹痛、腹泻、解粘液脓血便,大多为慢性病程。UC的的病因及其发病机制尚未完全阐明。目前认为遗传、环境以及机体自身免疫因素在其发病过程中起了重要作用。乳汁球微粒表皮生长因子8(milk fat globule-epidermal growth factor 8,MFG-E8)是一种分泌型多效糖蛋白,可在多种细胞中表达。MFG-E8在肠道炎症调节和肠道粘膜的修复中起到重要作用。有研究表明在疾病的急性状态下MFG-E8的表达是显著减少的,在停止给予葡聚糖硫酸酯钠(dextran sulfate sodium,DSS)喂养后的再生状态下MFG-E8是升高的,最后当疾病被废除后MFG-E8回复正常水平。三硝基苯磺酸(trinitrobenzene sulfonic acid,TNBS)诱导的结肠炎中发现MFG-E8表达的改变与上述相同。也有研究表明用rMFG-E8处理DDS诱导的小鼠结肠炎后观察到其在抑制肠道炎症是有效的。这些研究说明了MFG-E8在肠道炎症调节中起到重要作用。此外,有研究表明在DSS诱导的小鼠结肠炎恢复期,给予小鼠外源的重组MFG-E8能加快肠粘膜损伤的修复,MFG-E8在肠道受损粘膜组织再生修复过程中发挥着重要作用。核转录因子-κB(Nuclear Factor kappa B,NF-κB)是调控基因转录的重要因子。参与了许多免疫炎症反应的基因转录调控,细胞凋亡和肿瘤细胞转移等病理生理过程基因调控,在肠道炎症调节起到重要作用,在免疫细胞通信机制和细胞因子产生的失调的uc发病机制中构成其主要调节。有在哺乳动物中nf-κb家族由5个成员组成:rel、rela(p65)、relb、p50和p52,其中p65具有显著的促炎特性研究表明在uc患者肠道在uc病人的粘膜巨噬细胞和上皮细胞中是活化状态。研究发现nf-κbp65在uc患者肠道粘膜上皮、隐窝上皮和固有层单核细胞中高度表达,且细胞核的表达明显高于细胞质。nf-κb在uc中呈过度激活状态,并导致细胞因子及粘附分子等过度和持续表达,从而放大炎症反应。研究报道mfg-e8可以通过干预αvβ3信号通路减轻肠道粘膜炎症。外源性重组mfg-e8治疗小鼠急性肠炎中的肠粘膜损伤,主要通过限制核因子nf-κb的活性进而使促炎介质如tnf-α、il-1等表达下调。本研究通过检测mfg-e8、nf-κbp65在正常及uc患者肠粘膜的表达情况,并分析其相关关系以及与疾病活动性的关系,探讨其在uc的临床意义。目的:1.研究mfg-e8、nf-κbp65在正常人和不同程度uc患者肠粘膜的表达情况。2.探讨二者之间相互关系及二者与uc疾病活动性关系和发病过程的作用以及其临床意义。方法:收集川北医学院附属医院明确诊断的uc患者39例和正常人对照组19例。用免疫组化检测uc患者和正常对照组肠粘膜组织mfg-e8、nf-κbp65的表达水平。uc患者的临床严重程度按改良的truelove和witts严重程度分度,疾病活动度按改良的mayo评分系统计算疾病活动指数(dai,0-12分),根据baron标准进行内镜分级,按照truelove-richards标准进行病理组织学分级。结果:MFG-E8、NF-κBp65主要存在于人肠粘膜肠上皮细胞、隐窝上皮。在UC组MFG-E8表达明显低于对照组,相反NF-κBp65表达明显高于对照组。两者在UC和正常粘膜中的表达均存在统计学差异(P0.05)。MFG-E8在UC患者活动期和缓解期肠粘膜中的阳性表达率分别为6.3%、26.1%,NF-κBp65在UC患者活动期和缓解期肠粘膜中的阳性表达率分别为93.8%、69.6%,并且随疾病严重程度增加MFG-E8阳性数逐渐减少,轻度组高于重度组(P0.05),随内镜、病理组织学分级增加,MFG-E8阳性数逐渐减少。而NF-κBp65阳性数是随疾病严重程度逐渐增加,重度高于轻度(P0.05),随内镜、病理组织学分级增加,UC患者结肠粘膜中NF-κBp65阳性数增加,III级显著高于I级(P0.05)。在39例UC患者中MFG-E8、NF-κBp65阳性例数和阴性例数Pearson相关分析显MFG-E8与NF-κBp65表达呈负相关(r=-1.000 P0.01)。结论:1.MFG-E8、NF-κBp65表达水平与UC疾病严重程度和病情分期密切相关。2.MFG-E8、NF-κBp65的表达水平与内镜分级和病理学分级密切相关。3.MFG-E8与NF-κBp65呈负相关,提示MFG-E8和NF-κBp65可能参与UC疾病的发生、发展,联合检查其表达水平有助于判断病情的炎症程度。
[Abstract]:Background: ulcerative colitis (UC) is a nonspecific chronic intestinal inflammatory disease. The disease mainly involves the mucosa and submucosa of the rectum and colon. The main clinical manifestations are abdominal pain, diarrhea, and mucus purulent blood stool. Most of the causes and pathogenesis of.UC in the chronic course of disease have not been fully elucidated. Currently, it is believed that the pathogenesis and pathogenesis of the disease have not been fully elucidated. Heredity, environment and autoimmune factors play an important role in its pathogenesis. The milk ball microparticle epidermal growth factor 8 (milk fat globule-epidermal growth factor 8, MFG-E8) is a kind of secretory multi effect glycoprotein, which can express.MFG-E8 in many kinds of cells and play an important role in the regulation of intestinal inflammation and the repair of intestinal mucosa. Use. Studies have shown that the expression of MFG-E8 is significantly reduced in the acute condition of the disease, and MFG-E8 is elevated under the regenerative state of dextran sulfate sodium, DSS, and MFG-E8 reverting to normal levels after the disease is abolished. Three nitrobenzene sulfonic acid (trinitrobenzene sulfonic acid, TNBS) The changes in MFG-E8 expression are the same as those found in colitis guided. Some studies have shown that rMFG-E8 is effective in inhibiting intestinal inflammation after DDS induced colitis in mice. These studies show that MFG-E8 plays an important role in the regulation of intestinal inflammation. In addition, studies have shown the recovery of colitis induced by DSS in mice. The exogenous recombinant MFG-E8 can accelerate the repair of intestinal mucosal damage, and MFG-E8 plays an important role in the regeneration and repair of intestinal mucosa damaged mucosa. Nuclear factor kappa B (Nuclear Factor kappa B, NF- kappa B) is an important factor regulating gene transcription. Gene regulation of pathophysiological processes, such as death and tumor cell metastasis, plays an important role in the regulation of intestinal inflammation and constitutes its main regulation in the mechanism of immune cell communication and the dysregulation of cytokine production in UC. In mammals, the nf- kappa B family consists of 5 members: rel, rela (p65), RelB, P50 and p52, of which p65 has a display. The study showed that the intestinal tract was activated in the mucous macrophages and epithelial cells of UC patients in UC patients. The study found that nf- kappa bp65 was highly expressed in the intestinal mucosa, recess epithelium and lamina propria of UC patients, and the expression of the nucleus was significantly higher than that of the cytoplasm of.Nf- kappa B in UC. It is reported that mfg-e8 can reduce intestinal mucosal inflammation by interfering with alpha v beta 3 signaling pathway. Exogenous recombinant mfg-e8 is used to treat intestinal mucosal injury in acute enteritis in mice, mainly by limiting the activity of nuclear factor nf- kappa B to make proinflammatory mediators such as tnf- In this study, the expression of mfg-e8, nf- kappa bp65 in the intestinal mucosa of normal and UC patients was detected, and the relationship between the expression of nf- kappa bp65 and the activity of the disease was analyzed and the clinical significance of nf- kappa in UC was explored. Objective: 1. to study the expression of nf- kappa bp65 in the intestinal mucosa of normal people and other UC patients. The relationship between the two and the UC disease activity and the pathogenesis of the disease and its clinical significance. Methods: 39 cases of UC patients and 19 normal controls in Affiliated Hospital of Chuanbei Medical College were collected, and 19 cases of UC patients and normal controls were used to detect the expression level of nf- kappa bp65 in.Uc patients. The clinical severity was graded according to the improved truelove and witts severity, and the disease activity was calculated according to the improved Mayo score system (Dai, 0-12). The endoscopic classification was conducted according to the Baron standard, and the histopathological classification was carried out according to the truelove-richards standard. MFG-E8, NF- kappa Bp65 mainly existed in the intestinal mucosa intestinal epithelium. The expression of MFG-E8 in the UC group was significantly lower than that in the control group, but the expression of NF- kappa Bp65 was significantly higher than that in the control group. The expression of the two in the UC and normal mucosa was statistically different (P0.05) the positive expression rate of.MFG-E8 in the active and remission period of UC patients was 6.3%, 26.1%, and NF- kappa Bp65 in the active period of UC patients. The positive expression rate in the intestinal mucosa was 93.8%, 69.6%, and the positive number of MFG-E8 decreased with the severity of the disease, and the mild group was higher than the severe group (P0.05). With the endoscopy, the histopathological classification was increased and the positive number of MFG-E8 decreased gradually. The positive number of NF- kappa Bp65 was gradually increased with the severity of the disease, and the severity was higher than that of the mild (P0.05). With the increase of endoscopic and histopathological grading, the positive number of NF- kappa Bp65 in the colon mucosa of UC patients was increased, and the III level was significantly higher than that of I (P0.05). In 39 patients with UC, MFG-E8, the number of NF- kappa Bp65 positive and negative case number Pearson correlation analysis showed negative correlation between the expression of MFG-E8 and the expression of nuclear kappa. The severity of the disease is closely related to the staging of the disease. The expression level of NF- kappa Bp65 is closely related to the endoscopic classification and pathological classification..3.MFG-E8 is negatively correlated with NF- kappa Bp65. It suggests that MFG-E8 and NF- kappa Bp65 may be involved in the occurrence of UC diseases. The development of the Bp65 and NF- kappa Bp65 may help to determine the degree of inflammation of the disease.
【学位授予单位】：川北医学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R574.62

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