肥大细胞在急性应激性肠黏膜屏障损伤中的作用机制

背景：应激所致肠黏膜屏障损伤的机制以及肥大细胞（MC）在其中的作用尚未明确。目的：探讨肠黏膜MC（IMMC）在急性应激性肠黏膜屏障损伤中的作用机制。方法：Sprague—Dawley（SD）大鼠随机分为正常对照组（N组）、应激组（S组）,S组给予急性冷束缚应激建立模型,按照应激结束后处死时间进一步分为S2h、S4h、SSh、S16h、S24h组。取回肠末端观察组织病理学改变,以Chiu’S评分评估肠黏膜组织损伤程度,以甲苯胺蓝染色计数IMMC,以透射电镜观察肠黏膜组织和IMMC超微结构,以ELISA法检测肠黏膜组织组胺含量。结果：S组的Chiu’S评分均显著高于N组（P〈0．05）,呈先升后降的趋势,以S8h组最高。S2h、S4h组的IMMC计数显著高于N组（P〈0．05）,S8h、S16h、S24h组IMMC计数与N组相比差异无统计学意义（P〉0．05）。IMMC计数与Chiu’S评分无相关性（P〉0．05）。S组肠黏膜超微结构破坏明显,IMMC胞质大量脱颗粒。S2h、S4h、S8h组的肠黏膜组织组胺含量较N组显著降低（P〈0．05）,呈逐渐下降趋势。S16h、S24h组组胺含量与N组相比差异无统计学意义（P〉0．05）。肠黏膜组织组胺含量与Chiu’S评分呈负相关（P=0．03）。结论：急性应激状态下,IMMC脱颗粒释放炎性介质是导致肠黏膜屏障损伤的重要机制。     

肥大细胞在重症急性胰腺炎肠黏膜屏障功能损伤中的作用

肥大细胞(MC)是神经-免疫-内分泌系统中的关键细胞,参与调节机体多种病理生理过程。重症急性胰腺炎(SAP)发生时,大量MC被激活,释放多种细胞因子以及炎性介质,与SAP并发肠黏膜屏障功能损伤密切相关。本文就MC在SAP肠黏膜屏障功能损伤中的作用作一综述。     

肠碱性磷酸酶在肠黏膜屏障中的作用

肠碱性磷酸酶(intestinal alkaline phosphatase, IAP)是一种碱性磷酸酶,在维持肠黏膜屏障的稳定和肠道功能具有重要作用,其中包括调节十二指肠pH、反映肠道的发育情况及小肠上皮细胞的吸收能力,降低肠道脂多糖毒力、预防和减少肠道炎症、调节肠道菌群分布、抑制细菌位移、改善肠道钙吸收等功能.本文对近年来IAP在肠黏膜屏障中的作用研究进展做一综述.     

应激对肠粘膜屏障功能影响的研究进展

应激状态下，各种神经、免疫、内分泌机制作用于肠上皮，导致肠粘膜屏障功能的改变，大分子抗原过多地进入固有层和粘膜下层，引发不适宜的免疫反应，进一步加剧了肠道炎症，成为慢性炎症性肠病发生和发展的重要因素。     

肥大细胞在应激所致大鼠直肠高敏感性中的作用

目的　内脏高敏感性是肠易激综合征 (IBS)最重要的特征之一 ,精神因素可能与IBS发生有关。本研究旨在探讨急性精神应激对大鼠直肠敏感性的效应以及肥大细胞的可能作用。方法　通过对大鼠施加 2h的轻度束缚建立应激模型 ,以腹壁肌电活动评估它对直肠内气囊扩张的反应性 ,并取结肠标本进行肥大细胞计数 ,通过P物质刺激结肠体外释放组胺 ,研究肥大细胞的活化情况。此外 ,还进行了急性应激对躯体感觉和结肠转运效应的研究。结果　与假应激组相比 ,在 0 .5、0 .8及 1.2ml扩张容量下 ,轻度束缚应激使大鼠对直肠扩张的敏感性显著增强 (P <0 .0 1)。与假应激组相比 ,应激组大鼠P物质体外诱导的组胺释放明显增加 [分别为 (6 .4 5± 2 .6 9)和 (10 .71± 3.91)nmol/g组织 ,P <0 .0 5 ],而结肠肥大细胞计数无明显差异 [分别为 (2 .6 8± 0 .90 )和 (2 .79± 0 .75 ) /高倍视野 ,P >0 .0 5 ]。急性应激也加速结肠转运 ,并引起躯体痛觉缺失。结论　应激可显著增强大鼠直肠敏感性 ,肥大细胞活化可能在外周参与了这一致敏过程     

早期细胞凋亡在创伤性脑损伤肠黏膜屏障应激性变化中的作用

目的 探讨早期细胞凋亡在创伤性脑损伤(TBI)大鼠肠黏膜屏障应激性变化中的作用.方法 选用雄性Wistar大鼠64只,随机分为TBI组(32只)和假手术对照组(32只).2组大鼠分别按术后6、12、24和48 h时相点分为4个亚组(每个亚组8只).在光镜和透射电镜下观察肠黏膜组织形态学变化,同时用Annexin Ⅴ-PI双染法经流式细胞仪检测各组早期细胞凋亡率.结果 光镜下TBI组可见肠黏膜上皮细胞受损,电镜下可见其细胞间紧密连接较假手术对照组增宽,并可见典型的凋亡细胞.TBI组的创伤后早期即可见肠黏膜细胞的凋亡率较假手术对照组明显升高[6 h:(13.5±3.7)%比(6.1±1.7)%,P＜0.05;12 h:(66.1±6.0)%比(5.2±1.1)%,P＜0.05;24 h:(39.8±4.8)%比(8.4±2.6)%,P＜0.05;48 h:(7.5±1.3)%比(6.6±0.5)%].结论 大鼠TBI后的早期,肠黏膜屏障功能即可受损,肠黏膜上皮细胞早期凋亡率的增加可能在这一病理生理过程中起着重要作用.     

肥大细胞在肠易激综合征中的研究进展

肥大细胞的细胞生物学快速深入的研究证实,肥大细胞脱颗粒可由一系列物理、化学刺激经由不同途径诱发,而肥大细胞的功能不仅限于变态反应和前炎症反应,且与正常的生理、病理过程密切相关。近年来发现,肥大细胞在肠易激综合征的发病中发挥关键作用：包括炎症和粘膜的免疫生理、产生大量多功能生物化学介质、与神经免疫联系和脑－肠轴的关系及在肠道高敏感性中都起到重要作用。为此,有必要对肥大细胞的生物学作用进行更深入的研究及重新认识。     

血管活性肠肽在调节肠黏膜屏障功能中的作用

血管活性肠肽(VIP)是由28个氨基酸残基构成的脑肠肽.它既是一种胃肠激素,同时又是非肾上腺素能非胆碱能(NANC)神经递质,并参与调节肠黏膜的机械、化学、免疫屏障及肠道动力,能有效保护肠黏膜屏障功能.     

肠道菌群失衡在急性胰腺炎肠黏膜屏障损伤中的作用

急性胰腺炎(acute pancreatitis,AP)是临床常见的急腹症,其发病率呈逐年增高趋势.AP病情进展迅速,15％～20％的患者发展为重症急性胰腺炎(severe acute pancreatitis,SAP),病死率高达20％～30％.SAP常可导致肠道功能障碍,包括肠黏膜屏障损伤和肠道动力障碍,引起肠道细...     

Cellular and molecular basis of intestinal barrier dysfunction in the irritable bowel syndrome

The etiopathogenesis of the irritable bowel syndrome (IBS), one of the most prevalent gastrointestinal disorders, is not well known. The most accepted hypothesis is that IBS is the result of the disturbance of the 'brain-gut axis.' Although the pathophysiological mechanisms of intestinal dysfunction are complex and not completely understood, stress, infections, gut flora, and altered immune response are thought to play a role in IBS development. The intestinal barrier, composed of a single-cell layer, forms a physical barrier that separates the intestinal lumen from the internal milieu. The loss of integrity of this barrier is related with mucosal immune activation and intestinal dysfunction in IBS. The number of mast cells and T lymphocytes is increased in the intestinal mucosa of certain IBS patients, and the mediators released by these cells could compromise the epithelial barrier function and alter nerve signaling within the enteric nervous system. The association of clinical symptoms to structural and functional abnormalities of the mucosal barrier in IBS patients highlights the importance of understanding the physiological role of the gut barrier in the pathogenesis of this disorder. This review summarizes the clinical and experimental evidences indicating the cellular and molecular mechanisms of IBS symptomatology, and its relevance for future translational research.     

肠屏障功能障碍的研究现状与展望

肠屏障功能障碍正日益受到关注,多种疾病均可引起肠屏障功能障碍,促使细菌移位,加重原发病,形成恶性循环。此文就肠屏障功能障碍的发病机制、检测方法和治疗措施进展作一综述。     

梗阻性黄疸对肠黏膜屏障的影响

肠黏膜屏障包括机械屏障、免疫屏障、生物屏障和化学屏障,四者共同维持肠黏膜的正常防御功能。梗阻性黄疸患者引起肠黏膜屏障损伤,导致细菌移位及内毒素血症,后者又加重屏障功能障碍。本文主要就梗阻性黄疸对肠黏膜屏障损伤的机制作一综述。     

Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots： Stress, intestinal hyperpermeability and inflammation

Mast cells (MC) are pivotal elements in several physiological and immunological functions of the gastro- intestinal (GI) tract. MC translate the stress signals that has been transmitted through brain gut axis into release of proinflammatory mediators that can cause stimulation of nerve endings that could affect afferent nerve terminals and change their perception, affect intestinal motility, increase intestinal hyperpermeability and, in susceptible individuals, modulate the inflammation. Thus, it is not surprising that MC are an important element in the pathogenesis of inflammatory bowel disease and non inflammatory GI disorders such as IBS and mast cell enterocolitis.     

肠道屏障功能障碍的干预研究进展

目前已知,肠道屏障功能在多种严重疾病如烧伤、重症胰腺炎、肿瘤、严重肝病等的发生、发展过程中发挥重要的“枢纽”作用.随着人们对肠黏膜功能障碍在各种严重疾病发生、发展中所起的重要病理生理作用的不断认识,针对患者肠黏膜屏障功能变化进行干预的基础和临床研究日益受到广大学者的关注.本文就近年来国内外对这一领域的研究进展作一综述.     

Acute pancreatitis is characterized by generalized intestinal barrier dysfunction in early stage

Background and aimsThe role of intestinal-barrier in acute pancreatitis(AP) is poorly understood. We aimed to assess structural and functional changes in the intestinal-barrier in patients with early AP (time from onset<2 weeks) and the effect of enteral nutrition on them.MethodsIn this prospective observational study, patients with early AP not on enteral nutrition were compared with controls for baseline intestinal-permeability(lactulose: mannitol ratio(L:M)), endotoxinemia(serum IgM/IgG anti-endotoxin antibodies), bacterial-translocation(serum bacterial 16S rRNA) and duodenal epithelial tight-junction structure by immunohistochemistry(IHC) for tight-junction proteins(claudin-2,-3,-4, zonula occludens-1(ZO1), junctional adhesion molecule(JAM) and occludin) and electron microscopy. These parameters were reassessed after 2 weeks enteral feeding in a AP patients subset.Results96 patients with AP(age: 38.0 ± 14.5 years; etiology: biliary[46.8%]/alcohol[39.6%]; severe:53.2%, mortality:11.4%) and 40 matched controls were recruited. Patients with AP had higher baseline intestinal permeability(median L:M 0.176(IQR 0.073–0.376) vs 0.049(0.024–0.075) in controls; p < 0.001) and more frequent bacteraemia(positive bacterial 16S rRNA in 24/48 AP vs 0/21 controls; p < 0.001) with trend towards higher serum endotoxinemia(median IgG anti-endotoxin 78(51.2–171.6) GMU/ml vs 51.2(26.16–79.2) in controls; p = 0.061). Claudin-2, claudin-3, ZO1 were downregulated in both duodenal crypts and villi while claudin-4 and JAM were downregulated in duodenal villi and crypts respectively. 22 AP patients reassessed after initiation of enteral nutrition showed trend towards improving intestinal permeability, serum endotoxinemia and bacteraemia, with significant improvement in claudin-2,-3 in duodenal villi.ConclusionPatients with AP have significant disturbances in intestinal barrier structure and function in first 2 weeks from onset that persist despite institution of enteral nutrition.     

冷-束缚应激诱导肠功能紊乱大鼠肠黏膜屏障变化的实验研究

目的 建立冷-束缚应激(CRS)诱导肠功能紊乱大鼠模型,探讨肠黏膜屏障变化在肠功能紊乱发病机制中的可能作用.方法 选取2个月龄Wistar大鼠40只,随机分成模型组和正常对照组.模型组采用寒冷加束缚为应激源实施干预,对照组不予任何干预.实验期间观察两组大鼠粪便性状,应用Bristol分型进行评分,通过直结肠扩张(CRD)实验测定内脏敏感性,取大鼠远端结肠及回肠黏膜行病理组织学检查.采用气相色谱法(GC)测定两组大鼠5 h尿液中乳果糖(L)与甘露醇(M)排泄率(L/M)比值,反映肠黏膜屏障的变化情况.结果 模型组粪便多为软的团块状或泥浆样,对照组多为柔软的香肠状或团块状,两组大鼠Bristol分型评分比较有显著性差异(P＜0.05);模型组初始感觉阈值、疼痛感觉阈值、最大耐受阈值分别较对照组显著降低(P＜0.05);两组肠黏膜病理检查均未见明显异常;模型组大鼠5 h尿液中L与M排泄率比值(L/M)较对照组显著增大(P＜0.05).结论 肠功能紊乱大鼠肠黏膜通透性增大,肠黏膜屏障受损可能与肠功能紊乱发病机制有关.     

Effects of intestinal mucosal blood flow and motility on intestinal mucosa

AIM:To investigate the role of intestinal mucosal blood flow(IMBF) and motility in the damage of intestinal mucosal barrier in rats with traumatic brain injury.METHODS:Sixty-four healthy male Wistar rats were divided randomly into two groups:traumatic brain injury(TBI) group(n = 32),rats with traumatic brain injury;and control group(n = 32),rats with sham-operation.Each group was divided into four subgroups(n = 8) as 6,12,24 and 48 h after operation.Intestinal motility was measured by the propulsion ratio o...     

重症急性胰腺炎肠屏障功能障碍研究

重症急性胰腺炎患者常伴有肠屏障功能障碍,正常肠道屏障由机械屏障、化学屏障、免疫屏障与微生物屏障4部分构成.肠屏障功能障碍通常指上述4种屏障功能出现不同程度的破坏,本文就重症急性胰腺炎肠道屏障功能障碍时上述4种屏障的病理生理改变作一概述.     

Dimethyl sulfoxide inhibits zymosan-induced intestinal inflammation and barrier dysfunction

AIM: To investigate whether dimethyl sulfoxide(DMSO) inhibits gut inflammation and barrier dysfunction following zymosan-induced systemic inflammatoryresponse syndrome and multiple organ dysfunction syndrome.METHODS: Sprague-Dawley rats were randomly divided into four groups: sham with administration of normal saline(SS group); sham with administration of DMSO(SD group); zymosan with administration of normal saline(ZS group); and zymosan with administration of DMSO(ZD group). Each group contained three subgroups according to 4 h,8 h,and 24 h after surgery. At 4 h,8 h,and 24 h after intraperitoneal injection of zymosan(750 mg/kg),the levels of intestinal inflammatory cytokines [tumor necrosis factor-alpha(TNF-α) and interleukin(IL)-10] and oxides(myeloperoxidase,malonaldehyde,and superoxide dismutase) were examined. The levels of diamine oxidase(DAO) in plasma and intestinal mucosal blood flow(IMBF) were determined. Intestinal injury was also evaluated using an intestinal histological score and apoptosis of intestinal epithelial cells was determined by deoxynucleotidyl transferase d UTP nick end labeling(TUNEL) assay. The intestinal epithelial tight junction protein,ZO-1,was observed by immunofluorescence.RESULTS: DMSO decreased TNF-α and increased IL-10 levels in the intestine compared with the ZS group at the corresponding time points. The activity of intestinal myeloperoxidase in the ZS group was higher than that in the ZD group 24 h after zymosan administration(P 0.05). DMSO decreased the content of malondialdehyde(MDA) and increased the activity of superoxide dehydrogenase(SOD) 24 h after zymosan administration. The IMBF was lowest at 24 h and was 49.34% and 58.26% in the ZS group and ZD group,respectively(P 0.05). DMSO alleviated injury in intestinal villi,and the gut injury score was significantly lower than the ZS group(3.6 ± 0.2 vs 4.2 ± 0.3,P 0.05). DMSO decreased the level of DAO in plasma compared with the ZS group(65.1 ± 4.7 U/L vs 81.1 ± 5.0 U/L,P 0.05). DMSO significantly preserved ZO-1 protein expression and localization 24 h after zymosan administration. The TUNEL analysis indicated that the number of apoptotic intestinal cells in the ZS group was much higher than the ZD group(P 0.05).CONCLUSION: DMSO inhibited intestinal cytokines and protected against zymosan-induced gut barrier dysfunction.