三叶因子家族对支气管哮喘作用的研究进展

三叶因子家族（trefoilfactorfamily,TFF）是一类具有特殊三叶结构域的蛋白质家族。迄今为止在哺乳动物中发现三种TFF：TFFl、TFF2及TFF3,其表达具有相对的组织特异性和高度的细胞特异性。在呼吸道中TFF主要表达于杯状细胞、纤毛上皮细胞和黏膜下腺体,人体呼吸道以TFF3表达最丰富。三叶因子在呼吸道的防御、损伤后修复和细胞分化过程中发挥重要作用,它可能成为治疗支气管哮喘气道重塑的新靶点。     

pS2/TFF1蛋白在胃癌及其癌前病变组织中表达的研究

背景:pS2/TFF1蛋白属于三叶因子家族,是一类具有胃肠道黏膜保护和修复作用的生长因子类小分子多肽物质,研究pS2/TFF1蛋白可能为胃癌的防治开辟新的思路。目的:观察pS2/TFF1蛋白在胃癌及其癌前病变组织中的表达,探讨其与胃癌发生的关系。方法:采用免疫组化法检测30例慢性非萎缩性胃炎、35例慢性萎缩性胃炎、50例慢性萎缩性胃炎伴肠化生、37例异型增生、46例胃癌和30名健康志愿者胃黏膜组织中pS2/TFF1蛋白的表达。结果:正常胃黏膜组织-慢性非萎缩性胃炎-慢性萎缩性胃炎-慢性萎缩性胃炎伴肠化生-异型增生-胃癌组织中,pS2/TFF1蛋白阳性表达呈逐渐下降的趋势(分别为100%、93.3%、82.9%、78.0%、62.2%、56.5%),差异有统计学意义(P0.05)。与正常对照组、慢性非萎缩性胃炎组和慢性萎缩性胃炎组相比,慢性萎缩性胃炎伴肠化生组、异型增生组和胃癌组pS2/TFF1蛋白阳性表达均显著降低(P0.05),而后三组之间的差异无统计学意义(P0.05)。结论:pS2/TFF1蛋白表达降低是胃癌发生过程中的早期事件,有望成为诊断胃癌的标记物。     

三叶因子家族在胃癌发生中的作用机制

三叶因子家族（trefoil factor family，TFF）是一群主要由胃肠道黏液细胞分泌的小分子多肽，在黏膜修复和重建以及肿瘤的发生、发展过程中发挥重要作用，对其结构功能、遗传学改变等分子机制的研究一直是近20余年的研究热点。TFF在肠型胃癌中表达降低甚至缺失，在弥漫型胃癌中高表达。其在胃癌发生、发展过程中的机制涉及肿瘤抑制、促进肿瘤侵袭浸润以及促癌与抑癌的双重机制。通过对TFF在胃癌发生、发展中机制的深入研究，有望在胃癌防治方面开辟新途径。     

三叶因子家族肽在呼吸道中的作用研究

三叶因子家族 (trefoilfactorfamily ,TFF)肽是一类具有特殊结构 P结构域的蛋白质家族 ,其在哺育动物的表达具有相对的组织特异性和高度的细胞特异性。在呼吸道中主要表达于杯状细胞、纤毛上皮细胞和黏膜下腺体 ,以TFF3表达最为丰富 ,且其表达与气道黏蛋白相匹配。TFF家族与气道黏蛋白一起保护气道上皮、影响上皮细胞的迁移及调节气道炎症反应 ,可能在呼吸道的防御和修复过程中具有重要的作用。     

氨溴索对大鼠慢性阻塞性肺疾病气道损伤的防治作用

三叶因子家族（trefoil factor family，TFF）能有效地保护黏膜并促进损伤后修复。肠三叶因子（intestinal trefoil factor，lit即TFL）为TFF的成员之一，主要在小肠和结肠表达。Wiede等首次发现呼吸道上皮细胞分泌TFF3，林勇等旧。报道，     

三叶因子家族肽在呼吸道中的作用研究

三叶因子家族(trefoil factor family，TFF)肽是一类具有特殊结构-P结构域的蛋白质家族，其在哺育动物的表达具有相对的组织特异性和高度的细胞特异性。在呼吸道中主要表达于杯状细胞、纤毛上皮细胞和黏膜下腺体，以TFF3表达最为丰富，且其表达与气道黏蛋白相匹配。TFF家族与气道黏蛋白一起保护气道上皮、影响上皮细胞的迁移及调节气道炎症反应，可能在呼吸道的防御和修复过程中具有重要的作用。     

TFF3与胃癌关系研究进展

三叶因子家族包括乳癌相关肽(TFF1)、解痉多肽(TFF2)和肠三叶因子(TFF3). 三叶因子主要功能是维持胃肠道黏膜的完整性和促进损伤上皮修复, 此外还具有细胞信号转导, 调节细胞凋亡和促进肿瘤侵袭的功能, 从而在炎症和肿瘤过程中都起到了重要作用. 近年来的研究表明, TFF3与胃癌, 尤其是肠型胃癌关系密切.     

胃黏膜癌变过程中表皮生长因子受体、环氧合酶-2和三叶因子1的表达及其意义

胃黏膜癌变过程中存在癌基因激活和抑癌基因失活所致的细胞无限增殖和凋亡抑制，因此联合检测细胞增殖和凋亡相关因子对揭示胃黏膜的变化规律具有重要意义。目的：探讨表皮生长因子受体（EGFR）、环氧合酶（COX）．2和三叶因子（TFF）1在胃黏膜癌变过程中的变化规律及其意义。方法：经病理检查确诊的19例慢性非萎缩性胃炎、19例慢性萎缩性胃炎、18例慢性萎缩性胃炎伴肠化生、16例异型增生和16例胃腺癌纳入研究。以免疫组化方法检测各病变组织中EGFR、COX-2和TFF1的表达，并分析其间的相关性。结果：EGFR在非萎缩性胃炎组织中的表达显著低于其他胃黏膜病变组织（P〈0．01）；从非萎缩性胃炎→萎缩性胃炎→肠化生→异型增生→胃癌，COX-2的表达逐渐增高，而TFF1的表达逐渐减低。EGFR与COX-2的表达呈正相关（P〈0．01），与TFF1的表达呈负相关（P〈0．01）：COX-2与TFF1的表达呈负相关（P〈0．01）。结论：细胞增殖和凋亡相关因子EGFR、COX-2和TFF1表达异常在胃黏膜癌变过程中发挥重要作用。     

三叶因子1表达与胃黏膜损伤及胃癌的关系

目的　测定三叶因子 1(TFF1)在正常及病理条件下胃黏膜中的表达情况 ,探讨TFF1在胃黏膜损伤修复及胃癌抑制中的作用及意义。方法　应用免疫组化方法测定正常及不同病理条件下胃黏膜中TFF1的表达情况 ,通过图像分析软件分析阳性信号平均吸光度值以了解其表达情况。结果　胃炎、胃溃疡及十二指肠球部溃疡患者TFF1表达明显高于正常胃黏膜 (0 .5 1± 0 .0 5 ,0 .5 1± 0 .0 6 ,0 .5 0± 0 .0 6比 0 .4 4± 0 .0 6 ;P值均 <0 .0 1)。胃腺癌患者癌旁组织表达 (0 .5 1± 0 .0 7)明显高于正常胃黏膜 ,而腺癌组织的表达强度则与癌组织的分化程度呈正比 ,分化程度愈低 ,表达愈弱 ,低分化腺癌无阳性表达 ,中、高分化腺癌表达 (0 .4 1± 0 .0 7)略低于正常黏膜 ,但差异无显著性 (P >0 .0 5 )。结论　TFF1表达随黏膜损伤程度的加重而表达增强 ,提示其在胃黏膜保护及促进上皮重建机制中具有一定的作用。TFF1在癌旁组织中表达增强提示其可能与肿瘤抑制及分化机制有关 ,而在癌组织中表达减弱可能与其分泌减少有关。     

核转录因子-κB和三叶因子3与胃癌关系的研究进展

核转录因子-κB(NF-κB)是一种多功能转录因子,参与体内免疫应答、炎症反应、细胞增殖、凋亡调节和肿瘤形成等过程。三叶因子3(TFF3)作为胃肠黏膜的一个重要的黏膜保护因子,对维持其黏膜的完整性和促进肠黏膜损伤后重建和修复具有重要作用。在胃癌形成过程中TFF3和NF-κB可能相互影响、相互调节、共同发挥作用。TFF3和NF-κB对胃癌早期诊断和判断预后可能具有重要的提示作用,可为指导临床上胃癌的诊断及治疗提供新的潜在靶点。     

Preventive effect of hydrotalcite on gastric mucosal injury in rats induced by taurocholate

AIM: To study the preventive effect of hydrotalcite on gastric mucosal injury in rat induced by taurocholate, and to investigate the relationship between the protective mechanism of hydrotalcite and the expression of trefoil factor family 2 (TFF2) mRNA and c-fos protein.METHODS: Forty five male Wistar rats were randomly divided into hydrotalcite group, ranitidine group and control group. Gastric mucosal injury was induced by introgastric acidified taurocholate. OD value of TFF2 mRNA expression in gastric mucous cells was determined by hybridization and computer image analysis system. OD value of c-fos protein expression in gastric mucous cells was measured by immunohistochemistry and computer image analysis system.RESULTS: The gross mucosal injury index in hydrotalcite group was significantly lower than that in ranitidine group and control group (8.60±2.20 vs 16.32±4.27, 29.53±5.39;P＜0.05, P＜0.01). The expression level of TFF2 mRNA in hydrotalcite group was markedly higher than that in ranitidine group and control group (0.56±0.09 vs 0.30±0.05, 0.28±0.03,P＜0.05). The OD value of c-fos protein in hydrotalcite group was higher than that in ranitidine group and control group (0.52±0.07 vs 0.31±0.04, 0.32±0.05, P＜0.05).CONCLUSION: Hydrotalcite can protect gastric mucosal injury in rats induced by taurocholate, which may be related to the increased expression of TFF2 and c-fos protein.     

Spatio-temporal expression of trefoil peptide following severe gastric ulceration in the rat implicates it in late-stage repair processes

BACKGROUND: The trefoil peptide (TFF1) is a member of a family of mucin-associated regulatory peptides that are widely distributed in gastrointestinal tissues and have been implicated in the maintenance of the gastric mucosa. The role of TFF1 in gastric mucosal repair was examined by analysis of the spatio-temporal expression of TFF1 following gastric ulceration in the rat. METHODS: Gastric ulcers were induced in rats by application of glacial acetic acid to the serosa of the fundus. At various time points post injury (0-28 days), macroscopic and microscopic examination of the gastric mucosa was performed. In addition, the spatio-temporal expression of TFF1 protein and proliferating cell nuclear antigen were identified by immunohistochemistry, TFF1 message by in situ hybridization, and acidic/neutral secreting mucins by Alcian blue-periodic acid-Schiff staining. RESULTS: In normal rat gastric tissue, TFF1 peptide and mRNA were expressed in mucosal cells of the superficial epithelium. Trefoil peptide and mRNA were significantly induced between 4 and 28 days post ulceration, with expression extending beyond the superficial epithelium and being localized to acidic mucin-producing cells deep within the repairing mucosa. CONCLUSIONS: Spatio-temporal expression of TFF1 mRNA and peptide following macroscopic repair implicates TFF1 as a potential mediator of late stage-repair processes. Whether this is through direct stimulation of cellular differentiation or the enhancement of mucosal protective properties through an interaction with gastric mucins remains to be elucidated.     

Effect of omeprazole-induced achlorhydria on trefoil peptide expression in the rat stomach

BACKGROUND: Omeprazole is an inhibitor of the H+K+ ATPase of the gastric parietal cell, which is used clinically to suppress gastric acid secretion. It has also been found to inhibit gastric mucin production; however, its effects on the synthesis and secretion of the trefoil peptides, which are also expressed by mucus cells, and which play a key role in cytoprotection and epithelial repair, are unknown. METHODS: Rats (n=8) were given either omeprazole (30 mg/kg per day; p.o.) or inert carrier for 1 week, and the effects on synthesis and peptide expression of the gastric trefoil peptides, TFF1/pS2 and TFF2/SP, were compared. RESULTS: As expected, omeprazole treatment abolished H+ ion production with a mean gastric juice pH of 7.2 compared with 2.4 for controls. The omeprazole group had elevated total protein levels of 35-fold and TFF1/pS2 peptide levels elevated fourfold, respectively, but not TFF2/SP peptide in gastric juice, suggesting that the increased pH reduced the viscosity of adherent mucus, thereby increasing gastric juice concentrations by dissolution of adherent TFF1/pS2 and increased secretion. Concomitant with increased TFF1/pS2 secretion was a fall in predominantly antral mucosal trefoil peptide concentrations. In contrast to trefoil secretory rates, the steady-state synthesis of both TFF1/pS2 and TFF2/SP was unchanged after omeprazole treatment, implying both a large cellular pool of processed peptide and rapid secretion. CONCLUSION: The increase in the concentration of TFF1/pS2 in gastric secretions during chronic omeprazole-induced achlorhydria may be important in preventing tissue injury and promoting repair in response to an increased luminal bacterial population.     

Expression of TFF2 and Helicobacter pylori infection in carcinogenesis of gastric mucosa

AIM: To investigate the expression of TFF2 and Helicobacter pyloriinfection in carcinogenesis of gastric mucosa.METHODS: The expression of TFF2 was immunohistochemically analyzed in paraffin-embedded samples from 119 patients with endoscopic biopsy and subtotal gastrectomy specimens of gastric mucosal lesions, including 16 cases of chronic superficial gastritis (CSG), 20 chronic atrophic gastritis (CAG),35 intestinal metaplasia (IN), 23 gastric epithelial dysplasia (GED) and 25 gastric carcinoma (CA), and Helicobacter pylori infection was detected by Warthin-Starry staining.RESULTS: 1:TFF2 was located in the cytoplasm of gastrk mucous neck cell. The expression of TFF2 was 100 %,100 %, 0, 56.5 % and 0 in CSGs, CAGs, INs, GEDs and CAs, respectively. 2: The value of TFF2 positive cell density in CSG with Helicobacter pyloriinfection was higher than that without Helicobacter pyloriinfection. (52.89±7.27vs46.49±13.04, P＞0.05); But the value of TFF2 positive cell density in CAG and GED with Helicobacter pyloriinfection was significantly lower than that without Helicobacter pylori infection (18.17±4.09 vs 37.93±13.80, P＜0.01 and 14.44±9.32 vs 24.84±10.22, P＜0.05).CONCLUSION: Increase of TFF2 expression in CSG is perhaps associated with the protective mechanism after gastric mucosal injury. Decrease of TFF2 expression in CAG possibly attributes to the decrease in the number of gastric gland cell expressing TFF2. Re-expression of TFF2 in gastric epithelial dysplasia implies that TFF2 possibly contributes to the initiation of gastric carcinoma. The effect of Helicobacter pylori on the expression of TFF2 depends on the status of gastric mucosa.     

三叶因子1的研究与进展

TFF1是三叶因子家族成员之一,在胃肠道黏膜屏障和修复中发挥着重要的生理功能.通过与黏蛋白结合对胃肠道起保护作用,并涉及黏膜重建的不同步骤,特别是调节细胞.细胞连接、细胞移行.近年研究发现,TFF1与细胞迁移、增殖、分化、血管形成等密切相关.他可以延迟细胞从G1期向S期转化,从而减少细胞凋亡,参与细胞内蛋白折叠而且与消化道疾病的发生密切相关.TFF1在胃肠道不同的部位发挥的作用不同,在胃组织中发挥肿瘤抑制因子的作用,但在结肠组织中却发挥着致癌因子的作用,促进结肠肿瘤的发生和发展,并且通过不同的信号途径发挥作用.本文主要对上述的新近研究进行综述.     

Extracellular signal-regulated kinase 1- and 2-mediated gastric mucosal injury and repair in gastric ischemia–reperfusion of rats

Background The current study was undertaken to investigate the time course of gastric ischemia–reperfusion (GI-R)-induced gastric mucosal injury and repair and whether extracellular signal-regulated kinase 1/2 (ERK1/2) were involved in GI-R-induced gastric mucosal injury and repair. Methods Immunohistochemistry and Western blot analyses were used. Results Gastric mucosal injury induced by ischemia alone was mild. However, the injury worsened after reperfusion, reaching a maximum at 1 h, and was accompanied by increased apoptotic cells and decreased proliferative cells. Then, the gastric mucosal cells began to repair the injury by enhanced proliferation, which peaked at 24 h after reperfusion, and by 72 h the damaged gastric mucosa was mostly repaired. The ERK1/2 (nonactivated ERK1/2) protein expression level and distribution profile showed no significant changes during the entire reperfusion phase, but the p-ERK1/2 (activated ERK1/2) level changed dramatically. The p-ERK1/2 protein level was decreased at 0.5 h after reperfusion began, and then gradually increased, peaking after 3 h of reperfusion; these changes in p-ERK1/2 occurred simultaneously in the cytoplasm and nucleus. On the other hand, inhibition of the activation of ERK1/2, induced by PD98059, a specific ERK1/2 upstream inhibitor, aggravated the gastric mucosal injury, and apoptosis was increased and proliferation was reduced in the gastric mucosal cells after the same duration of reperfusion. Conclusions Serious gastric mucosal damage involving apoptotic cells occurred rapidly at an early stage of reperfusion and was closely related to the suppression of ERK1/2 activation. The activated ERK1/2 signaling transduction pathway played an important role. Activated ERK1/2 participated in the regulation of gastric mucosal injury and repair induced by GI-R, and might be mediated by the inhibition of apoptosis and the promotion of proliferation in gastric mucosal cells.     

Trefoil factor 2 in gland mucous cell mucin in the mucous gel covering normal or damaged gastric mucosa using the Mongolian gerbil model

OBJECTIVE: Trefoil factor 2 (TFF2) is localized in gastric gland mucous cells. The purpose of the study was to determine whether TFF2 and gastric mucin are localized in mucous cells and in the surface mucous gel layer (SMGL) of the normal gastric mucosa or in the mucoid cap adherent to gastric mucosal lesions in Mongolian gerbils. MATERIAL AND METHODS: Gastric mucosal lesions were induced in Mongolian gerbils using oral administration of Helicobacter pylori (H. pylori), subcutaneous administration of indomethacin, or oral administration of 30% ethanol. Tissue samples were fixed in Carnoy's solution for preservation of the SMGL, dehydrated, and embedded in paraffin. Histochemical staining for gastric mucins and immunostaining for TFF2 were performed. RESULTS: It was found that surface mucous cell mucin and gland mucous cell mucin were segregated in the SMGL covering the normal gastric mucosa, and the mucin of the mucoid cap covering the mucosal lesions was primarily gland mucous cell mucin. There was a co-localization of TFF2 in gland mucous cell mucin in gland mucous cells, the SMGL, and the mucoid cap. CONCLUSIONS: The co-localization of TFF2 in gland mucous cells and in the adherent mucus suggests a physical interaction between TFF2 and gland mucous cell mucin, and the participation of TFF2 trapped in the adherent mucus functions in mucosal defense, healing, and repair.     

Pathophysiological Investigation of the Gastric Surface Mucous Gel Layer of Patients with <Emphasis Type="Italic">Helicobacter pylori</Emphasis> Infection by Using Immunoassays for Trefoil Factor Family 2 and Gastric Gland Mucous Cell-Type Mucin in Gastric Juice

Background  

The trefoil factor family (TFF) 2 protein is produced by gastric gland mucous cells (GMCs), and the secreted TFF2 shares a mucosal barrier function with GMC-type mucin. Recently, we presented an enzyme-linked immunosorbent assay (ELISA) method for measurement of GMC-type mucin in the gastric juice.