幽门螺杆菌毒力因子进展研究

幽门螺杆菌(Helicobacter pylori,H.pylori)是一种革兰阴性杆菌,于1893年首次从慢性活动性胃炎患者的胃黏膜活检组织中被成功分离培养,是目前所知的少数能够在人胃中生存的微生物之一。H.pylori感染不仅可引起胃炎、消化道溃疡、胃黏膜组织相关性(MALT)淋巴瘤等消化系统疾病,其所携带的毒力因子还与胃癌的发生发展有关。不同基因型的H.pylori所携带的毒力因子不同,但只有小部分的感染个体会进展为胃癌的现象。虽然目前诸如CagA、VacA、BabA和OipA等许多毒力因子都已被证明与胃癌的发生有确切关系,但其具体机制仍在进一步的研究当中。本文将主要针对H.pylori中与胃癌相关的毒力因子及其致癌机制进行简要综述,以进一步明确其在胃癌发生发展中的生物学作用。     

幽门螺杆菌毒力基因分型和宿主遗传多态性与胃病关系研究进展

幽门螺杆菌(Helicobacter pylori)感染能导致慢性胃炎、消化性溃疡、胃粘膜相关的淋巴样组织(Mu-cosa-associated lymphoid tissue,MALT)淋巴瘤和胃腺癌等疾病的发生。1994年世界卫生组织国际癌症研究中心(IARC)将H.pylori列为胃癌第一级因子。H.pylori感染引起的不同临床结局主要与H.pylori致病因子和宿主遗传易感性有关,大部分重大疾病发生在特定的细菌毒力因子(如cagA,vacA)与易感宿主遗传背景共同存在时。文章综述了H.pylori菌株的毒力基因的分型和宿主的遗传多态性对胃病发生的影响。     

不同部位、分化和起源胃癌中H.pylori、CagA基因的探讨

目的通过检测不同部位和不同组织类型中胃癌组织中幽门螺杆菌(H.pylori)和细胞毒素相关基因(CagA基因),探讨H.pylori、CagA基因与胃癌的关系,以及H.pylori、CagA基因导致胃癌的可能机制。方法应用快速尿素酶试验和组织切片革兰染色及血清H.pylori CagA抗体检测胃癌患者H.pylori,应用PCR检测胃癌组织中H.pylori CagA基因。结果胃癌组织中随活检部位不同,H.pylori检出率也不同,以胃窦部检出率最高为76.9%,与胃体大弯侧、胃角和贲门相比差异均有非常显著性(P0.005),胃体大弯侧、胃角与贲门相比差异均有非常显著性(P0.005),胃底与贲门相比差异无显著性(P0.05)。胃窦部癌的CagA检出率(85.6%)最高,与其他部位相比差异均有非常显著性(P0.005),胃角胃癌CagA检出率显著高于胃体大弯侧和贲门胃癌(P0.005)。高分化胃癌H.pylori检出率为73.1%,低分化胃癌H.pylori检出率为44.1%,二者相比差异均有非常显著性(P0.01)。肠型胃癌H.pylori检出率为76.7%,弥漫型胃癌H.pylori检出率为33.3%,二者相比差异有显著性(P0.05),高分化胃癌CagA检出率为26.3%,低分化胃癌CagA检出率为80.0%,二者相比差异均有非常显著性(P0.01)。肠型胃癌CagA检出率为80.4%,弥漫型胃癌CagA检出率为57.1%,二者相比差异无显著性(P0.05)。结论不同部位和不同组织类型中胃癌组织中H.pylori和CagA基因的表达存在一定差异性,对探讨胃癌的发生及胃癌的防治有一定的指导意义。     

幽门螺杆菌与胃黏膜相关淋巴瘤相关性研究

目的研究幽门螺杆菌(H.pylori)与胃黏膜相关淋巴瘤相关性。方法通过胃镜和相关辅助检查,对24例胃黏膜相关淋巴瘤病人胃内幽门螺杆菌进行动态观察。结果24例胃黏膜相关淋巴瘤病人中,18例出现H.pylori感染(75%);治疗后H.pylori感染例数减少(6/24,25%);1年后H.pylori病人感染又增加(11/24,46%)。结论抗H.pylori及胃黏膜相关淋巴瘤常规治疗方法有效,但易反复,可考虑辅以微生态调节剂治疗。     

幽门螺杆菌感染与细胞自噬的研究进展

幽门螺杆菌(Helicobacter pylori,H. pylori)是一种革兰阴性微需氧病原菌,也是定植于人类胃黏膜上皮中最特异的一种致病菌。它与人消化性溃疡、慢性胃炎、胃癌及胃黏膜相关组织淋巴瘤(MALT)等疾病密切相关。此后又发现H. pylori可能是一种兼性胞内菌,该菌可能通过自噬在胃上皮细胞和巨噬细胞中得以生存、繁殖并引起慢性持续性感染。本文根据近年发表的自噬相关文献,对H. pylori感染不同细胞后自噬对其存活的影响以及H. pylori不同配体引起的自噬调节作一综述。     

幽门螺杆菌感染者Th1/Th2细胞免疫应答变化

目的观察幽门螺杆菌(H.pylori)相关性胃病患者血清Th1/Th2细胞因子(干扰素-γ,IFN-γ、白细胞介素-4,IL-4)水平变化,以探讨其在发病中的可能免疫致病机制。方法采用酶联免疫吸附测定法(ELISA)测定17例慢性浅表性胃炎、15例胃癌前病变和20例胃癌患者血清IFN-γ及IL-4的含量。比较H.pylori阳性3组患者之间、H.pylori阳性与阴性各相应组患者之间血清2种细胞因子的差异。结果 H.pylori阳性的浅表性胃炎组、胃癌前病变组及胃癌组血清IL-4含量随病变的进展有逐渐升高的趋势,但3组之间差异无统计学意义(P>0.05);H.pylori阳性的3组血清IFN-γ含量差异无统计学意义(P>0.05);H.pylori阳性与阴性的各相应组血清IFN-γ含量差异无统计学意义(P>0.05);H.pylori阳性的胃癌前病变组和胃癌组与H.pylori阴性的相应组血清IL-4含量差异无统计学意义(P>0.05);H.pylori阳性的浅表性胃炎组血清IL-4含量较H.pylori阴性的浅表性胃炎组明显降低(P<0.05)。结论 H.pylori感染可能抑制Th2型免疫应答,导致H.pylori感染持续存在;H.pylori感染相关胃部病变进展过程中,可能存在Th1型应答向Th2型应答漂移,与胃癌的发生可能有一定的相关性。     

幽门螺杆菌感染与胃癌共刺激分子OX40和 OX40L表达的相关性

目的研究幽门螺杆菌(H.pylori)感染与胃癌共刺激分子OX40、OX40L表达的相关性。方法收集本院2017年1月至2019年1月进行胃癌手术的68例患者为研究对象。采用Giemsa染色和PCR方法检测胃癌组织H.pylori感染情况。应用免疫组织化学法检测胃癌和癌旁组织中共刺激分子OX40、OX40L的表达,并分析共刺激分子OX40、OX40L表达与胃癌组织H.pylori感染的相关性。分析OX40、OX40L表达与胃癌患者临床病理特征的关系。采用二元Logistic回归分析胃癌组织H.pylori感染的影响因素。结果胃癌组织中OX40、OX40L阳性表达率显著高于癌旁组织(均P0.05);Giemsa染色和PCR检测胃癌组织中H.pylori感染阳性率分别为86.76%(59/68)和91.18%(62/68)。H.pylori阳性胃癌组织中OX40、OX40L阳性表达率显著高于H.pylori阴性胃癌组织(均P0.05)。OX40、OX40L表达与胃癌患者肿瘤浸润深度、分化程度、T分期、淋巴结转移均无显著相关性(均P0.05),而与胃癌肿块大小相关(P0.05)。OX40、OX40L阳性表达是胃癌组织中H.pylori感染的危险因素。结论 H.pylori感染可能与胃癌组织中OX40、OX40L异常表达相关,可为探究H.pylori致癌机制提供一定参考。     

幽门螺杆菌在胃内定植的相关影响因素

胃内定植是引起幽门螺杆菌(Helicobacter pylori,H.pylori)感染的先决条件。H.pylori可穿过胃黏液层并与胃上皮细胞相互作用。这个定植过程主要受到H.pylori动力和尿素酶的影响。同时H.pylori形态、胃内pH、外膜蛋白及益生菌等也在其中扮演重要角色。该研究主要对H.pylori胃内定植过程中的相关影响因素进行综述。     

TFF2在胃癌中的表达及与幽门螺杆菌感染关系的研究

目的探讨三叶因子Ⅱ(Trefoil factors2,TFF2)在胃癌和癌前病变中的表达及与幽门螺杆菌感染(Helicobacter pylori,H.pylori)的关系。方法选取经病理证实的慢性浅表性胃炎、胃溃疡、慢性萎缩性胃炎和胃癌4种不同胃黏膜病变的标本140例,用免疫组化法检测标本中TFF2的表达及H.pylori的感染情况,并分析TFF2的表达与H.pylori的感染的关系。结果在慢性浅表性胃炎、胃溃疡、慢性萎缩性胃炎和胃癌中,TFF2和H.pylori的表达率依序呈逐渐增加的趋势,但TFF2在胃癌组织中表达降低。H.pylori阳性组TFF2的表达率低于阴性组,TFF2的阳性率与H.pylori感染率之间呈负相关(r=-0.335,P<0.05)。结论 TFF2的表达和H.pylori的感染与肿瘤的发生密切相关,检测该指标可为胃癌诊断、判断预后和指导治疗提供理论依据。     

幽门螺杆菌相关胃癌与多胺代谢CSCD

幽门螺旋杆菌(Helicobacter pylori, H. pylori)选择性地在人的胃黏膜中定植,是引发胃癌的最强危险因素之一。多胺是一类广泛存在于真核细胞中带高密度正电荷的烷基类小分子化合物,参与细胞增殖、分化、凋亡等重要的生理过程,多种疾病的发生发展与多胺代谢紊乱相关。近期研究发现,H.pylori感染能诱导宿主胃黏膜上皮细胞和巨噬细胞中多胺代谢异常。特别是该菌对多胺代谢途径中的关键酶ARG2(arginase 2,精氨酸酶2)、ODC(ornithine decarboxylase,鸟氨酸脱羧酶)和SMO(soermine oxidase,精胺氧化酶)的激活作用,与H. pylori免疫逃逸,慢性炎症维持、DNA损伤和胃癌的发生发展密切相关,提示多胺代谢途径可能成为H. pylori相关胃癌防治的新靶点。     

Accumulation of 8-nitroguanine in human gastric epithelium induced by Helicobacter pylori infection

Helicobacter pylori infection causes chronic inflammation, which can lead to gastric carcinoma. A double immunofluorescence labeling study demonstrated that the level of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) apparent in gastric gland epithelium was significantly higher in gastritis patients with H. pylori infection than in those without infection. A significant accumulation of proliferating cell nuclear antigen, a prognostic factor for gastric cancer, was observed in gastric gland epithelial cells in patients with H. pylori infection as compared to those without infection, and its accumulation was closely correlated with the formation of 8-nitroguanine and 8-oxodG. These results suggest that nitrosative and oxidative DNA damage in gastric epithelial cells and their proliferation by H. pylori infection may lead to gastric carcinoma. 8-Nitroguanine could be not only a promising biomarker for inflammation but also a useful indicator of the risk of gastric cancer development in response to chronic H. pylori infection.     

Helicobacter pylori antibodies and gastric cancer: a gender-related difference

Helicobacter pylori has been proposed as a causative agent of gastric cancer. The aim of this study was to define serum antibodies response against different H. pylori antigens in patients with gastric cancer. Serum samples were collected from 115 Lithuanian patients with non-cardia gastric cancer and 110 age- and sex-matched controls without cancer. Heat-stable, low-molecular-mass, and outer membrane proteins were used as antigens to analyze serum IgG antibody response against H. pylori by enzyme-linked immunosorbent assay. Seroprevalence of H. pylori using low-molecular-mass antigen was significantly higher in gastric cancer patients, compared to controls (77% versus 57%, p<0.05). Significant differences in the prevalence of H. pylori infection between gastric cancer patients and controls were found in females using all three studied antigens: heat-stable (98% versus 84%, p<0.05), low-molecular-mass (88% versus 48%, p<0.05) and outer membrane proteins (78% versus 57%, p<0.05). In males, no significant differences were revealed between gastric cancer patients and controls. There may be other cofactors in addition to H. pylori that are important for the development of gastric cancer. H. pylori seems, however, to be a more important for development of gastric cancer in females than in males or males may have more confounding risk factors for gastric cancer than females.     

儿童幽门螺杆菌感染

幽门螺杆菌感染不仅能引起胃炎、消化性溃疡,诱发胃癌等胃肠道的病变,还与许多胃肠外疾病密切相关,如果不经过特殊治疗将终生带菌,严重的影响小儿的生长发育和身心健康。这些问题引起了儿科医生和儿童保健医生的共同关注。儿童期既是幽门螺杆菌感染的特殊时期,也是控制感染的关键时期。本文将从小儿幽门螺杆菌国内外的感染状况、相关疾病、诊断方法、治疗及预防等几个方面综述如下。     

Acid, helicobacter and immunity: a new paradigm for oesophagogastric cancer.

Epidemiological evidence has clearly shown a highly significant relationship between Helicobacter pylori infection and the development of duodenal ulcer and distal gastric adenocarcinoma. Despite H. pylori being a common aetiological factor for both disorders, the two disease phenotypes are virtually mutually exclusive. This indicates that the host response to infection has a pivotal role in determining outcome; these disease phenotypes relate to the effect of infection on gastric acid secretion, duodenal ulcer being closely related to sustained acid secretion whereas gastric cancer follows gastric atrophy and impaired gastric acid secretion. Cancer at the oesophageal junction and that associated with Barrett's oesophagus is now the most rapidly increasing tumour in the gastrointestinal tract. The challenge for the next millennium, therefore, is to try and develop methods for identifying patients at risk of developing oesophagogastric cancer. A common feature in the pathogenesis of both gastric and oesophageal adenocarcinoma is inflammation presenting clinically as gastritis and oesophagitis. The pathway from gastritis to gastric atrophy, dysplasia and carcinoma is thought to be a multi-step process, probably triggered by free radicals within the gastric epithelium and increased exposure to luminal carcinogens. However, it has been unclear as to which aspect of the host response determines whether an individual will move along the neoplasia pathway. Recent work has shown that qualitative aspects of the immune environment in the stomach may account for a substantial part of the phenotypic divergence following H. pylori infection. Interleukin-1 beta polymorphisms relate closely to the propensity for an individual to develop distal gastric cancer and maybe useful for predicting risk in family members. In Barrett's oesophagus, we have recently shown that the immune environment may also be important in determining whether an individual will develop cancer. Although we did not find that Barrett's oesophagus was a profoundly inflammatory condition (unlike esophagitis in the squamous epithelium), where there was evidence of inflammation it was qualitatively different from that of oesophagitis in that a Th-2 response with increased expression of IL-4 predominated in Barrett's, whereas a Th-1 proinflammatory response characterised oesophagitis in squamous epithelium. It seems likely that the specific immune environment within Barrett's metaplasia may be an important driver towards dysplasia and carcinoma. Thus, the immune environment in the stomach and esophagus may be critical in determining whether an individual is at risk of developing neoplastic complications of H. pylori infection and gastroesophageal reflux. Identification of the genetic factors which underpin these responses may ultimately result in development of methods to identify individuals at high risk.     

Helicobacter pylori and Non-malignant Diseases

It is well known that Helicobacter pylori infection is associated with many nonmalignant disorders such as gastritis, peptic ulcer, gastroesophageal reflux disease (GERD), gastric polyp, nonsteroidal anti-inflammatory drug (NSAID)/aspirin-induced gastric injury, and functional dyspepsia. In 2008, interesting articles on the association of H. pylori infection with these disorders were presented, some of which intended to reveal the mechanisms of inter-individual differences in response to H. pylori infection, and have demonstrated that genetic differences in host and bacterial factors as well as environmental factors account for these differences. A decline in the occurrence of peptic ulcer related to H. pylori was confirmed. An inverse relationship between H. pylori infection and GERD was also confirmed but the impact of gastric atrophy on the prevention of GERD remained debatable. For NSAID-induced gastric injury, eradication of H. pylori infection has been recommended. During this year, eradication of H. pylori infection was recommended for patients treated with antiplatelet therapy as well as aspirin and NSAID. It was also reported that for patients with functional dyspepsia, eradication of H. pylori offers a modest but significant benefit.     

Diverse H. pylori strains,IL-10 promoter polymorphisms with high morbidity of gastric cancer in Hexi area of Gansu Province,China

In Hexi area of Gansu Province, people have a higher susceptibility of gastric cancer than people in the rest area of China. There is substantial geographic variation in the incidence of gastric cancer. In this article, the present author explored the roles of H. pylori infection and IL-10 promoter polymorphisms in development of gastric cancer in this area. A total of 304 participants were admitted to our study, and they were divided into two groups: control group and case group. Blood samples from all subjects were collected for gene extraction using DNA extraction kits. IL-10 polymorphisms were determined by SNaPshot Multiplex. To test H. pylori infection and its typing H. pylori antibody Immunoblotting Kits were used. This research suggested that environmental factor played an important role in the pathogenesis of gastric carcinoma in the area, H. pylori infection increased the risk of gastric cancer (OR = 2.612, 95% CI 1.636-4.170) and subject with H. pylori I-type positive was at significantly higher risk for progression to gastric cancer (OR = 4.712, 95% CI 2.656-8.537). For subjects with the ATA/GCC or GCC/GCC haplotype of the IL-10-1082/-819/-592 polymorphism relative to the ATA/ATA haplotype group, the risk of gastric cancer development was significantly increased. It has been demonstrated that the presence of IL-10-819 C alleles and IL-10-592 C alleles was associated with an increased risk for gastric cancer development in H. pylori-infected patients and IL-10 promoter polymorphisms and H. pylori have a synergistic effect on gastric cancer in Hexi population.     

胃癌前病变患者胃蛋白酶原、促胃液素-17水平变化及幽门螺杆菌感染情况

目的研究胃癌前病变患者胃蛋白酶原、促胃液素-17及幽门螺杆菌(H.pylori)感染情况变化。方法试验组患者选取2017年8月至2018年8月间于我院进行治疗的100例胃癌前病变患者,对照组选取来我院体检中心进行体检的健康人员60例,对比两组人群胃蛋白酶原、促胃液素-17及H.pylori感染情况变化。结果试验组PGI(57.45±11.52)、PGII(8.65±1.75)、PGR(5.89±1.26)和促胃液素-17(8.05±1.45)水平显著低于对照组(均P<0.05);试验组H.pylori感染率81.00%显著高于对照组感染率41.67%,差异有统计学意义(P<0.05)。结论胃癌前病变患者PGI、PGII、PGR和促胃液素-17水平较低,并且H.pylori感染率高,患病与H.pylori感染有一定关系,胃蛋白酶原、促胃液素-17和H.pylori感染率对胃癌前病变临床诊断有重要作用,能够作为胃癌前病变患者筛查参考指标。     

Synergism of Helicobacter pylori infection and stress on the augmentation of gastric mucosal damage and its prevention with alpha-tocopherol

Despite evidence that Helicobacter pylori (H. pylori) infection is closely associated with stress in gastric ulcer patients, the underlying mechanism why ulcer recurrence after stress is augmented especially in patients with H. pylori remains unknown. In this study, we found that oxidative stress played a critical role in the augmented mucosal damage provoked by water immersion restraint stress (WIRS) in H. pylori infection and that an antioxidant, alpha-tocopherol, could ameliorate the aggravation of stress-associated gastric mucosal damage. Two hundred forty SD rats were divided into two groups according to H. pylori inoculation, and after 24 weeks of H. pylori infection, the water immersion restraint stress was imposed for 30, 120, or 480 min, respectively. To evaluate the therapeutic effects of an antioxidant, alpha-tocopherol was administrated 40 mg/kg daily prior to imposing WIRS. Remarkably increased hemorrhagic lesions and bleeding indexes were noted in the H. pylori-infected group with statistical significance (P < 0.05) compared to the noninfected group at the same duration of WIRS. Significantly higher oxidative stress documented by iNOS, lipid peroxides, and GSH level was detected in gastric homogenates of the H. pylori-infected group. Proteomic analysis using 2-dimensional electrophoresis showed a decrease of HSP27 and other chaperone proteins. alpha-Tocopherol pretreatment significantly prevented the gastric mucosal damage, caused by WIRS in the presence of H. pylori. alpha-Tocopherol induced HSP27 expression, which was well correlated with downregulation of iNOS mRNA. Conclusively, the presence of H. pylori caused significant deterioration of stress-induced gastric mucosal lesions through increased oxidative stress and thus antioxidant treatment such as alpha-tocopherol protected the gastric injuries.