幽门螺杆菌感染的动物模型研究进展

胃癌是世界上最常见的恶性肿瘤之一，其发生是一个多病因、多阶段的过程。1994年，WHO根据大规模的流行病学研究结果，确定H．pylori为I类致癌因子。H．pylori是慢性活动性胃炎、消化性溃疡的重要病因，与胃黏膜相关淋巴样组织淋巴瘤（MALT）及胃癌关系密切。为克服人体研究的局限性，许多学者致力于H．pylori感染的动物模型研究，试图采用动物实验的方法进一步阐明H．pylori在胃癌发生中的作用及机制，以及用于评价H．pylori疫苗的预防和保护效果。     

幽门螺杆菌致癌作用的研究

摘要幽门螺杆菌（H. pylori）感染，特别是CagA^＋株感染，与胃癌的发生密切相关，但其分子机制仍不清楚。对H．pylori致胃黏膜癌变的分子机制进行深入研究，结果显示胃黏膜H．pylori感染可增加胃癌的易感性，导致线粒体DNA微卫星不稳（mtMSI）和线粒体DNA核内整合，使线粒体细胞色素氧化酶（COX）Ⅰ、COXⅡ、COXIImRNA表达下调，Bid和Bax表达上调。提示H．pylori通过线粒体途径影响细胞凋亡，导致细胞增殖和凋亡的失衡，从分子水平揭示了H．pvlori诱导胃癌发生的机制。     

幽门螺杆菌致胃癌发生的机制

胃癌的发生发展并不是由单一因素引起，而是多种致癌因素多阶段相互作用的结果，在慢性浅表性胃炎→萎缩性胃炎→肠上皮化生→异型增生→胃癌这一癌变模式中，幽门螺杆菌(Helicobacter pylori，H．pylori)可能起着先导作用，是胃癌发生的启动因子之一。Forman发现H．pylori感染人群发生胃癌的危险性高出阴性组3倍，每年有300，000胃癌新病例与H．pylori感染有关，这是已知胃癌病因中危险性最大的。     

幽门螺杆菌和胃癌——富有挑战性的研究课题

胃癌的发生是一个随慢性胃炎进行性发展的多步骤、多因素过程,在萎缩、肠化和异型增生之后,最终发展成胃癌[1]。一些环境因素如幽门螺杆菌（H．pylori）、盐过量摄入、胆汁反流、N-亚硝基化合物和缺乏抗氧化剂等均与胃癌发生的不同阶段相关联［1］。在这些危险因素中,H．pylori被认为是癌发生序列过程中的触发因子,强有力的证据证明H．Pylori感染是两种可能的癌前病变——慢性萎缩性胃炎和肠化的病因[2-4]某些国家H．pylori感染率与总人口中的胃癌死亡率有关,提示了胃癌与H．pyori感染的关系[5]。虽然1994年世界卫生组织国际癌症研…     

胃癌和慢性胃炎患者幽门螺杆菌蛋白质组学分析

背景：胃癌的发生是一个多因素多步骤的过程,幽门螺杆菌（H．pylori）感染在此过程中发挥重要作用。目的：建立胃癌和慢性胃炎H．pylori的双向凝胶电泳（2-DE）图谱,识别鉴定差异表达的蛋白质．探讨细菌本身因素在胃癌发病过程中的作用。方法：取H.pylori而阳性的胃癌和慢性胃炎患者胃黏膜组织后分离培养H.pylori,收集菌体并采用BCA法行蛋白定量,以2-DE分离Hpylori蛋白．采用PDQuest软件分析差异表达的蛋白质点．应用电喷雾四极杆飞行时间串联质谱（Q—TOF）进行鉴定,并在Mascot数据库中进行检索。结果：胃癌和慢性胃炎H．pylori总蛋白均获得分辨率高、重复性好的2-DE图谱。共6个蛋白质点在胃癌和慢性胃炎中存在表达差异．其中超氧化物歧化酶、尿素酶仪亚单位、分子伴侣60kDa在胃癌Hpylori菌株中高表达,而巯基过氧化物酶、二磷酸核苷激酶、S．核糖基同型半胱氨酸裂解酶在慢性胃炎H．pylori菌株中高表达。结论：成功建立了分辨率高且重复性好的胃癌和慢性胃炎H．pylori蛋白的2-DE图谱,并鉴定出两种疾病相关菌株中差异表达的蛋白质点．这些蛋白质点可能在胃癌的发生中起重要作用。     

重视幽门螺杆菌相关性胃癌的线粒体机制研究

日益增多的资料提示，幽门螺杆菌（H．pylori）感染与胃癌的发生有密切关系，世界卫生织织（WHO）已把其列为胃癌的首要致病因子。长期大规模的随访研究证明，胃癌只发生于有H．pylori感染的胃黏膜，而不发生于无H．pylori感染胃黏膜，动物实验研究亦发现，H．pylori不仅可以增强甲基硝基亚硝基胍的诱癌作用，长期H．pylori感染本身即可诱发出胃窦腺癌。尽管众多研究证明H．pylori感染与胃癌有关，但H．pylori感染引起胃癌的分子机制仍不清楚。线粒体是迄今发现的人类细胞核外唯一具有自己基因组，且能不依赖nDNA进行复制、转录和翻译的细胞器，被称为“人类第25号染色体”。过去认为线粒体只是人体的“能量供应站”，但线粒体的功能远比人们了解的更为复杂。近年，我们对H．pylori致胃黏膜细胞损伤的线粒体途径进行了深入的研究，结合国内外文献，综合叙述如下。     

胃癌与幽门螺杆菌相关性研究进展

研究认为幽门螺杆菌(Helicobacter pylori,H.pylori)感染是引起胃癌的一个重要因素,其包含的毒力基因及生活方式能够诱导胃上皮化生、癌变。但H.pylori引起胃癌的机制尚不清楚,已经成为一个公认的全球健康问题。大量的流行病学、临床和实验研究支持H.pylori是胃癌发生、发展过程中的启动和促动因子,做好H.pylori根除工作对于胃癌预后和预防至关重要。H.pylori疫苗的发展对于胃癌的防治提供了一种新的思路。本文旨在对H.pylori与胃癌相关性的研究进展作一概述。     

根除幽门螺杆菌在预防胃癌中的作用

胃癌在全球恶性肿瘤致死亡的原因中位居第二位,幽门螺杆菌（H．pylori）感染是胃癌发生的重要病因。动物研究显示根除H.pylori,特别是在早期阶段,能有效预防胃癌的发生。部分病例通过根除npylori可阻止胃癌前病变的发展并可能使其逆转。最新研究表明根除H．pylori可降低胃癌发生的风险,对无萎缩或肠化生者可能尤其有效。本文就根除H．p）tori在预防胃癌中作用的研究进展作一综述。     

幽门螺杆菌与胃癌相关机制的研究进展

胃癌是最常见的恶性肿瘤之一,幽门螺杆菌(Helicobacter pylori,H.pylori)感染是最重要的危险因素.全球超过50%的人口感染H.pylori,但只有不到2%最终患胃癌.宿主因素,环境因素也起着非常重要的作用,因此胃癌的发生是一个多因素、多步骤的过程,是H.pylori、宿主、环境因素共同作用的结果.     

幽门螺杆菌胃癌动物模型的研究进展

幽门螺杆菌(H．pylori)感染引起胃部疾病已被大量流行病学及实验研究所证实。为了进一步揭示H．pylori与胃癌的关系，用H．pylori建立合适的动物模型将有助于研究胃癌的发病机制。此文对近年来该领域H．Pylori胃癌动物模型的研究作一综述，并介绍几种成功的胃癌动物模型及存在的问题。     

Role of Helicobacter pylori in the pathogenesis of gastric carcinoma and progression of lymphoid nodules to lymphoma.

The pathology of gastritis associated with Helicobacter pylori infection is summarized. The literature is reviewed regarding the role of H pylori in the pathogenesis of gastric carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. The potential mechanisms of gastric carcinogenesis include transformation of the gastric mucosa by metabolic products of H pylori, transformation of the host cell by incorporation of H pylori DNA and genotoxic effects of the inflammatory response to the organism. A model for gastric carcinogenesis is proposed in which H pylori causes cell proliferation, and the risk of DNA damage is increased, leading to inadequate repair and malignant transformation. Investigation of early gastric carcinomas concluded that two main pathways operated in gastric carcinogenesis, both starting from H pylori gastritis and leading to phenotypically variable gastric or intestinal tumour growth. The histological features and molecular genetics of MALT lymphoma are briefly reviewed. There is evidence that tumour cells of low grade B cell MALT lymphoma proliferate specifically in response to H pylori. This response is dependent on T cell activation by H pylori. A proposed model for the pathogenesis of MALT lymphoma postulates that B lymphocytes with a genetic change acquire a growth advantage resulting in a monoclonal proliferation in response to H pylori-activated T cells. Further genetic changes may result in escape from T cell dependency.     

Effect of Helicobacter pylori infection on Bax protein expression in patients with gastric precancerous lesions

AIM: To investigate the effect of Helicobacter pylori (H pylori) infection on Bax protein expression, and explore the role of H pylori in gastric carcinogenesis. METHODS: H pylori was assessed by rapid urease test and Warthin-Starry method, and expression of Bax protein was examined immunohistochemically in 72 patients with pre-malignant lesions. RESULTS: Bax protein was differently expressed in intestinal metaplasia and gastric dysplasia, and showed 63.99% positivity. The positivity of Bax protein expression in Hpylori-positive gastric precancerous lesions (72.3%) was significantly higher than that in H pylori-negative gastric precancerous lesions (48.0%, X~2=4.191, P<0.05). H pylori infection was well correlated with the expression of Bax protein in gastric precancerous lesions (r=0.978, P<0.01). After eradication of H pylori, the positivity of Bax protein expression significantly decreased in H pylort-positive gastric precancerous lesions (X~2=5.506, P<0.05). In the persisting H pylori-infected patients, the positivity of Bax protein expression was not changed. CONCLUSION: H pylori infection may be involved in the upregulation of Bax gene, which might be one of the mechanisms of H pylori infection-induced gastric epithelial cell apoptosis. H pylori might act as a tumor promoter in the genesis of gastric carcinoma and eradication of H pylori could inhibit gastric carcinogenesis.     

Helicobacter pylori-infected animal models are extremely suitable for the investigation of gastric carcinogenesis

Although various animal models have been developed to clarify gastric carcinogenesis, apparent mechanism of gastric cancer was not clarified in recent years. Since the recognition of the pathogenicity of Helicobacter pylori (H pylori), several animal models with H pylori infection have been developed to confirm the association between H pylori and gastric cancer. Nonhuman primate and rodent models were suitable for this study. Japanese monkey model revealed atrophic gastritis and p53 mutation after long-term infection of H pylori. Mongolian gerbil model showed the development of gastric carcinoma with H pylori infection alone, as well as with combination of chemical carcinogens, such as N-methyl-N-nitrosourea and N-methyl-N-nitro-N-nitrosoguanidine. The histopathological changes of these animal models after H pylori inoculation are closely similar to those in human beings with H pylori infection. Eradication therapy attenuated the development of gastric cancer in Hpylori-infected Mongolian gerbil. Although several features of animal models differ from those seen in human beings, these experimental models provide a starting point for further studies to clarify the mechanism of gastric carcinogenesis as a result of H pylori infection and assist the planning of eradication therapy to prevent gastric carcinoma.     

Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis

OBJECTIVES: Helicobacter pylori is an identified carcinogen for gastric cancer, however, the underlying mechanisms remain to be defined. In this review, we sought to elucidate the role of apoptosis in gastric carcinogenesis, to determine the influence of H. pylori infection on apoptosis, and finally to provide insights into the mechanisms by which H. pylori may lead to gastric carcinogenesis. METHODS: A broad-based MEDLINE and Current Contents literature search was performed to identify relevant publications between 1966 and March 2000 addressing H. pylori infection, apoptosis, cell proliferation, gastric carcinoma, oncogenes, and tumor suppressor genes, as well as the products of these genes. Abstracts from recent major conferences that provided adequate additional data were also included. RESULTS: Apoptotic cells are rare in the glandular neck region (the generative cell zone) of normal gastric mucosa. With progression of atrophic gastritis, the generative cell zone shifts downward and a relatively large number of apoptotic cells occur. In intestinalized glands, both apoptotic cells and proliferative cells are present in deeper portions of the glands, corresponding to the generative zone. A higher frequency of apoptosis has been observed in gastric dysplasia than in coexisting gastric carcinomas, whereas the number of proliferative cells is significantly higher in gastric carcinoma than in dysplasia. Upregulation of oncogene bcl-2 in premalignant lesions and "downregulation" of the gene after malignant change is probably a common event. Accumulation of p53 protein is first detected in dysplasia, although mutation of the pS3 gene may occur in intestinal metaplasia. H. pylori infection induces apoptosis in gastric epithelial cells, which returns to normal after eradication of the infection. Numerous molecules produced by H. pylori including cytotoxin (VacA), lipopolysaccharide, monochloramine, and nitric oxide may directly induce apoptosis. Moreover, H. pylori-stimulated host inflammatory/immune responses lead to release of a large amount of cytokines. Cytokines produced by type 1 T helper cells, such as TNF-alpha and IFN-gamma, markedly potentiate apoptosis. Gastric cell proliferation is significantly higher in patients with H. pylori infection than in normal controls, and eradication of the infection leads to a reduction in cell proliferation. Apoptosis and cell proliferation are also increased in precancerous lesions such as gastric atrophy, intestinal metaplasia, and dysplasia in the presence of H. pylori infection. However, H. pylori-induced apoptosis may no longer be cell cycle-dependent in these lesions because of the occurrence of alterations and mutations of apoptosis-regulating genes, resulting in a loss of balance between apoptosis and cell proliferation. CONCLUSIONS: It is hypothesized that H. pylori-induced apoptosis may play a key role in gastric carcinogenesis by increasing cell proliferation and/or resulting in gastric atrophy.     

How does Helicobacter pylori cause gastric cancer through connexins: An opinion review

Helicobacter pylori(H. pylori) is a Gram-negative bacterium with a number of virulence factors, such as cytotoxin-associated gene A, vacuolating cytotoxin A,its pathogenicity island, and lipopolysaccharide, which cause gastrointestinal diseases. Connexins function in gap junctional homeostasis, and their downregulation is closely related to gastric carcinogenesis. Investigations into H.pylori infection and the fine-tuning of connexins in cells or tissues have been reported in previous studies. Therefore, in this review, the potential mechanisms of H. pylori-induced gastric cancer through connexins are summarized in detail.     

Helicobacter pylori in Gastric Malignancies

Helicobacter pylori infection remains common worldwide and is significantly associated with gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT)lymphoma. This article reviews recent developments in the field of H. pylori with an emphasis on mechanisms of carcinogenesis, and the bacterial, environmental and host factors that may alter risk of developing gastric cancer or gastric MALT lymphoma. The topic of eradication of H. pylori to prevent the development of malignancy and the possibility of a vaccine against H. pylori are also explored.     

Cell proliferation in the gastric corpus in Helicobacter pylori associated gastritis and after gastric resection.

Patients who have undergone gastric resection are at higher risk of developing gastric carcinoma than normal subjects, and bile reflux is believed to play a role in carcinogenesis. An increase in mucosal cell proliferation increases the likelihood of a neoplastic clone of epithelial cells emerging, particularly where there is chronic epithelial injury associated with bile reflux. Helicobacter pylori is considered a major risk factor for gastric cancer in the intact stomach. It has been shown previously that antral cell proliferation is increased in H pylori gastritis and falls to normal levels after eradication of the organism. Little is known of corpus cell proliferation in H pylori gastritis or after gastric resection. Using in vitro bromodeoxyuridine labelling of endoscopic biopsy specimens we have found that corpus cell proliferation is increased in H pylori gastritis. Cell proliferation was greater in corpus biopsy specimens of resected stomachs than in H pylori gastritis. Subgroup analysis of patients who had undergone gastric resection indicated that those positive for H pylori had higher levels of cell proliferation than those negative for the organism. These findings provide further evidence that H pylori and bile have a role in gastric carcinogenesis and suggest that their presence has a synergistic effect on gastric epithelial cell proliferation.     

Grading of histology, expression of apoptosis and cell proliferation in gastric mucosa adjacent to gastric adenoma or adenocarcinoma]

BACKGROUND/AIMS: Helicobacter pylori (H. pylori) infection can lead to gastric adenoma and carcinoma through atrophic gastritis and intestinal metaplasia. Imbalance between apoptosis and proliferation may play a role in gastric carcinogenesis. We tried to investigate H. pylori infection rate, grade of gastritis, environmental risk factors, expression rate of apoptosis and cell proliferation in mucosa adjacent to tumor, and we also tried to find significant factors associated with gastric carcinogenesis. METHODS: Endoscopically diagnosed twenty cases of intestinal type gastric carcinoma, 20 cases of gastric adenoma, and 40 cases of control (normal or gastritis) were enrolled. H. pylori infection rate, histologic grading, apoptosis and immunohistochemical stain (Ki-67 and p53) to check mucosal proliferation were done in endoscopically biopsied tissues at antrum and body at least 2 cm apart from adenoma or carcinoma. RESULTS: In three groups, H. pylori infection rates were not significantly different. In the multivariate analysis, only atrophy of gland was a significant risk factor for adenoma compared to control group (OR 3.7). Intestinal metaplasia in antrum and alcohol drinking were significant risk factors for carcinoma compared to control group (OR 4.4 and 4.9 respectively). Expressions of apoptosis, Ki-67 and p53 were not significantly different in three groups. CONCLUSIONS: Intestinal metaplasia in antrum and alcohol drinking are significant risk factors for gastric carcinoma. Degree of mucosal proliferation and apoptosis in gastric mucosa adjacent to tumor are not significantly different in three groups.