Role of Helicobacter pylori cytotoxin in the gastric mucosa

胃粘膜幽门螺杆菌感染与慢性B型胃炎和消化性溃疡疾病密切相关。然而，幽门螺杆菌相关疾病的致病机制尚不清楚。幽门螺杆菌产生的细胞毒素可诱导靶细胞空泡化，是主要致病因素之一。本课题主要研究幽门螺杆菌细胞毒素在胃粘膜中的作用，检测幽门螺杆菌细胞毒素是否影响人单核细胞对胃细胞的增殖和白细胞介素-1 β (il -1 β)、肿瘤坏死因子- α (TNF- α)等炎性细胞因子的产生。我们发现1)幽门螺杆菌细胞毒素抑制人胃培养细胞的生长和增殖，并干扰细胞表面表皮生长因子（EGF）与其受体的结合。2)幽门螺杆菌刺激人分离单核细胞炎性细胞因子的产生和信使RNA的表达。3)在胃粘膜防御中起核心作用的前列腺素E_2抑制幽门螺杆菌诱导的人单核细胞的炎症产生。4)这些炎性细胞因子在大鼠实验模型中通过增加粘附分子表达和中性粒细胞浸润诱导胃溃疡复发，诱导溃疡边缘MCP-1表达。5)幽门螺杆菌感染的胃黏膜高浓度的白细胞介素-8刺激了体外模型中中性粒细胞的上皮内边缘性聚集，损害了上皮屏障功能。6)对幽门螺杆菌感染的人粘膜活检标本进行免疫组化研究，发现胃黏膜中ICAM-1、LFA-1、Mac-1表达升高。这些发现有助于幽门螺杆菌相关疾病的发病机制和幽门螺杆菌细胞毒素在胃粘膜中的作用。

Helicobacter pylori infection in the gastric mucosa is strongly associated with chronic type B gastritis and peptic ulcer disease. However the pathogenic mechanisms of the H.pylori related disease is not known. Cytotoxin, which is produced by H.pylori and induces vacuolization in the target cells, is one of the major causative factors. In this research project, we focused on the role of the H.pylori cytotoxin in the gastric mucosa and examined whether H.pylori cytotoxin affects proliferation of the gastric cells and inflammatory cytokine production such as interleukin-1 beta (IL-1beta) and tumor necrosis factor- alpha (TNF- alpha) by human monocytes. We found that 1) H.pylori cytotoxin inhibited growth and proliferation of phuman gastric cultured cells and interferes with epidermal growth factor (EGF) binding to its receptor on the cell surface. 2) H.pylori stimulated inflammatory cytokine production and expression of messenger RNA by human isolated monocytes. 3) Prostaglandin E_2, which plays a central role in the gastric mucosal defense, inhibited H.pylori-induced inflammatory production by human monocytes. 4) These inflammatory cytokine induced gastric ulcer recurrence through increased expression of adhesion molecules and neutrophil infiltration in the rat experimental models and induced MCP-1 expression at the ulcer margin. 5) Interleukin-8 which is high concentration in the H.pylori infected gastric mucosa stimulated intraepithelial margination of neutrophils and impaired epithelial barrier function in the in vitro models. 6) Immunohistochemical study using human biopsy specimens of the H.pylori infected mucosa showed increased expression of ICAM-1, LFA-1, and Mac-1 in the gastric mucosa. These findings contributes pathogenesis of H.pylori related disease and the role of H.pylori cytotoxin in the gastric mucosa.