Role of Helicobacter pylori cytotoxin in the gastric mucosa

幽门螺杆菌在胃粘膜的感染与慢性B型胃炎和消化性溃疡密切相关。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，是其主要致病因素之一。在这项研究中，我们重点研究了幽门螺杆菌细胞毒素在胃粘膜中的作用，并检测了幽门螺杆菌细胞毒素是否影响胃细胞的增殖和人单核细胞产生炎性细胞因子，如白介素1β(IL-1β)和肿瘤坏死因子-α(TNF-α)。我们发现：1)幽门螺杆菌细胞毒素抑制胃液培养细胞的生长和增殖，并干扰表皮生长因子与细胞表面受体的结合。2)幽门螺杆菌可刺激人单核细胞产生炎性细胞因子和表达信使RNA。3)在胃粘膜防御中起核心作用的前列腺素E_2可抑制幽门螺杆菌诱导的人单核细胞炎症反应。4)这些炎性细胞因子通过增加胃溃疡模型中黏附分子的表达和中性粒细胞的浸润而导致胃溃疡复发，并诱导溃疡边缘MCP-1的表达。5)在体外模型中，Hp感染的胃粘膜中高浓度的IL-8刺激中性粒细胞上皮内边际形成，损害上皮屏障功能。6)幽门螺杆菌感染胃粘膜活检标本的免疫组织化学研究显示，胃粘膜ICAM-1、LFA-1和Mac-1的表达增加。这些发现有助于幽门螺杆菌相关性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.