Oxidative damage to gastric epithelal cells by H pylori

幽门螺杆菌是一种慢性感染，影响世界上50%的人口，在所有感染者中引起胃炎，而只有一小部分人以溃疡或腺癌的形式发展上皮疾病。细菌和宿主因素似乎都在这些人类疾病的发病机制中发挥作用，但具体机制尚不清楚。已知幽门螺杆菌和细胞因子在幽门螺杆菌感染中增加，诱导胃上皮细胞生长的改变，如诱导程序性细胞死亡。在感染期间招募到胃粘膜的吞噬白细胞被激活，产生活性氧（ROS），我们已经证明它可以改变胃上皮细胞的生长并诱导细胞凋亡。幽门螺杆菌感染也会诱导胃上皮细胞中ROS的积累，这可能取决于细菌的基因型。胃上皮细胞对氧化应激的反应是最初产生ROS，随后激活氧化还原敏感信号通路，该信号通路已被证明可以控制调节细胞生长、修复和死亡过程的基因转录。特别令人感兴趣的是ros诱导的无尿嘧啶/无嘧啶内切酶-1 （AP内切酶）的激活，AP内切酶是一种多功能蛋白，是氧化损伤DNA碱基切除修复途径中的限速酶，它也激活转录因子，包括激活蛋白(AP)-1和p53。因此，这一提议的一般假设是氧化应激有助于幽门螺杆菌感染期间发生的上皮细胞损伤。幽门螺杆菌感染通过AP内切酶刺激氧化还原敏感信号导致胃上皮细胞凋亡的具体假设将在以下具体目的中进行检验：幽门螺杆菌感染时氧化应激对胃上皮细胞损伤（凋亡）的影响目的2：探讨幽门螺杆菌是否调控胃上皮细胞AP内切酶的表达和功能；目标3。明确AP内切酶如何调控细胞凋亡和促凋亡基因的转录。这些在培养的人类细胞系和人体组织中的研究将解决氧化应激对胃上皮细胞损伤的影响这一悬而未决的问题。控制上皮细胞对氧化应激反应的分子机制也将被定义。这一新知识将提高我们对幽门螺杆菌感染相关上皮细胞损伤发病机制的理解，并有助于确定预防和治疗人类胃病的策略。

Helicobacter pylori is a chronic infection that affects 50% of the world's population causing gastritis in all infected while only a subset develop disease of the epithelium in the form of ulceration or adenocarcinoma. Both bacterial and host factors appear to play a role in the pathogenesis of these human diseases but the specific mechanisms remain unclear. H. pylori and cytokines known to be increased in H. pylori infection, induce alterations of gastric epithelial cell growth such as the induction of programmed cell death. Phagocytic leukocytes recruited to the gastric mucosa during infection become activated, generating reactive oxygen species (ROS) that we have shown to alter gastric epithelial cell growth and induce apoptosis. Infection with H. pylori also induces the accumulation of ROS in gastric epithelial cells that may be dependent on bacterial genotype. Gastric epithelial cells respond to oxidative stress with the initial generation of ROS and subsequent activation of a redox-sensitive signaling pathway which has been shown to control the transcription of genes that regulate cell growth, repair and death processes. Of particular interest is ROS-induced activation of apurinic/apyrimidinic endonuclease-1 (AP endonuclease), a multifunctional protein that is the rate-limiting enzyme in the DNA base excision repair pathway of oxidative lesions, which also activates transcription factors including activator protein (AP)-1, and p53. Thus, the general hypothesis underlying this proposal is that oxidative stress contributes to the epithelial cell injury that occurs during H. pylori infection. The specific hypothesis that H. pylori infection stimulates redox-sensitive signaling through AP endonuclease that leads to apoptosis in gastric epithelial cells will be examined in the following specific aims: Aim 1. Evaluate oxidative stress in gastric epithelial cell injury (apoptosis) during H. pylori infection; Aim 2 Determine if H. pylori regulates the expression and function of AP endonuclease in gastric epithelial cells; Aim 3. Define how AP endonuclease regulates apoptosis and the transcription of pro-apoptotic genes. These studies in cultured human cell lines and human tissue will address unanswered questions regarding the effect of oxidative stress on gastric epithelial cell injury. The molecular mechanisms governing the epithelial response to oxidative stress will also be defined. This new knowledge will improve our understanding of the pathogenesis of epithelial cell damage associated with H. pylori infection and help identify strategies for the prevention and treatment of human gastric disease.