SMOKELESS TOBACCO--MECHANISMS OF BUCCAL MUCOSA INJURY

无烟烟草——颊粘膜损伤的机制

• 批准号: 2128831
• 负责人: Israel Rubinstein
• 金额: $ 6.63万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2128831
• 关键词: DNA replication; bradykinin; cell cycle; cellular pathology; cheek pouch technique; drug interactions; drug metabolism; drug related neoplasm /cancer; endopeptidases; enzyme activity; epithelium; gene expression; genetic regulation; hamsters; inflammation; messenger RNA; metalloenzyme; molecular pathology; neuropeptide receptor; oncogenes; oral mucosa; peptidyl dipeptidase A; smokeless tobacco; tissue /cell culture; vascular endothelium permeability

The use of smokeless tobacco (ST) in increasing in the United States. Recent epidemiological and clinical evidence suggests that regular use of ST is associated with buccal mucosa injury, inflammation and epithelial cell dysplasia. However, the mechanisms that mediate these effects are still poorly understood. The basic tenet of this proposal is that ST induces buccal mucosa injury, inflammation and epithelial cell proliferation, in part, by altering local kinin metabolism. We hypothesized that exposure of the buccal mucosa to ST is associated with: 1) local generation and release of bradykinin (BK) that has potent inflammatory and mitogenic effects; 2) decreased activity and/or expression of the membrane-bound metalloenzymes angiotensin-converting enzymes (ACE; EC 3.4.15.1) and neutral endopeptidase (NEP; EC 23.4.24.11) that are widely distributed in the buccal mucosa and degrade BK very effectively; 3) potentiation of BK-induced buccal mucosa epithelial cell proliferation; and 4) upregulation Ki-ras oncongene expression in buccal mucosa epithelial cells leading upregulation of BK receptors in these cells. The net result would be a decrease in BK catabolism in the buccal mucosa combined with and increase in the number and/or affinity of its receptors in epithelial cells leading to potentiation of BK-induced plasm extravasation and epithelial cell proliferation. In the present proposal, we will use the hamster cheek pouch to investigate the following specific aims: 1) to determine whether ST increases vascular permeability in the hamster check pouch, and whether these effects are modulated by ACE and NEP; 2) to investigate whether ST induces BK generation and release in the hamster cheek pouch; 3) to determine whether ST decreases the activity and expression of ACE and NEP in the hamster cheek pouch; 4) to investigate whether ST interacts with BK to induce hamster cheek pouch epithelial cell DNA synthesis and proliferation in vitro, and whether these effects are modulated by ACE and NEP; and 5) to determine whether ST upregulates BK receptors in cultured hamster cheek pouch epithelial cells, and whether these effects are associated with increased expression of Ki-ras mRNA. The results of the proposed studies will provide new insights into mechanisms that may mediate the injurious effects of ST in the buccal mucosa. In the long term, they may also provide a rationale for the development of novel strategies to treat oral lesions associated with the regular use of ST in human subjects.

无烟烟草（ST）在美国的使用率正在上升。 最近的流行病学和临床证据表明， ST与颊粘膜损伤、炎症和 上皮细胞发育不良 然而，介导这些的机制 影响仍然知之甚少。 这项建议的基本原则是 ST诱导颊粘膜损伤、炎症和上皮细胞 增殖，部分通过改变局部激肽代谢。 我们 假设颊粘膜暴露于ST与： 1)局部产生和释放缓激肽（BK）， 炎症和促有丝分裂作用; 2）活性降低和/或 膜结合金属酶血管紧张素转换酶的表达 酶（ACE; EC 3.4.15.1）和中性内肽酶（NEP; EC 23.4.24.11） 它们广泛分布于口腔粘膜中， 3）加强BK诱导的颊粘膜上皮细胞增殖 增殖; 4）上调颊粘膜Ki-ras癌基因表达 粘膜上皮细胞导致BK受体的上调， 细胞 最终结果将是颊部BK催化剂的减少 粘膜结合并增加其数量和/或亲和力 上皮细胞中的受体导致BK诱导的血浆增强 外渗和上皮细胞增殖。 本 建议，我们将使用仓鼠颊囊调查 以下具体目的：1）确定ST是否增加血管 仓鼠检查袋的渗透性，以及这些影响是否 研究ST是否诱导BK 在仓鼠颊囊中产生和释放; 3）确定 ST是否降低ACE和NEP的活性和表达， 仓鼠颊囊; 4）研究ST是否与BK相互作用， 诱导仓鼠颊囊上皮细胞DNA合成， 体外增殖，以及这些作用是否受ACE调节 和NEP;和5）确定ST是否上调BK受体， 培养仓鼠颊囊上皮细胞，以及这些影响是否 与Ki-ras mRNA表达增加有关。 的结果 拟议的研究将提供新的见解的机制， 介导ST在颊粘膜中的损伤作用。 从长远 术语，它们也可以为小说的发展提供理论基础。 治疗与定期使用ST相关的口腔病变的策略 在人类实验对象中。