SMOKELESS TOBACCO--MECHANISMS OF BUCCAL MUCOSA INJURY

无烟烟草——颊粘膜损伤的机制

• 批准号: 2683933
• 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 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683933
• 关键词: DNA replication; bradykinin; cell cycle; cellular pathology; cheek pouch technique; drug interactions; drug metabolism; drug related neoplasm /cancer; enzyme activity; epithelium; gene expression; genetic regulation; hamsters; inflammation; messenger RNA; metalloenzyme; molecular pathology; neprilysin; 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.

美国无烟烟草（ST）的使用量不断增加。 最近的流行病学和临床证据表明，经常使用 ST 与颊粘膜损伤、炎症和 上皮细胞发育不良。 然而，调节这些的机制 的影响仍然知之甚少。 本提案的基本宗旨 是ST引起颊粘膜损伤、炎症和上皮细胞 增殖部分是通过改变局部激肽代谢来实现的。 我们 假设颊粘膜暴露于 ST 与以下因素相关： 1) 局部产生并释放具有强效作用的缓激肽 (BK) 炎症和促有丝分裂作用； 2) 活动减少和/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） 广泛分布于颊粘膜并能非常有效地降解 BK 有效地; 3) BK诱导的颊粘膜上皮细胞的增强作用 增殖; 4) 上调颊部 Ki-ras 癌基因表达 粘膜上皮细胞导致 BK 受体上调 细胞。 最终结果是颊部 BK 分解代谢减少 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。 在现在 建议，我们将使用仓鼠颊囊来调查 以下具体目标： 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 由ACE和NEP调制； 2) 考察ST是否诱发BK 仓鼠颊囊中的生成和释放； 3）确定 ST是否降低了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，以及这些效应是否受 ACE 调节 和新经济政策； 5) 确定 ST 是否上调 BK 受体 培养仓鼠颊囊上皮细胞，是否有这些影响 与 Ki-ras mRNA 表达增加有关。 结果 拟议的研究将为可能的机制提供新的见解 介导 ST 对颊粘膜的损伤作用。 在漫长的 术语中，它们还可以为小说的发展提供基本原理 治疗与定期使用 ST 相关的口腔病变的策略 在人类受试者中。