SMOKELESS TOBACCO--MECHANISMS OF BUCCAL MUCOSA INJURY

无烟烟草——颊粘膜损伤的机制

• 批准号: 2128832
• 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/2128832
• 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.

在美国增加了无烟烟草（ST）。 最近的流行病学和临床证据表明，定期使用 ST与颊粘膜损伤，炎症和 上皮细胞发育不良。 但是，介导这些的机制 效果仍然很了解。 该提议的基本宗旨 是否诱导颊粘膜损伤，炎症和上皮细胞 部分通过改变局部基因代谢。 我们 假设颊粘膜暴露于ST与： 1）具有有效性的局部发电和释放BRADYKININ（BK） 炎症和有丝分裂作用； 2）减少活动和/或 膜结合金属酶血管紧张素转换的表达 酶（ACE; EC 3.4.15.1）和中性内肽酶（NEP; EC 23.4.24.11） 广泛分布在颊粘膜中，非常降解BK 有效地; 3）BK诱导的颊粘膜上皮细胞的增强 增殖; 4）颊上上调ki-ras oncogene表达 粘膜上皮细胞导致BK受体的上调 细胞。 最终结果将减少颊中BK分解代谢 粘膜与其数量和/或亲和力相结合并增加 上皮细胞中的受体导致BK诱导的血浆增强 渗出和上皮细胞增殖。 现在 提案，我们将使用仓鼠脸颊袋调查 以下特定目的：1）确定ST是否增加血管 仓鼠检查袋中的渗透性以及这些效果是否是 由ACE和NEP调节； 2）研究ST是否诱导BK 在仓鼠脸颊袋中产生和释放； 3）确定 ST是否降低了ACE和NEP的活性和表达 仓鼠脸颊袋； 4）调查ST是否与BK相互作用 诱导仓鼠脸颊袋上皮细胞DNA合成和 体外增殖，以及这些影响是否由ACE调节 和NEP； 5）确定ST是否上调BK受体 培养的仓鼠脸颊袋上皮细胞，以及这些影响是否影响 与Ki-Ras mRNA的表达增加有关。 结果 拟议的研究将为可能的机制提供新的见解 介导ST在颊粘膜中的有害作用。 长时间 术语，他们还可能为发展新颖的理由提供理由 治疗与经常使用ST相关的口腔病变的策略 在人类主题中。