Uptake of Fluoroquinolones and Tetracyclines by Gingiva

牙龈吸收氟喹诺酮类和四环素类药物

基本信息

批准号：
6607397
负责人：
JOHN D WALTERS
金额：
$ 19.91万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-05-01 至 2006-06-30
项目状态：
已结题

项目摘要

Destructive periodontitis is associated with infections by A. actinomycetemcomitans and P. gingivalis. Their ability to invade epithelial cells makes them difficult to treat by mechanical debridement alone, but antimicrobial agents enhance their elimination. Fluoroquinolones and tetracyclines are very useful because they are cell-permeant and have favorable activity. Through mechanisms that remain unclear, both have an unusual ability to be taken up by cells and both attain higher levels in gingival fluid (GF) than in serum. Recent studies suggest that active transport plays important roles. Cultured epithelial cells take up both agents by active transport, and gingival connective tissue also accumulates fluoroquinolones (attaining levels that are higher than those in serum). We hypothesize that gingival fibroblasts possess active transporters that allow them to accumulate fluoroquinolones and tetracyclines in the gingival connective tissue. The resulting distribution of these agents is responsible for the high levels they attain in GF. Epithelial cells in the gingiva also take up these agents, providing access to intracellular pathogens. The objective of this proposal is to define the mechanisms by which fluoroquinolones and tetracyclines are transported and concentrated in the gingiva. Specific aim 1 is to characterize and identify the transport systems by which gingival fibroblasts and epithelial cells take up these agents. Specific aim 2 is to determine whether transport of these agents is modulated by growth factors or cytokines. Specific aim 3 is to compare the distribution of fluoroquinolones and tetracyclines in serum, gingival connective tissue, and gingival fluid. Insight gained from this work could facilitate the development of new therapeutic approaches that exploit these transport systems. Strategies that optimize the uptake and distribution of antimicrobial agents should enhance the elimination of invasive pathogens from the periodontium and other types of mucosa.

破坏性牙周炎与曲霉曲霉和牙龈疟原虫的感染有关。它们侵入上皮细胞的能力使它们仅通过机械清创术而难以治疗，但是抗菌剂可以增强其消除。氟喹诺酮类和四环素非常有用，因为它们是细胞的份额并且具有有利的活性。通过尚不清楚的机制，两者都具有不寻常的能力被细胞吸收，并且在牙龈液（GF）中的水平都比血清更高。最近的研究表明，主动运输起着重要作用。培养的上皮细胞通过主动运输占据两种药物，牙龈结缔组织也积累了氟喹诺酮（达到高于血清中的水平）。我们假设牙龈成纤维细胞具有活性转运蛋白，使它们可以在牙龈结缔组织中积累氟喹诺酮类和四环素。这些代理的产生分布负责他们在GF中获得的高水平。牙龈中的上皮细胞也吸收了这些药物，从而获得了细胞内病原体的访问。该提案的目的是定义氟喹诺酮类和四环素在牙龈中运输和集中的机制。具体目的1是表征和确定牙龈成纤维细胞和上皮细胞占用这些药物的传输系统。具体目的2是确定这些药物的运输是否由生长因子或细胞因子调节。具体目的3是比较血清，牙龈结缔组织和牙龈液中氟喹诺酮类和四环素的分布。从这项工作中获得的洞察力可以促进开发利用这些运输系统的新治疗方法。优化抗菌剂的摄取和分布的策略应增强消除牙周和其他类型的粘膜的侵入性病原体。