Uptake of Fluoroquinolones and Tetracyclines by Gingiva

破坏性牙周炎与伴生放线菌和牙龈假单胞菌的感染有关。它们入侵上皮细胞的能力使它们很难单独通过机械清创治疗，但抗菌剂可以增强它们的消除。氟喹诺酮类和四环素类药物是非常有用的，因为它们是细胞固有的，具有良好的活性。通过尚不清楚的机制，两者都具有被细胞吸收的不同寻常的能力，并且在牙周液(GF)中的水平都高于血清中的水平。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转运吸收这两种药物，牙龈结缔组织也积累氟喹诺酮类药物(达到的水平高于血清中的水平)。我们假设牙龈成纤维细胞具有活性的转运蛋白，使它们能够在牙龈结缔组织中积聚氟喹诺酮类和四环素类药物。由此产生的这些制剂的分布是它们在GF中达到高水平的原因。牙龈中的上皮细胞也会吸收这些物质，从而提供接触细胞内病原体的途径。这项建议的目的是确定氟喹诺酮类药物和四环素类药物在牙龈中转运和浓缩的机制。具体目标1是表征和鉴定牙龈成纤维细胞和上皮细胞吸收这些药物的运输系统。具体目标2是确定这些药物的运输是否受生长因子或细胞因子的调节。具体目的3是比较氟喹诺酮类药物和四环素类药物在血清、牙龈结缔组织和牙周液中的分布。从这项工作中获得的洞察力可能有助于开发利用这些运输系统的新治疗方法。优化抗菌剂的吸收和分布的策略应该加强从牙周组织和其他类型的粘膜中消除侵袭性病原体。

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.