UPTAKE OF FLUOROQUINOLONE ANTIMICROBIALS BY PHAGOCYTES

描述（改编自研究者摘要）：虽然多晶型 白细胞（PMNs）和单核吞噬细胞是非常有效的， 清除感染，几种细菌（包括牙周病原体 伴放线放线杆菌[A.a.]）能抵抗吞噬杀伤。 针对细胞内病原体的抗微生物疗法由于细菌感染而变得复杂。 许多物质不能穿透吞噬细胞。 然而，吞噬细胞 环丙沙星和其他氟喹诺酮类药物的高亲和力。 当被加载 使用这些杀菌剂，PMN表现出增强的吞噬杀伤作用， 可以潜在地用作氟喹诺酮递送的载体， 从血流迁移到感染部位（例如，牙周 口袋）。 对于吞噬细胞摄取的机制知之甚少 氟喹诺酮类。 该实验室的最新研究表明， 环丙沙星转运是一个不依赖Na+的过程， 被阳离子氨基酸抑制，已知与 氨基酸转运系统y+。 激活蛋白激酶C（PKC）的药物 诱导环丙沙星转运的Vmax急剧增加， 一种似乎涉及丝裂原活化蛋白激酶（MAP）的机制 激酶）级联。 这一提议将检验系统y+是 氟喹诺酮在吞噬细胞中蓄积的主要机制， 由PKC和MAP激酶调节。 长远目标是加强 抗菌治疗的有效性。 具体目标1： 并确定中性粒细胞和单核细胞摄取的转运系统 氟喹诺酮类。 具体目标2是确定刺激 氟喹诺酮在吞噬细胞中的转运，并确定其机制， 该过程受到调节，强调PKC和MAP激酶的作用。 具体目标3是确定吞噬细胞是否摄取氟喹诺酮 有助于增强氟喹诺酮类药物向牙周的递送 口袋或增强杀死匿名者。 吞噬细胞杀伤的增强将 在袋的厌氧环境中特别有用，其中 氧化杀伤机制无效。 最终，这项工作可以 促进新的方法来治疗由A.a.和其他 抵抗吞噬细胞杀伤的病原体（例如，沙门氏菌和衣原体）。

DESCRIPTION (Adapted from investigator's Abstract): While polymorphonuclear leukocytes (PMNs) and mononuclear phagocytes are highly effective at clearing infections, several bacteria (including the periodontal pathogen Actinobacillus actinomycetemcomitans [A.a.]) can resist phagocytic killing. Antimicrobial therapy against intracellular pathogens is complicated by the inability of many agents to penetrate phagocytes. However, phagocytes take up ciprofloxcin and other fluoroquinolones with high affinity. When loaded with these bactericidal agents, PMNs exhibit enhanced phagocytic killing and can potentially serve as vehicles for fluoroquinolone delivery as they migrate from the bloodstream to infection sites (e.g., the periodontal pocket). Little is known of the mechanism by which phagocytes take up fluoroquinolones. Recent work from this laboratory indicates that PMN ciprofloxcin transport is a Na+-independent process that is competitively inhibited by cationic amino acids, properties known to be associated with amino acid transport system y+. Agents that activate protein kinase C (PKC) induce a dramatic increase in the Vmax of ciprofloxcin transport through a mechanism that appears to involve the mitogen-activated protein kinase (MAP kinase) cascade. This proposal will test the hypothesis that system y+ is the major mechanism for fluoroquinolone accumulation in phagocytes and is regulated by PKC and MAP kinase. The long-term objective is to enhance the effectiveness of antimicrobial therapy. Specific Aim 1 is to characterize and identify the transport system(s) by which PMNs and monocytes take up fluoroquinolones. Specific Aim 2 is to identify agents that stimulate fluoroquinolone transport in phagocytes and define the mechanisms by which this process is regulated, emphasizing the role of PKC and MAP kinase. Specific Aim 3 is to determine whether fluoroquinolone uptake by phagocytes contributes to enhanced delivery of fluoroquinolones to the periodontal pocket or enhanced killing of A.a.. Enhancement of phagocytic killing would be especially useful in the anaerobic environment of the pocket, where oxidative killing mechanism are ineffective. Ultimately, this work could facilitate new approaches for treating infections by A.a. and other pathogens that resist phagocytic killing (e.g., Salmonella and Chlamydia).