UPTAKE OF FLUOROQUINOLONE ANTIMICROBIALS BY PHAGOCYTES

描述(改编自研究人员摘要)：虽然中性粒细胞 白细胞(PMN)和单核巨噬细胞在 清除感染，几种细菌(包括牙周病原体 伴生放线杆菌[A.A.]可以抵抗吞噬细胞的杀戮。 针对细胞内病原体的抗菌治疗因 许多制剂不能穿透吞噬细胞。然而，吞噬细胞 与环丙沙星等氟喹诺酮类药物亲和力高。加载时 使用这些杀菌剂，PMN表现出增强的吞噬杀伤力和 可能作为氟喹诺酮类药物的载体，因为它们 从血流转移到感染部位(例如牙周 口袋)。吞噬细胞的吞噬机制知之甚少。 氟喹诺酮类药物。这个实验室最近的研究表明，PMN 环丙沙星转运是一种钠不依赖的过程，具有竞争性 被阳离子氨基酸抑制，已知与以下特性有关 氨基酸转运系统y。激活蛋白激酶C(PKC)的试剂 诱导环丙沙星转运的Vmax显著增加 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 氟喹诺酮类药物在吞噬细胞中蓄积的主要机制是 受PKC和MAP激酶的调节。我们的长远目标是加强 抗菌治疗的有效性。具体目标1是描述 确定中性粒细胞和单核细胞的转运系统(S) 氟喹诺酮类药物。具体目标2是确定刺激 氟喹诺酮类药物在吞噬细胞中的转运及其机制 这个过程是受调控的，强调了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类药物 有助于增强氟喹诺酮类药物对牙周的吸收 口袋或强化杀戮AA..。增强吞噬细胞的杀伤力将 在袋子的厌氧环境中尤其有用，在 氧化杀死机制是无效的。最终，这项工作可能会 促进治疗AA感染的新方法。及其他 抵抗吞噬细胞杀伤的病原体(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).