UPTAKE OF FLUOROQUINOLONE ANTIMICROBIALS BY PHAGOCYTES

吞噬细胞对氟喹诺酮类抗菌药物的摄取

• 批准号: 2897203
• 负责人: JOHN D WALTERS
• 金额: $ 11.04万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2897203
• 关键词: Actinobacillus actinomycetemcomitans; acidity /alkalinity; aerobiosis; aminoacid transport; anaerobiosis; antibacterial agents; antisense nucleic acid; body fluids; chemoattractants; cytokine; drug metabolism; enzyme activity; gingiva; human tissue; lipopolysaccharides; membrane transport proteins; mitogen activated protein kinase; monocyte; neutrophil; northern blottings; oligonucleotides; phagocytes; protein kinase C; sodium ion

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).

描述（改编自研究者的摘要）：虽然多形核 白细胞 (PMN) 和单核吞噬细胞非常有效 清除感染，多种细菌（包括牙周病原体 Actinobacillus actinomycetemcomitans [A.a.])可以抵抗吞噬杀伤。 针对细胞内病原体的抗菌治疗因以下因素而变得复杂 许多药剂无法穿透吞噬细胞。 然而，吞噬细胞 与环丙沙星等氟喹诺酮类药物具有高亲和力。 加载时 使用这些杀菌剂，中性粒细胞表现出增强的吞噬杀灭作用 可以作为氟喹诺酮类药物递送的载体，因为它们 从血流迁移到感染部位（例如牙周组织） 口袋）。 对于吞噬细胞摄取的机制知之甚少 氟喹诺酮类药物。 该实验室最近的工作表明 PMN 环丙沙星转运是一种不依赖于 Na+ 的过程，具有竞争性 被阳离子氨基酸抑制，已知与相关的特性 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 似乎涉及丝裂原激活蛋白激酶（MAP 激酶）级联。 该提案将检验系统 y+ 的假设 氟喹诺酮类药物在吞噬细胞中积累的主要机制是 受 PKC 和 MAP 激酶调节。 长期目标是增强 抗菌治疗的有效性。 具体目标 1 是表征 并确定中性粒细胞和单核细胞占用的运输系统 氟喹诺酮类药物。 具体目标 2 是确定刺激剂 氟喹诺酮在吞噬细胞中的转运并定义其机制 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输送 口袋或增强杀灭A.a.。增强吞噬杀灭会 在口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 促进治疗 A.a. 感染的新方法。和其他 抵抗吞噬杀灭的病原体（例如沙门氏菌和衣原体）。