新型氟喹诺酮类药物贝西沙星对原代人角膜上皮细胞的抗炎作用。

Anti-inflammatory effects of besifloxacin, a novel fluoroquinolone, in primary human corneal epithelial cells.

作者信息

Zhang Jin-Zhong, Cavet Megan E, Ward Keith W

机构信息

Global Preclinical Development, Bausch & Lomb, Rochester, New York 14603, USA.

出版信息

Curr Eye Res. 2008 Nov;33(11):923-32. doi: 10.1080/02713680802478704.

DOI:10.1080/02713680802478704

PMID:19085374

Abstract

PURPOSE

The aim of this study was to determine the anti-inflammatory effects of besifloxacin, a novel fluoroquinolone under clinical evaluation for the treatment of ophthalmic infections, in human corneal epithelial cells (HCEpiC).

METHODS

Cytokine expression in primary HCEpiC was stimulated by interleukin-1beta (IL-1beta), and Luminex technology was used to determine the effect of besifloxacin on IL-1beta-induced cytokine release. Effect of besifloxacin on nuclear factor kappa B (NFkappaB), and mitogen-activated protein kinase (MAPK) was assessed by measuring inhibitory kappa B protein (IkappaB) degradation, NFkappaB nuclear translocation, and MAPK phosphorylation by Western blotting. Moxifloxacin, a marketed fluoroquinolone, was used as the control. Anti-inflammatory efficacy of besifloxacin was also evaluated in rabbits infected with methicillin-resistant Staphylococcus aureus (MRSA).

RESULTS

Stimulation of HCEpiC with IL-1beta increased release of 12 of the 29 cytokines measured. Besifloxacin significantly inhibited IL-1beta-induced cytokine release in a dose-dependent manner, with a comparable (IL-8) or better (G-CSF, GM-CSF, IL-6, MCP-1, MIP-1beta, TGF-alpha, and TNF-alpha) efficacy compared to moxifloxacin. A significant inhibitory effect of besifloxacin was observed at 1 or 10 microg/ml. Besifloxacin inhibited IkappaB degradation, NFkappaB nuclear translocation, and activation of p38 and JNK MAPKs. Based on improvement of clinical score, besifloxacin showed statistically significant anti-inflammatory effect compared to saline treatment.

CONCLUSIONS

Besifloxacin acts as an anti-inflammatory agent in corneal epithelial cells in vitro, by inhibiting the NFkappaB and MAPK pathways. Besifloxacin also exhibits anti-inflammatory efficacy in vivo. The anti-inflammatory attribute may enhance its efficacy in the treatment of ocular infections with an inflammatory component and warrants further investigation.

摘要

目的

本研究旨在确定贝西沙星（一种正在进行治疗眼部感染临床评估的新型氟喹诺酮类药物）对人角膜上皮细胞（HCEpiC）的抗炎作用。

方法

用白细胞介素-1β（IL-1β）刺激原代HCEpiC中的细胞因子表达，并用Luminex技术测定贝西沙星对IL-1β诱导的细胞因子释放的影响。通过蛋白质免疫印迹法测量抑制性κB蛋白（IkappaB）降解、NFκB核转位和丝裂原活化蛋白激酶（MAPK）磷酸化，评估贝西沙星对核因子κB（NFκB）和丝裂原活化蛋白激酶（MAPK）的作用。莫西沙星（一种已上市的氟喹诺酮类药物）用作对照。还在感染耐甲氧西林金黄色葡萄球菌（MRSA）的兔中评估了贝西沙星的抗炎功效。

结果

用IL-1β刺激HCEpiC增加了所测29种细胞因子中12种的释放。贝西沙星以剂量依赖性方式显著抑制IL-1β诱导的细胞因子释放，与莫西沙星相比，其疗效相当（IL-8）或更好（G-CSF、GM-CSF、IL-6、MCP-1、MIP-1β、TGF-α和TNF-α）。在1或10微克/毫升时观察到贝西沙星有显著抑制作用。贝西沙星抑制IkappaB降解、NFκB核转位以及p38和JNK MAPKs的活化。基于临床评分的改善，与盐水治疗相比，贝西沙星显示出统计学上显著的抗炎作用。