Anti-inflammatory effects of besifloxacin, a novel fluoroquinolone, in primary human corneal epithelial cells.
OBJECTIVE
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.
Zhang
Jin-Zhong
JZ
Global Preclinical Development, Bausch & Lomb, Rochester, New York 14603, USA. jinzhong_zhang@bausch.com
Cavet
Megan E
ME
Ward
Keith W
KW
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D009877:Endophthalmitis / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D019573:Epithelium, Corneal / Q000166:cytology* / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000077266:Moxifloxacin; D016328:NF-kappa B / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D011817:Rabbits
D000893:Anti-Inflammatory Agents; D001372:Aza Compounds; D001381:Azepines; D016207:Cytokines; D024841:Fluoroquinolones; D053583:Interleukin-1beta; D016328:NF-kappa B; D011804:Quinolines; C522124:besifloxacin; D020928:Mitogen-Activated Protein Kinases; D000077266:Moxifloxacin