The cytotoxicity and mechanism of fluoroquinolones on human corneal epithelial cells
Date Issued
2010
Date
2010
Author(s)
Tsai, Tzu-Yun
Abstract
Bacterial keratitis is a common ocular infection and a leading cause of ocular morbidity and blindness worldwide. However, according to our previous report regarding 10-year experience of microbial keratitis at the National Taiwan University Hospital, contact lens-related pseudomonal keratitis was the most common form of microbial keratitis in Taiwan. Effective topical therapy, using fortified antimicrobials or monotherapy commercial ophthalmic preparation selected based on the results of diagnostic corneal smears and cultures, is essential for management of patients with microbial keratitis. Above seventy percent of offending eyes could be successfully treated topically.
Fluoroquinolones (FQs) were derived from the non-fluorinated drug nalidixic acid, which was developed during the early 1960s. FQs are potent antimicrobial agents with a broad antibacterial spectrum and are suitable for monotherapy. They act rapidly by inhibiting bacterial DNA gyrase and topoisomerase IV, which are selective for bacterial cells. FQs are nowadays widely used in clinical practice to treat ocular infection, with intravitreal topical and systemic routes of administration. In fact, several investigators have reported bacterial keratitis resistant to FQs and delays in the healing rate and corneal perforation after administration of FQs preparation. Moreover, many eye drops contain preservatives known to cause severe side effects to the ocular surface. Benzalkonium chloride (BAC) is the preservative currently used the most, and many in vivo and in vitro studies have showed its toxicity on corneal epithelial cells.
Base on our preliminary report regarding to the toxicity toward the corneal epithelial cells between different FQs, the cytotoxicity observed with FQ eye drops seems to be caused mainly by the preservative. However, we found that the new generation of FQs, moxifloxacin, no less cytotoxicity towards corneal epithelial cells than the old generation preparations. Therefore, the purpose of this study is to compare and identify the specific types of cytotoxic damage that might occur with exposure to various FQs and BAC.
Besides, fluoroquinolones antimicrobial agents are widely used in clinical practice as broad-spectrum antibiotics with good bioavailability. However, they have been reported to induce tendinopathy, and the main target is Achilles tendon rupture. All the studies began during 2000 and showed that tendinitis and tendon rupture during treatment with fluoroquinolone antibiotics is thought to be mediated via oxidative stress and mitochondrial damage. Some innovative studies showed fluoroquinolones could modulate cycle cell progression and apoptosis in cancer cells or enhance the function of chemotherapeutic agents in cytotoxicity in tumor-derived cells. Therefore, we want to identify the mechanism of cytotoxicity of fluoroquinolones on human corneal epithelial cell which had not been investigated before in literatures.
Our study showed that the main source of cytotoxicity from commercial fluoroquinolone ophthalmic solutions came from preservatives, benzalkonium chloride. The mechanism is through increased the level of reactive oxygen species, and then induces cell apoptosis. However, the latest four generation of fluoroquinolones, moxifloxacin, also showed obvious cytotoxicity. Significant cell toxicity was found in the moxifloxacin group after 3 hours incubation than benzalkonium chloride, which induced oxidative stress and cell apoptosis in early stage. The limitation of our study was the in vivo setting and the use of immortalized human corneal epithelial cell line instead of primary cultures of corneal epithelial cells. The preliminary results of the our study provided us a new way and more information for further new methods in studying the mechanism of cytotoxicity of fluoroquinolones.
Subjects
Fluoroquinolone
corneal epithelial cell
cytotoxicity
apoptosis
reactive oxygen species
SDGs
Type
thesis
File(s)![Thumbnail Image]()
Loading...
Name
ntu-99-P97421014-1.pdf
Size
23.32 KB
Format
Adobe PDF
Checksum
(MD5):26f578b69888dac32a8845438189c6d2