Abstract
Glaucoma is a progressive optic neuropathy, which, if left untreated, leads to blindness. The most common and most modifiable risk factor in glaucoma is elevated intraocular pressure (IOP), which can be managed surgically by filtration surgery. The postoperative subconjunctival scarring response, however, remains the major obstacle to achieving long-term surgical success. Antiproliferatives such as mitomycin C are commonly used to prevent postoperative scarring. Efficacy of these agents has been tested extensively on monkey and rabbit models of glaucoma filtration surgery. As these models have inherent limitations, we have developed a model of glaucoma filtration surgery in the mouse. We show, for the first time, that the mouse model typically scarred within 14 d, but when augmented with mitomycin C, more animals maintained lower intraocular pressures for a longer period of time concomitant with prolonged bleb survival to beyond 28 d. The morphology of the blebs following mitomycin C treatment also resembled well-documented clinical observations, thus confirming the validity and clinical relevance of this model. We demonstrate that the antiscarring response to mitomycin C is likely to be due to its effects on conjunctival fibroblast proliferation, apoptosis and collagen deposition and the suppression of inflammation. Indeed, we verified some of these properties on mouse conjunctival fibroblasts cultured in vitro. These data support the suitability of this mouse model for studying the wound healing response in glaucoma filtration surgery, and as a potentially useful tool for the in vivo evaluation of antifibrotic therapeutics in the eye.
Highlights
The most common reason for failure in glaucoma filtration surgery (GFS) is scarring and fibrosis
Errors arising from variability in individual baselines are eliminated and the presented data is reflective of the intraocular pressure (IOP) alteration from the baseline that is characteristic of each animal as a result of the surgery
The mean % IOP of the operated versus the paired unoperated eye in the control animals reduced from 99% ± 14% on day 7 to 65% ± 20% on day 14, and rose back up to 84% ± 28% on day 21 and 85% ± 14% on day 28. This profile suggests that a reduction in IOP in the operated eyes is maximal in the second week after surgery with a return to baseline thereafter
Summary
The most common reason for failure in glaucoma filtration surgery (GFS) is scarring and fibrosis. Pharmacological approaches, such as the use of antifibrotic agents, have been attempted in experimental and clinical studies. MMC inhibits RNA and protein synthesis and it interacts with molecular oxygen, which in turn generates free radical damage to DNA and protein [6]. These nonspecific effects are, associated with severe and often blinding complications that include hypotonous maculopathy [7], thin, cystic and leaky blebs that are prone to infections, and bleb-related endophthalmitis [8,9]. GFS fails in a substantial number of high-risk eyes despite the use of these antiproliferative agents. The subject and understanding of the subconjunctival wound healing response is far from complete, and the quest to find a safer alternative and more specific antiscarring agent remains a top priority
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