Corneal fibrotic wound repair

Corneal scarring following trauma, infections, or refractive surgery can produce blinding complications, but current treatment options are limited and outcomes are typically poor. Thus, there is a need for new treatments that will prevent or reduce corneal scarring with minimal side effects. To accomplish this, however, the basic processes that regulate corneal scarring need to be understood more thoroughly. Corneal wound healing is an exceedingly complex process that is coordinated and regulated in large part by autocrine and paracrine interactions of growth factors, cytokines, and proteases produced by epithelial cells, fibroblasts, and lacrimal gland cells. Also important are the interactions of corneal epithelial cells with components of the stromal extracellular matrix. Lacking from the understanding of corneal wound healing, however, has been a simultaneous spatial localisation of growth factors, corneal cells, and extracellular matrix proteins in healing corneal wounds. In this issue of the BJO (p 000) Ivarsen and colleagues address this knowledge gap by combining laser confocal microscopy and immunohistochemistry to create a three dimensional relation of these components during healing of rabbit LASIK corneal wounds. They report binding of leucocytes to conjunctival vessels and their migration into the cornea at day 1 following surgery. From day 4, elongated fibroblasts migrated from the periphery to align in a circumferential band approximately 250 μm wide next to the flap edge. The lateral extensions of this stromal band were limited to the incised area in the epithelial basement membrane. Immunostaining for TGF-β isoforms, TGF-β receptor II, and CTGF, showed they were expressed in the band from day 2. Myofibroblasts were identified at week 3 in a fibrotic matrix. With time, the peripheral circumferential band became narrower and showed an increased organisation with a gradual decline in reflectivity. At all times, keratocytes within and below the flap remained quiescent and only minimal fibrosis developed at the interface. These data extend the results reported previously,¹ and show for the first time that the major region of reflectivity (haze) in LASIK corneal wounds was restricted to a narrow band peripheral to the corneal flap edge, and most importantly, was co-localised with areas of elevated growth factors (TGF-β and CTGF) and with gaps in the epithelial cell basement membrane. Furthermore, the fibrotic wound healing at the LASIK flap margin is associated with myofibroblast transformation and wound contraction and appears to involve TGF-β and CTGF signalling pathways. Extrapolation of these results to healing of other types of corneal wounds implies that it may be possible to regulate corneal scarring by controlling the activity of these key genes at the site where epithelial cells interact with the stromal matrix. This sets the stage for future research evaluating approaches to regulate activity of target genes, including neutralising antibodies, antisense oligonucleotides, RNAi, or ribozymes. If successful, it may be possible one day to control corneal scarring using gene specific approaches.