The Science of Glaucoma Surgery -Filtration Surgery and the Role of Cytokines

Glaucoma surgery is classified into a number of areas: intra-ocular drainage, filtration surgery and cyclo-coagulation. Although filtration surgery is the most effective way to lower intraocular pressure (IOP), no surgical technique manages to result in fulfills complete efficacy and safety. Trabeculectomy, one type of filtration surgery, is a common surgical procedure for glaucoma. Though trabeculectomy is fairly effective in lowering intraocular pressure, it is not rare that refractive errors remain or the patients suffer from severe surgical complications. Thus, surgical results of glaucoma surgery need to be improved. In this review, I explain the work we have done to address this issue, and discuss our results and novel trials. Our clinical studies clarified that cataract surgery affects the results of trabeculectomy to some extent. Additionally, previous vitrectomy, previous glaucoma surgery, uveitic glaucoma, neovascular glaucoma and secondary glaucoma associated with family amyloid polyneuropathy were identified as prognostic factors influencing the results of trabeculectomy. These factors may change the intraocular environment, and thereby affect wound healing following trabeculectomy, resulting in poor IOP control. Focusing on the changes in the intraocular environment caused by background factors, we examined cytokine levels in the aqueous humor. In pseudophakic eyes, even more than a year following post-phacoemulsification, the levels of proinflammatory cytokines, such as interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1 were elevated in the aqueous humor. These cytokines have positive correlations, and remain elevated in eyes with uveitic glaucoma or neovascular glaucoma, suggesting that they exercise a combined impact on wound healing. Of those, MCP-1 in paticular had significant effect on the results of trabeculectomy. To evaluate the effects of the changes in intraocular environment on the filtering bleb after trabeculectomy, we quantitatively assessed the bleb using three-dimensional anterior OCT (3D AS-OCT). Three-dimensional imaging identified the filtration opening on the edge of the scleral flap as an aqueous route after trabeculectomy, and its function was confirmed during bleb revision surgery. Subsequent prospective study using 3D AS-OCT clarified that the filtration openings tended to close time-dependently, affecting future IOP control, and the width of the filtration openings was correlated with the level of aqueous MCP-1. To elucidate wound-healing mechanisms after trabeculectomy at a cellular level, we conducted cell biological experiments using macrophages and conjunctival fibroblasts. It is known that trans-differentiation of fibroblasts into myofibroblasts, which was induced by macrophages and other cells, is a key for the progression of wound healing process. The trans-differentiation of fibroblasts was suppressed by either ROCK inhibitors or epigenetic drugs. Using in vivo imaging with a two-photon microscope, we found that either ocular surgery or MCP-1 treatment activated subconjunctival inflammatory cells. From the viewpoint of rebalancing the pathological shift of intraocular environment, it is suggested that anti-MCP-1 therapy and CCR2 inhibitors could be novel clues assisting in the improvement of surgical results of glaucoma surgery.