Wong, Tina Tzee Ling; (2004) The role of matrix metalloproteinases in conjunctival wound healing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Matrix metalloproteinases (MMPs) are a family of enzymes that are important for many key cellular processes. Dysregulated MMP activity has been implicated in aberrant wound healing, excessive scarring and fibrosis. Scarring in the subconjunctival tissue is the major cause of surgical failure in the treatment for glaucoma. The use of antimetabolites, 5-fluorouracil and mitomycin-C has revolutionised glaucoma surgery in patients at high risk of excess scarring. Their use however, may lead to sight-threatening complications as a result of extensive cell death and apoptosis. Tenon's fibroblasts are central to the wound healing process following glaucoma filtration surgery. Recent evidence suggests that growth-arrested fibroblasts are capable of performing cellular functions such as MMP activity, important for wound healing giving rise to a persistent healing response. The experiments outlined in the thesis, both in vitro and in vivo provide evidence that inhibiting MMP activity effectively modifies the cellular events that lead to scarring following surgery. Cell culture studies using fibroblast seeded 3-D collagen gels, a model employed to investigate the mechanisms of wound contraction demonstrated a notable reduction in gel contraction in the presence of Ilomastat, a broad-spectrum MMP inhibitor. MMP expression, protein production and activity were all profoundly inhibited, with no evidence of cellular toxicity. Furthermore, Ilomastat resulted in a reduction in total scar formation following experimental glaucoma filtration surgery in an aggressive model of subconjunctival scarring. In addition, there were notably fewer myofibroblasts at the wound site. Myofirboblasts are specialised cells that are involved in wound contraction and fibrosis. The use of post-operative Ilomastat prolonged conjuntival bleb survival and therefore surgical success compared to vehicle. This thesis increases our understanding of the effect of MMPs on Tenon's fibroblast activity during wound healing, and introduces a novel approach to modulating the scarring response by MMP inhibition.

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