Occleston, Nicholas Laurence; (1996) Cellular and molecular basis of wound healing: Effects of growth arrest induced by antimetabolites on ocular fibroblast behaviour. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The wound healing response, in which the fibroblast is a key player, is a major cause of clinical morbidity throughout the human body. This response is of particular importance in the eye, as it plays a role in the pathogenesis or failure of treatment of many visually disabling or blinding conditions in the world today. An example of this is the failure of the surgical treatment of glaucoma due to excessive scarring. Previous studies have shown that single exposures to antimetabolites result in the long term growth arrest of ocular fibroblasts in vitro, and reduced scarring in vivo following glaucoma surgery. The overall effects of these treatments on fibroblast wound healing behaviour are not known. Additionally, growth arrested fibroblast feeder layers have been routinely used to serially cultivate keratinocytes for over twenty years, the mechanisms underlying this support of keratinocyte growth being unclear. This thesis investigated the effects of single exposures to antimetabolites on molecular and cellular aspects of ocular fibroblast wound healing behaviour. Growth arrested ocular fibroblasts were found to produce a number of regulatory molecules both at the message and protein levels using a quantitative reverse transcriptase polymerase chain reaction technique and enzyme linked immunosorbent assays. The molecules produced included: growth factors (transforming growth factor beta-1 and basic fibroblast growth factor); growth factor receptors (transforming growth factor beta type II receptor, fibroblast growth factor receptor and epidermal growth factor receptor); and extracellular matrix molecules (collagen type I, collagen type III and fibronectin) up to 48 days post-growth arrest. Fibroblasts were also found to migrate and contract collagen following growth arrest. Additionally, matrix metalloproteinases were identified as a novel, essential and possibly ubiquitous component of fibroblast-mediated collagen contraction. The experiments in this thesis have led to an increased understanding of the biology of growth arrest in vitro, and may explain how growth arrested fibroblasts support keratinocyte growth in vitro. Additionally, these findings may have clinical implications with respect to the modulation of scarring in vivo. Finally, the identification of a novel and potentially ubiquitous mechanism of collagen contraction may lead to the development of new anti-scarring strategies.

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