| Summary: | Cutaneous scars can be itchy, painful, disfiguring, psychologically damaging and even pathological. The myofibroblast cell phenotype, that differentiates from fibroblasts during healing, is central to the formation of normal and pathological scars. However, there remains no reliably effective therapy that prevents scarring. This research explores the efficacy and mechanism of action of a potential new antiscarring agent - insulin. Research at the RAFT Institute of Plastic Surgery has demonstrated that insulin inhibits differentiation of skin fibroblasts into myofibroblasts in both human and mouse cell cultures an in a murine in vivo wound healing model. The aim of this thesis is twofold. Firstly, to determine insulin's mechanism of action, in order to exploit it in future therapies. Several potential avenues were explored contemporaneously and included relatively inconclusive assessment of insulin's effects on EDA-fibronectin, FAK kinase, stress fibres and Thy-1. The most promising potential mechanism of insulin's action was its interaction with the cytokine transforming growth factor (3 (TGF-P) in particular the production of autocrine TGF-p and its activation. Human fibroblasts were cultured under various conditions and insulin's action investigated using techniques including immunohistochemistry, proliferation assays, multiplex and real time RT-PCR mRNA analysis, ELISA and SDS PAGE protein electrophoresis and Western blot analysis. The second aim is to test insulin's antiscarring efficacy in humans by means of a prospective randomised controlled trial. The procedure of bilateral breast reduction was chosen as it meant patients were administered both insulin and placebo treatments therefore allowing intrapatient controls. Scars were assessed 3 months after surgery using digital imaging, clinical scar scales, panel assessments, and multiphoton microscopy analysis of moulds of the scars. These studies have enabled progress in the development of a novel antiscarring therapy based on the antifibrotic properties of insulin.
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