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Title: An investigation of aspects of normal and abnormal wound resolution
Author: Brown, Nicola Jane
ISNI:       0000 0001 3498 822X
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 1998
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Keloids are classically regarded as scars that `outgrow the boundary of the original injury'. Ambiguous data concerning certain characteristics of keloid fibroblasts (such as proliferation rates and collagen production), however, have served only to confuse researchersT. he lack of an in vivo model and of detailed clinical accounts are added problems. In this study, a murine granulomatous tissue resolution model was used to investigate the profile of a number of cytokines suspectedto be involved in the aetiology of keloids. The results obtained from these experiments were then extrapolated to clarify the observations made in keloids. The results of these extrapolated comparisons revealed elevated levels of interleukin (IL)-4, IL-10, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and transforming growth factor beta (TGF)-ß in keloid samples and decreasedle vels of interferon (IFN)-y and IL-2. The murine model was also used to investigate the implications of the low levels of IFN-y known to be present in the serum of keloid patients and shown here to be present in clinical samples. The results were found to support the hypothesis that the addition of IFN-y reduces the fibrosis so typical of keloids by rectifying the abnormality of the absence of IFNy content. The same model was used to provide evidence that the inhibition of VEGF activity in resolving wounds may halt the development of keloid lesions. The immunohistochemical profiles of cellular proliferation, apoptosis, lymphokines and cytokines for resolution (and, to a certain extent, the model) were used to compare with the abnormally resolved wounds which were available as clinical samples. Immunohistochemistry was also employed to describe the cellular nature of the clinical tissue samples in detail and to facilitate the development of the following hypothesis for keloid formation and propagation: lymphocytes migrate to the site of an (alleged) endogenous antigen present in the skin. The nature of these lymphocytes is characteristic of a type 2 immune response, they produce IL-4 (and IL-10) which in turn inhibit(s) the production of IFN-y and IL-2. Aside from this immunological response, wound resolution is taking place: fibroblasts are producing PDGF, EGF and TGF-ß to aid matrix remodelling and collagen synthesis. The provisional matrix is being vascularised by the action of VEGF, to allow the replenishment of nutrients; regression of blood vessels occurs through the action of an apoptosis-dependent mechanism, as does the 'normalisation' of fibroblastic populations. The keloid scar continues to grow after the cessation of resolution because the immune response to the 'endogenous' antigen continues and the lymphocytes continue to migrate to the site of the wound and continue to stimulate fibroblast proliferation and collagen production through the release of IL-4.
Supervisor: Not available Sponsor: ONO Pharmaceuticals, Japan
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Experimental Pathology ; Wound resolution ; Keloids