De Giorgio-Miller, Alexander Michael; (2002) The role of fibrin in skin fibrosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Patients with chronic venous insufficiency develop characteristic skin changes on the lower leg, known as lipodermatosclerosis. There is limited information regarding the cellular and molecular mechanisms that regulate the development of this fibrotic condition even though it often proceeds to leg ulceration. Chronic venous hypertension causes extravasation of plasma fibrinogen from the cutaneous vasculature resulting in extensive fibrin deposition. Patients with lipodermatosclerosis show reduced fibrinolytic activity leading to a persistence of fibrin in the skin. Although fibrin deposition is an important part of normal tissue repair, it is also associated with many fibrotic conditions. This thesis addresses the hypothesis that reduced fibrinolysis and the persistence of fibrin matrix are associated with enhanced accumulation of collagen by dermal fibroblasts, resulting in the development of fibrotic skin disorders such as lipodermatosclerosis. The aims of this thesis were to characterise the fibrotic skin changes related to lipodermatosclerosis and to investigate the role of fibrin matrix on procollagen production by dermal fibroblasts in normal and reduced fibrinolytic conditions. Skin affected by lipodermatosclerosis showed extensive fibrin deposition and increased procollagen gene expression in the dermal and subcutaneous layers compared with control skin. The role of fibrin on procollagen production by dermal fibroblasts was assessed in vitro and in vivo using novel strategies. Procollagen production by dermal fibroblasts was significantly increased when grown in fibrin gels compared with monolayer cultures. Furthermore, multiple, combined subcutaneous injections of fibrinogen and thrombin in Balb-c mice resulted in a significantly increased level of collagen deposition, compared with PBS-treated or untreated control skin. Under reduced fibrinolytic conditions, dermal fibroblasts grown in fibrin gels produced a further significantly increased level of procollagen compared with control cultures. This was confirmed in vivo, as multiple subcutaneous injections of fibrinogen and thrombin in tissue plasminogen activator-deficient mice resulted in a significantly increased level of collagen deposition compared with the skin of wild-type mice. Enhanced collagen accumulation was found to be due to increased procollagen gene expression and decreased collagen degradation through reduced activation of matrix metalloproteases. In conclusion, this thesis has shown that reduced fibrinolysis and the persistence of a fibrin matrix results in an excessive accumulation of collagen in both in vitro and in vivo systems. These events may occur during the development of LDS as well as other fibrotic disorders where extensive fibrin matrix deposition is a key feature.

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