Blanc-Brude, Olivier Philippe; (2000) Role of coagulation cascade peptides in the regulation of fibroblast proliferation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Fibroblast proliferation and extracellular matrix deposition play a critical role in tissue repair and fibrosis. These functions are thought to be modulated by cytokines and growth factors, but these mechanisms are only partially understood. Tissue injury is associated with blood vessel disruption and the activation of coagulation cascade factors VII, IX, X and II (prothrombin) which result in the cleavage of blood fibrinogen into a haemostatic fibrin clot. In addition, increased levels of active coagulation cascade factors and fibrin deposition are associated with fibrotic diseases of the lung, liver, kidney, heart and vasculature. Recently, thrombin has been shown to promote fibroblast chemotaxis, proliferation and procollagen production in vitro and it has been proposed that it may contribute to tissue repair and fibrosis. Little is known about the cellular effects of the other coagulation cascade factors. The aim of this thesis is to study the effects of coagulation factors VIIa, IXa, Xa and fibrinogen cleavage products on fibroblast proliferation in vitro. This thesis shows that factor Xa is mitogenic for fibroblasts and the kinetics of this effect are equivalent to that of thrombin. Studies with specific inhibitors and antibodies demonstrated that this effect is dependent on its catalytic site, but independent of thrombin generation. Furthermore, this is mediated by platelet-derived growth factor production and autocrine stimulation similarly to thrombin. In contrast, factor IXa and fibrinogen-derived peptides have no effects, but factor VIIa and stimulates proliferation at high concentrations. Further studies of receptor expression, activation and intracellular calcium signalling showed that factor Xa stimulates proliferation via binding to effector cell-protease receptor-1 and the proteolytic activation of protease-activated receptor-1. In conclusion, this thesis demonstrated for the first time that coagulation cascade factors Xa and VIIa are mitogenic for fibroblasts, but not all peptides generated during blood coagulation. Furthermore, the mitogenic effect of factor Xa is mediated by a novel dual receptor system involving binding to effector-cell protease receptor-1 and activation of protease-activated receptor-1. These observations suggest that factor Xa may play a role in the regulation of fibroblast proliferation during normal tissue repair and fibrosis.

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