The process of soft tissue injury repair at the cellular lew I can be decomposed into three phases: acute inflammation including coagulation, proliferation and remodelling. While the later phases are well understood the early phase is less so. We produce a series of new mathematical models for the early phases coagulation and inflammation. The models produced are relevant not only to soft tissue injury repair but also to the many disease states in which coagulation and inflammation play a role. The coagulation cascade and the subsequent formation of the enzyme thrombin are central to the creation of blood clots. By focusing on a subset of reactions that occur within the coagulation cascade, we develop a model that exhibits a rich asymptotic structure. Using singular perturbation theory we produce a sequence of simpler time-dependent model which enable us to elucidate the physical mechanisms that underlie the cascade and the formation of thrombin. There is considerable interest in identifying new therapeutic targets within the coagulation cascade, as current drugs for treating pathological coagulation (thrombosis) target multiple factors and cause the unwelcome side effect of excessive bleeding. Factor XI is thought to be a potential therapeutic target, as it is implicated in pathological coagulation but not in haemostasis (the stopping of bleeding), but its mechanism of activation is controversial. By extending our previous model of the coagulation cascade to include the whole cascade (albeit in a simplistic way) we use numerical methods to simulate experimental data of the coagulation cascade under normal as well as specific-factor-deficient conditions. We then provide simulations supporting the hypothesis that thrombin activates factor XI. The interest in inflammation is now increasing due to it being implicated in such diverse conditions as Alzmeimer's disease, cancer and heart disease. Inflammation can either resolve or settle into a self-perpetuating condition which in the context of soft tissue repair is termed chronic inflammation. Inflammation has traditionally been thought gradualIy to subside but new biological interest centres on the anti-inflammatory processes (relating to macrophages) that are thought to promote resolution and the pro-inflammatory role that neutrophils can provide by causing damage to healthy tissue. We develop a new ordinary differential equation model of the inflammatory process that accounts for populations of neutrophils and macrophages. We use numerical techniques and bifurcation theory to characterise and elucidate the physiological mechanisms that are dominant during the inflammatory phase and the roles they play in the healing process. There is therapeutic interest in modifying the rate of neutrophil apoptosis but we find that increased apoptosis is dependent on macrophage removal to be anti-inflammatory. We develop a simplified version of the model of inflammation reducing a system of nine ordinary equations to six while retaining the physical processes of neutrophil apoptosis and macrophage driven anti-inflammatory mechanisms. The simplified model reproduces the key outcomes that we relate to resolution or chronic inflammation. We then present preliminary work on the inclusion of the spatial effects of chemotaxis and diffusion.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:588090 |
| Date | January 2012 |
| Creators | Dunster, Joanne L. |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/27797/ |
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