Medicine (St Vincent's) - Theses
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ItemUnderstanding the effects of Radiotherapy and Surgical injury on Local immunity and Lymphatic Architecture and Function( 2019)This thesis aims to provide insight into the pathophysiological mechanisms behind two important clinical problems encountered in patients surviving oncological treatments: 1) Infections in previously radiated sites and 2) Lymphoedema that follows surgical injury to lymphatics or radiation of nodal basins (RTx). Both infection and lymphoedema have significant impact on patient morbidity and quality of life (QOL). Lymphoedema, in particular, has a significant “psychological and social health cost”, and is associated with significant costs in providing long term conservative management to prevent symptom progression and maintenance of QOL outcomes for patients. Therefore, socioeconomic implications of these diseases certainly warrants further investigation of the disease pathophysiology and potential avenues for prevention and treatment. This thesis provides a review of knowledge regarding normal structure, function and development of the lymphatic system, lymphangiogenesis and lymphatic remodelling and how these processes relate to lymphoedema. In addition, the processes of antigen capture and transfer to lymph nodes for presentation to lymphocytes will also be addressed as a background to understanding infections in radiated sites. Subsequently, methods to investigate lymphatic morphology utilising a murine Prox1-eGFP model and confocal imaging were detailed, as was an automated segmentation and analysis method to allow high throughput analysis of lymphatic vessel morphology following sugical or RTx injury in detail. Functional techniques utilised to assess antigen presentation and fluid transport to draining lymph nodes (dLNS)have also been described in detail. We have demonstrated in this thesis that RTx significantly reduces CCL21 expression by LECs and has subsequent effects on antigen presentation from RTx tissue. These results have implications for the increased rates of infection noted after RTx. Moreover, RTx significantly impairs early wound lymphangiogenesis in vivo. While surgical injury alone induces remodelling of both lymphatic capillaries and deep collecting lymphatic vessels (CLVs) distal to sites of surgical, combined injury with RTx and Surgery markedly exacerbates these remodelling responses. By using longer time points, we have also explored possible mechanisms behind chronic lymphoedema, and have demonstrated that RTx continues to impair wound lymphatic regeneration in combination with severe surgical injury. Furthermore, the distal limb appears to demonstrate evidence of progressive remodelling at late time points following lymphatic injury. As with earlier time points, combined injury with RTx and Surgery, appears to promote exacerbated secondary lymphangiogenesis in the distal limb at later time points. Potential molecular mechanisms behind these differences between the groups have then been subsequently explored through RNA sequencing and multiple PCR analyses of total tissue mRNA. The broader implications of the findings of this thesis to clinical lymphoedema and RTx are then addressed, as well as potential future directions for research to build on the findings of this thesis.