Veterinary Science Collected Works - Theses
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ItemCharacterisation of the Molecular, and Lung Tissue, Pathogenesis in a Sheep Model of Bleomycininduced Pulmonary Fibrosis( 2021)Idiopathic pulmonary fibrosis (IPF) is one of the most devastating respiratory diseases. It is most frequently diagnosed in older people who are above 55 years of age. It is a progressive fibrotic process in the lungs, in which the mean survival time lies between 3-5 years after diagnosis. The aetiology of IPF is not known, and the disease mechanism is not well understood. The development of animal models for human pulmonary fibrosis are useful for gaining knowledge of physiological and pathological disease mechanisms. They are often used to identify potential therapeutic targets that can be exploited to treat the disease. Establishing a more accurate and representative animal model will provide a more complete understanding of the lung fibrosis and how it relates to the human IPF. Our laboratory has developed a novel bleomycin sheep model for pulmonary fibrosis that shares many of the characteristic features of IPF pathology in humans. The model involves the local bronchoscopic instillation of two doses of bleomycin into specific lung segments of sheep and then assessing the localized bleomycin-induced pathology and segmental lung function. We have examined several aspects of pathology in the model, such as: the structural and functional correlations; the longevity of the pathology; and the microvascular remodelling in the parenchymal fibrosis. It has also been utilized for evaluation of therapeutic effects of some novel drug targets for lung fibrosis. A detailed characterization of the molecular and inflammatory aspects of bleomycin-induced lung fibrosis in sheep has not been studied before. Chapter two of this thesis reports on the histopathology and inflammation components of bleomycin-induced lung fibrosis; in the sheep model and the more frequently used mouse model. I found the unique presence of tertiary lymphoid follicles in bleomycin-treated sheep lung tissue parenchyma which share similar characteristic features of the tertiary lymphoid aggregates described in IPF patients. Importantly, these well- organized tertiary lymphoid follicles were absent in mouse lung parenchyma following bleomycin exposure. I also discovered presence of higher fibrotic fractions and fibrotic scores in bleomycin-injured sheep lungs compared to mouse lungs. In addition, increased infiltration of T and B cells in lungs post bleomycin were examined in sheep. Conversely, the infiltration of these cells declined in the mouse model by 28 days after the first bleomycin dose. In chapter three, I studied endoplasmic reticulum stress (ER stress) and apoptosis in type II alveolar epithelial cells (AECs) and macrophages, which have been identified as key drivers in IPF. The findings showed increased levels of ER- stress and apoptosis in type II AECs and macrophages in sheep lung parenchyma after bleomycin damage. Moreover, the elevated levels of ER stress and apoptosis are alleviated by in vivo blockade of the KCa3.1 ion channel in the sheep model for pulmonary fibrosis. In chapter four, I studied the molecular pathogenesis of the disease by evaluating phylogenetically conserved small non-coding RNA (miRNA) expression profiles in the sheep model of lung fibrosis. I found that 49 miRNAs were significantly expressed in sheep lung tissues due to bleomycin injury, which includes the most common miRNA families that are closely related to IPF. Importantly, 18 miRNAs were significantly expressed only in the sheep model and IPF patients, while 17 miRNAs were commonly expressed in sheep and mouse models, and IPF patients, that are yet to be studied. In addition, pathway enrichment analysis of 49 differentially expressed miRNAs showed a significant enrichment of the pathways that are closely associated with the IPF pathogenesis. Overall, the sheep model presented in this thesis potentially serves as a valuable bridging model for lung fibrosis, as it will contribute to the increased translational value of animal trials to predict if treatments can be successful in clinical settings. While I have found many exciting findings with respect to molecular and pathological alterations that occur in injured sheep lungs, and potential drug treatments that can be exploited to ameliorate the disease, there is still much to learn about this disease and its potential therapeutic treatments. The insights of this thesis create exciting new avenues for basic and clinical research.