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Title: Development of a primary airway epithelial cell culture model and explanted tissue archive to study the role of neutrophilic inflammation and airway remodelling in cystic fibrosis lung disease
Authors: Brodlie, Malcolm James
Issue Date: 2011
Publisher: Newcastle University
Abstract: Cystic fibrosis (CF) is the most common inherited life-limiting condition in the United Kingdom. Lung disease, involving retention of mucopurulent secretions, neutrophilic inflammation and endobronchial infection is the major cause of mortality. CF is caused by variants in the CF-transmembrane conductance regulator gene, however the exact pathogenesis of lung disease is not fully understood. Valid experimental models are therefore critical to advance research. I describe the establishment of a successful method to culture primary bronchial epithelial cells (PBECs) from explanted CF lungs removed at transplantation. This technique has yielded an important resource to further study the pathogenesis of CF lung disease. The cytokine interleukin-17 orchestrates the activity of neutrophils and increases mucin gene expression in BECs – two key features of CF lung disease. I demonstrate that interleukin-17 is increased in the airway of people with advanced CF lung disease. I also show evidence suggesting that neutrophils themselves may be a source of interleukin-17 potentially leading to an ever-increasing spiral of inflammation. In a CF mouse model ceramide accumulates in BECs and is associated with neutrophilic inflammation and susceptibility to Pseudomonas aeruginosa infection. Furthermore, amitriptyline treatment normalised ceramide, inflammation and susceptibility to infection. The role of ceramide is a complex area, however, with a divergence of opinion in the literature and paucity of human data. I demonstrate using immunohistochemistry that ceramide is increased in the lower airway epithelium in advanced CF lung disease compared to pulmonary hypertension and unused lung donors and is correlated with neutrophilic inflammation and increased in those colonised with Pseudomonas aeruginosa. Ceramide species C16:0, C18:0 and C20:0 but not C22:0 are increased in lung homogenates of CF lungs compared to pulmonary hypertension measured using the independent technique of high performance liquid chromatographymass spectrometry. Both interleukin-17 and ceramide represent important topics for further translational CF lung disease research.
Description: PhD Thesis
Appears in Collections:Institute of Cellular Medicine

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