UBC Theses and Dissertations
The role of epithelial-fibroblast communication in asthma and chronic obstructive pulmonary disease Osei, Emmanuel Twumasi
Asthma and COPD are incurable chronic inflammatory diseases of the lung that involve inflammation and remodeling in the airways. An abnormal interaction between the airway epithelium and fibroblasts in the epithelial mesenchymal trophic unit (EMTU) has been suggested to be a possible disease mechanism in asthma and COPD. The airway epithelium forms the first line of defense in the airways while fibroblasts are the structural cells responsible for producing extracellular matrix (ECM) proteins and maintaining the structural integrity of the lung. In this thesis we developed a co-culture model to study the factors involved in airway epithelial cell and fibroblast interaction and how a dysregulated communication between these two cells contributes to asthma and COPD pathogenesis. We also used multiphoton imaging and 3-dimensional collagen contraction assays to assess the effect of abnormal ECM repair by airway fibroblasts, proposed to cause airway remodeling in asthma and COPD. We found in the co-culture model that the airway epithelium through the release of IL-1α controls the inflammatory and ECM remodeling phenotype of lung fibroblasts. Further, exposing airway epithelial cells to cigarette smoke, the major risk factor for COPD, caused a higher release of IL-1α which subsequently led to the release of higher levels of inflammatory mediators. Again, due to the presence of a single nucleotide polymorphism, rs2910164 (GG allele), COPD-derived lung fibroblasts from our co-culture had a lower induction of miRNA-146a-5p, an anti-inflammatory miRNA that regulates IL-1 signaling, compared to controls. Again, we found asthmatic-derived airway epithelial cells released higher levels of IL-1α and that IL-1 causes the release of inflammatory mediators, the down-regulation of ECM proteins in airway fibroblasts and affects their ability to organize gelatin into fibrillar collagen. In the airways of asthmatics patients, we found that there was disorganization of fibrillar collagen fibers in the lamina propria, due to a defect in the ability of asthmatic-derived airway fibroblasts to remodel collagen fibers compared to controls. Taken together our work sheds new light on how abnormal epithelial-fibroblast communication may contribute to the chronic inflammation and airway remodeling described in asthma and COPD, further it opens new avenues for therapeutic research.
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