Delbert Richard Dorscheid
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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2019)
No abstract available.
Adjusting for amount of smoking, women have a 50% increased risk of COPD compared with men. It is not known what the anatomic basis/mechanism(s) of these sex-related differences in COPD might be. The main objective of this study is to characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodelling and emphysema in a murine model of COPD. We showed here for the first time that smoke-induced COPD in female compared to male mice have increased small airway remodelling, and may be biologically driven by estrogen through down-regulation of antioxidant defences and activation of TGFβ1 signalling, resulting in increased expression of collagen matrix in the airway walls. These effects can be ameliorated by ovariectomy before smoke exposure or use of the estrogen antagonist, tamoxifen, during smoke exposure, suggesting that estrogen is involved in this process. Using the flexiVent system to assess the functional relationship with the observed structural changes, we showed evidence of cigarette smoke-induced lung abnormalities. Tissue damping (G), and complex input resistance of the respiratory system (Zrs) at low oscillating frequency were elevated in female compared to male mice after smoke exposure, and this effect was attenuated after ovariectomy. Quasistatic pressure-volume curve revealed a decrease in inspiratory capacity in female mice but not in male mice after smoke exposure, and this effect was attenuated after ovariectomy. Chronic smoke exposure did not increase goblet cell expression in the distal airways of all groups, suggesting that the increase in distal airway resistance in smoke-exposed female mice is unlikely to be derived from luminal exudates.Finally, using a human bronchial epithelial cell culture model in air liquid interface, we showed that transfection with nuclear factor of activated T-cell (NFAT)c1 or NFATc2 siRNA blunted estrogen or progesterone-induced increase in MUC5AC mRNA expression, respectively.Collectively, our data showed that estrogen may be involved in the excess risk for small airways disease in a mouse model of COPD, and MUC5AC expression is regulated by estrogen and progesterone via NFATc1 and NFATc2 in normal human bronchial epithelial cells.
Epithelial cells line the conducting airways of the lung and act as a protective barrier tothe daily challenges such as viral particles, pollutants and allergens. As a result, theepithelium is routinely damaged which is followed by rapid and effective repair. Thishighlights the importance of understanding the mechanisms involved in normal airwayepithelial repair such that diseases like asthma can be better understood. Our laboratoryhas highlighted the role of carbohydrates structural modification as essential in mediatingepithelial repair. The identity of the functional carbohydrate structures and theirassociated protein(s) remain unknown. The principal goals of my research were to take aglycomics based approach to identify mediators of airway epithelial repair. This work isbroken down into three sections where we (1) investigated the identity of the Cicerarietinum agglutinin (CPA) associated protein ligand, (2) investigated the identity of theAllomyrina dichotoma agglutinin (AlloA) associated protein ligand on the surface ofairway epithelial cells, and (3) began to characterize their potential role in airwayepithelial wound repair. We have identified two novel carbohydrate epitopes using thelectins CPA and AlloA and their associated proteins as candidates that participate inairway epithelial wound repair. Using CPA to precipitate lectin associated protein(s),Annexin II (AII) was isolated and enriched when precipitated from wounded monolayersof airway epithelial cells. The expression of AII and its presentation on the surface ofepithelial cells closely resembled our initial cell surface CPA staining. Simultaneouswork identified fetuin as an AlloA associated protein. Fetuin is a serum glycoproteinpreviously shown to bind AII on the surface of epithelial cells. Our subsequent work focused on the role of AII, specifically cell surface AII, in this process. As a receptor fortenascin-C, we followed wound repair activation following AII/tenascin-C binding in ourmodel of repair. We found that AII facilitated tenascin-C binding which stimulatedepithelial cell wound closure rates. This study is the first to identify AII as a mediator ofepithelial wound repair and identify the potential role of cell surface AII as a receptor fortenascin-C binding.