Delbert Richard Dorscheid
Relevant Degree Programs
Affiliations to Research Centres, Institutes & Clusters
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - April 2022)
The normal airway epithelium serves as a physical and immune barrier against environmental challenges and effectively repairs frequent injuries. Asthma is characterized by excessive and persistent airway epithelial damage and shedding, and barrier dysfunction. Interleukin-13 (IL)-13 is known to be a key cytokine in driving inflammatory and remodelling processes in asthma. Our laboratory demonstrated that IL-13 is a critical mediator of normal airway epithelial repair. Actions of IL-13 are mediated by IL-13 receptor α1 (IL-13Rα1)/IL-4 receptor alpha subunit (IL-4Rα) and IL-13 receptor α2 (IL-13Rα2). The understanding of IL-13 biology was previously ligand centric and focused on airway remodeling effects induced by IL-13-IL-13Rα1/IL-4Rα signalling via STAT6 activation. IL-13Rα2 was viewed as a high-affinity decoy receptor with a soluble form that binds IL-13 and inhibits signalling. Here, we present an updated paradigm, where balanced expression and appropriate regulation of IL-13 receptor subunits play major roles in epithelial repair and inflammatory responses. Our goal was to characterize the critical role of IL-13 receptor subunits and subsequent signalling pathways in modulating normal repair processes and maintaining airway epithelial barrier function. Using in vitro models of airway epithelial wound repair, we identified a novel signalling role for IL-13Rα2 in contrast to its established action as a decoy receptor. IL-13 signals via IL-13Rα2/IL-4Rα subunit to induce heparin-binding EGF-like factor (HB-EGF)-dependent activation of epidermal growth factor receptor (EGFR) and subsequent repair. IL-13 receptor subunit expression is dynamically altered in response to injury, particularly membranous IL-13Rα2 and IL-4Rα subunit positive airway epithelial cells (AEC) and colocalization of IL-13Rα2 and IL-4Rα subunit in AEC are both upregulated post-mechanical wounding. We demonstrated that IL-13Rα1 play a complex regulatory role in IL-13-IL-13Rα2 downstream signalling pathways and anti-inflammatory responses. In donor lung tissue, the airway epithelium of asthmatics expressed significantly decreased levels of IL-13Rα2 and increased levels of IL-13Rα1 compared with non-asthmatics. Dysregulated expression of IL-13 receptor subunits in airways of asthmatics may contribute to the epithelial barrier dysfunction observed in asthma. IL-13 receptor biology expanded by our work will aid in the development of novel therapeutics and relevant phenotyping assays for existing and novel therapies targeting the IL-13 and IL-4 pathways.
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.
No abstract available.
Master's Student Supervision (2010 - 2021)
Long-acting β2-agonists (LABAs) are a staple of Chronic Obstructive Pulmonary Disease (COPD) maintenance treatment frequently prescribed to patients for prolonged bronchodilation. Recent studies have suggested that they may also be anti-inflammatory, as demonstrated by lowered neutrophil infiltration and lower mucus secretion. The mechanism of action behind these effects are unknown and further study is needed to elucidate the pathways involved. The purpose of this project was to study the effect of the LABA olodaterol on an in vitro model of the airway epithelium in response to an inflammatory stimulus. Primary airway epithelial cells derived from COPD and control non-COPD patient bronchial brushings were grown into air-liquid interface (ALI) cultures. Cells underwent priming with olodaterol in addition to respiratory syncytial virus (RSV) infection. Culture media was quantified for interleukin-8 (IL-8) secretion via ELISA. Whole cultures underwent immunohistochemistry for quantification of Muc5AC staining, an airway mucin protein. The 1HAEo- and the NCI-H292 cell lines were used to model the bronchial epithelium. Olodaterol was used to pre-treat both cell lines, after which either RSV or lipopolysaccharide (LPS) was added as an inflammatory stimulus and the IL-8 content was measured. Protein lysates were characterized using western blotting for the β2-adrenergic receptor (β2AR), the binding receptor for LABAs. siRNA was used to silence the β2AR. RT-qPCR was used to quantify the knockdown efficiency.ALI cultures showed that COPD subjects secreted higher baseline IL-8 levels than non-COPD controls, indicating that COPD subjects have an altered inflammatory phenotype. When both COPD and non-COPD ALIs were treated with olodaterol and RSV, olodaterol attenuated RSV-induced secretion of IL-8 and Muc5AC in both subject groups. In both 1HAEo- and NCI-H292 cells, RSV and LPS were able to stimulate high IL-8 secretion that was inhibited by treatment with olodaterol. siRNA gene silencing of β2AR in NCI-H292 cells negated olodaterol-mediated attenuation of LPS and RSV-induced IL-8 secretion, suggesting that the anti-inflammatory effect of olodaterol proceeds through the canonical binding receptor. LABAs such as olodaterol have clear anti-inflammatory effects in vitro and may hold clinical relevance. Further studies are needed to determine if these effects have a significant impact on patient therapy.