Characterization of transforming growth factor-β1 in β2 adrenergic receptor dysfunction and signaling mechanisms in human airway smooth muscle

Underlying source(s) of airway smooth muscle hypercontractility and hyporesponsiveness to bronchodilatory therapy in the context of inflammatory diseases of the lung remain unclear. In asthma and chronic obstructive pulmonary disease (COPD), it is unclear if the airway dysfunction is due to intrinsic genetic or epigenetic contribution that precipitate increased basal tone and enhanced contractile responses, or attenuated bronchodilation capability of the airways. Airway smooth muscle (ASM) cells are primary cells modulating bronchomotor tone, but that alterations in the cells may be a primary contributor to airway dysfunction associated with asthma and COPD. Studies suggest that β-adrenergic receptor (β2AR) dysfunction in the inflammatory environment occurs via exposure to inflammatory cytokines including exposure to IL-1β, IL-13, TNFα, and TGF-β, and lipid mediators. The purpose of this thesis was to characterize β2AR dysfunction within the context of TGF-β1 exposure, as well as to characterize responsiveness to dexamethasone, a glucocorticoid. Modulation of gene expression, cyclic AMP (cAMP) levels, and myosin light chain (MLC) phosphorylation have been posited to play important roles in regulating both bronchoconstriction and bronchodilation in asthma. Furthermore, β2AR agonists (β2- agonists), and both direct and indirect signaling components downstream of the receptor, are effective treatments for asthma and other inflammatory conditions to induce relaxation of the airways. However, persistent usage of these therapeutics causes desensitization and downregulation of the receptor. Overall, the focus of this thesis is examining the efficacy of bronchodilators in the context of TGF-β1 exposure, as well as the effects of dexamethasone in modulating the effects of TGF-β1.M.S.Includes bibliographical reference