Investigating the role of the calcium-sensing receptor (CaSR) in lung remodelling

Previous studies have demonstrated an extracellular cation-sensor, the calcium-sensing receptor (CaSR), plays a central role in lung development, tissue morphogenesis and inflammation in the lung as well as tissue remodelling in other organs. However, the role of the CaSR in lung remodelling is currently unknown. During my PhD I have 1) developed novel methods for determining airway and interstitial lung remodelling in vivo; 2) investigated the role of the CaSR in age-related lung remodelling in vivo using aging mice with targeted CaSR-deletion from SM22α-positive cells; 3) investigated the role of the CaSR in pre-clinical models of IgE/Th2 asthma, alarmin-driven asthma and COPD-like neutrophilic exacerbation in the presence or absence of inhaled negative allosteric modulators (NAM) of the CaSR; and 4) investigated the role of the CaSR in cell signalling and remodelling processes in vitro using human lung fibroblasts exposed to a remodelling mediator, TGF-β, in the presence of absence of NAM treatment. The key findings of this thesis are: 1. The CaSR in SM22α-positive cells is central to age-related airway and interstitial ECM remodelling. 2. Inhaled NAM treatment ameliorates airway remodelling, particularly goblet cell metaplasia, in models of IgE/Th2 asthma and interstitial remodelling and/or inflammation in alarmin-driven asthma. 3. The CaSR is expressed in human lung fibroblasts and NAM treatment ameliorates TGF-β1-induced upregulation of CaSR and associated G-protein expression; non-canonical TGF-β signalling; and cellular processes implicated in lung remodelling, including cell-adhesion, apoptosis, secretion, growth, proliferation and extracellular matrix (ECM) remodelling. Together these findings strongly indicate that the CaSR plays a central role in physiological and pathophysiological lung remodelling