The Calcium-Sensing Receptor (CaSR) as a potential mediator of pollution-induced airway cell responses

Mansfield, Bethan 2022. The Calcium-Sensing Receptor (CaSR) as a potential mediator of pollution-induced airway cell responses. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Exposure to ambient air pollution causes detrimental health effects and can sometimes be fatal, especially for those with lung diseases, such as asthma. Particulate matter (PM) forms a major component of ambient air pollution, drives acute exacerbations (worsening) of asthma symptoms, however, the cellular mechanisms underlying PM-induced asthma exacerbations are so far unclear. The extracellular calcium-sensing receptor (CaSR) has been previously implicated in the development of asthma-like features in a range of in vivo models of asthma. Importantly, a negative allosteric modulator at the CaSR (CaSR NAM) reduces asthma-like features in these models. However, whether the CaSR plays a role in PM-induced airway cell responses was unclear. Therefore, during my thesis I investigated the role of the CaSR in PM-induced functions of airway and blood derived structural and immune cells. My principal discoveries are: 1. PM directly activates the CaSR in human embryonic kidney 293 cells (HEK293) which stably express the human CaSR (HEK-CaSR) cells, by increasing intracellular Ca2+, an effect which can be abolished by co-treatment with NAM and that is not observed in control, vector-transfected (HEK-0) cells, which lack the CaSR 2. The CaSR is expressed at the protein level in airway epithelial cells and lung-and blood-derived immune cells, involved in sensing and responding to inhaled PM, and in the pathogenesis of lung diseases which are exacerbated by exposure to PM 3. The CaSR plays a key role in PM- and pro-inflammatory cytokine-induced maturation of dendritic cells (DC), and PM-induced cytokine secretion by DCs, effects which are reduced by CaSR NAM. In addition to my novel findings; 4. Undifferentiated basal human bronchial epithelial cells are characterised by low functional expression of the CaSR, using intracellular Ca2+ as a biological readout for CaSR activation, therefore more work is required to establish a more suitable CaSR-expressing in vitro model of airway epithelial cells 5. Exposure of PM to “Healthy” alveolar macrophages (AMs) does not affect efferocytosis, a key resolving function of AMs, therefore, more work is required to better understand the effects of PM on key functions of AMs Together, my findings promote the CaSR as one of the mechanisms behind PM-sensing and responding in the airways, which drives pro-inflammatory features associated with asthma exacerbations. Therefore, CaSR NAM have the potential to provide an effective “all-in-one” therapeutic for asthma to directly counteract exaggerated inflammatory responses to inhaled stimuli, such as PM.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	21 October 2022
Date of Acceptance:	21 October 2022
Last Modified:	21 Oct 2022 13:58
URI:	https://orca.cardiff.ac.uk/id/eprint/153638

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