Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/5347
Title: The Effects of Cigarette Smoke on Airway Smooth Muscle Function
Authors: Lin, JinHeng
Issue Date: 2021
Publisher: Newcastle University
Abstract: Cigarette smoking is the largest risk factor for developing chronic obstructive pulmonary disease (COPD), which is associated with hyperresponsiveness of airway smooth muscle. While it is well established that chronic exposure to cigarette smoke (CS) leads to dysregulated calcium signalling, airway inflammation and remodelling of the airway smooth muscle, there is limited information about the acute effects of CS or CS extract (CSE) on human airway smooth muscle cell (hASMC) function, particularly Ca2+ homeostasis. Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is also linked to disrupted Ca2+ homeostasis in ASMC, but its role in ASMC function remains poorly understood. This study investigated the following: (1) The role of CFTR in regulating Ca2+ homeostasis in ASMC; (2) The acute effects of aqueous CSE on hASMC Ca2+ homeostasis; and (3) The acute effects of gaseous CS on hASMC Ca2+ homeostasis. The results demonstrate that (1) CFTR inhibition in rat ASMC had minor effects on store-operated Ca2+ entry and the extent of Ca2+ reuptake; (2) Acute exposure to CSE or CS rapidly elevated cytosolic Ca2+ in hASMC through stimulation of plasmalemmal Ca2+ influx, but not through the release of calcium from intracellular sarcoplasmic reticulum stores; (3) Both CSE and CS specifically stimulated Ca2+ influx through the neurogenic pain receptor channel, transient receptor potential ankyrin 1 (TRPA1), but not through L-type or store-operated Ca2+ channels; (4) The CSE/CS-induced calcium influx through TRPA1 led to myosin light-chain phosphorylation, a key process regulating ASMC contractility. Overall, results suggest that CFTR plays a minor role in regulating calcium homeostasis in ASM. However, this study provides the first experimental evidence that TRPA1 is an important target of both CSE and CS in hASMC. The CSE/CS-induced activation of TRPA1 may lead to exacerbated ASMC contraction thus contributing to airway hyperresponsiveness in COPD.
Description: Ph. D. Thesis.
URI: http://hdl.handle.net/10443/5347
Appears in Collections:Biosciences Institute

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