Year: 2014
Type: dissertation
Abstract: Rationale: Airway smooth muscle dysfunction is a cardinal feature of asthma that is\nbelieved to contribute to the symptoms and recurrent exacerbations. However, the\nmechanisms driving this dysfunction are not fully understood.\nHypothesis: Intrinsic abnormalities of the ASM from asthma exist and contribute to the\nfunctional differences in vitro which correlate with clinical characteristics\nMethods: Primary airway smooth muscle cells from healthy control subjects and\nasthmatics were used. Baseline protein and gene expression studies were assessed by mass\nspectrometry and microarrays. Functional differences were assessed, such as survival,\nproliferation, migration, wound healing and contraction. Oxidative stress DNA damage was\nassessed by immunohistology and comet assay, reactive oxygen species (ROS)\nquantification, and the role of NADPH oxidase (NOX4) and superoxide dismutase (SOD2)\nwere assessed by quantitative gene expression and pharmacological inhibitors, mimetic and\ngene silencing.\nResults: In ex vivo airway smooth muscle cultures, asthmatic smooth muscle\ndysfunction persisted, indicating exaggerated contractility and pro-inflammatory mediator\nrelease compared to ASM from healthy controls. The oxidative burden and damage in\nasthmatic ASM was increased with increased expression of NOX4 which negatively\ncorrelated to the airflow obstruction. Agonist induced hyper-contractile response was\nabrogated by using pharmacological inhibition or by silencing the mRNA.\nSummary: Intrinsic abnormalities of the airway smooth muscle exist in asthma.\nAsthmatic ASM cells possess intrinsic abnormalities in gene and protein expression,\nsynthetic mediator production and exaggerated agonist induced contraction. Increased\nexpression of NOX4 in asthmatic ASM promotes the susceptibility of a hyper-contractile\nresponse, implicating NOX4 as a potential therapeutic target for the treatment of asthma.
Author: Amanda Sutcliffe
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W841727599