Mechanistic models of force adaptation in airway smooth muscle cells - application to asthma
Project description
Lung inflammation and airway hyperresponsiveness (AHR) are hallmarks of asthma, but their interrelationship is unclear. Excessive shortening of airway smooth muscle (ASM) in response to bronchoconstrictors is likely an important determinant of AHR. Hypercontractility of ASM could stem from a change in the intrinsic properties of the muscle, or it could be due to extrinsic factors such as chronic exposure of the muscle to inflammatory mediators in the airways with the latter being a possible link between lung inflammation and AHR. The aim of this project will be to investigate the influence of chronic exposure to a contractile agonist on the force-generating capacity of ASM via a cell-level model of an ASM cell. Previous experimental studies have suggested that the muscle adapts to basal tone in response to application of agonist and is able to regain its contractile ability in response to a second stimulus over time. This is thought to be due to a transformation in the cytoskeletal components of the cell enabling it to bear force, thus freeing up subcellular contractile machinery to generate more force. Force adaptation in ASM as a consequence of prolonged exposure to the many spasmogens found in asthmatic airways could be a mechanism contributing to AHR seen in asthma. We will develop and use a cell model in an attempt to either confirm this hypothesis or determine other mechanisms that may give rise to the observed phenomenon of force adaptation.
Project published references
Adaptation of airway smooth muscle to basal tone relevance to airway hyperresponsiveness, Bosse et al, American Journal of Respiratory Cell Molecular Biology,Vol 40. pp 13–18, 2009
The role of contractile unit reorganization in force generation in airway smooth muscle, B S Brook and O E Jensen, Mathematical Medicine and Biology, 2013. doi:10.1093/imammb/dqs031
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