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Mechanical and molecular contribution of airway smooth muscle to airway hyperresponsiveness in asthma

University of British Columbia

This thesis focuses on the mechanical and molecular role of airway smooth muscle (ASM) in asthma with the aim to determine the contribution of ASM to both asthma and airway hyperresponsiveness (AHR). The first three chapters involve studies probing the mechanical properties of tracheal ASM strips and how these may contribute to the development of AHR. They will aim to show that ASM can contribute to AHR without fundamental changes to the tissue. Specifically, the first chapter investigated the ASMs response to force oscillations mimicking breathing maneuvers under levels of activation that induce force adaptation, a phenomenon potentially seen in asthmatics. It shows that force adaptation can persist under conditions that mimic breathing maneuvers and therefore could contribute to AHR and ASM hypercontractility. The second chapter investigated the role of tone in limiting the strain imposed on ASM by breathing maneuvers and the subsequent response of ASM to those strains. The stiffening of muscle in response to agonist precedes force development and acts to decrease the strain applied to the ASM. As strain decreased, the effect on the muscle contractility was blunted. Interestingly, a prior history of oscillations induced a bronchoprotective effect in the strip and caused a two times greater decline in force than would normally be expected by the small strains indicating that prior DIs are effective in limiting the responsiveness of the ASM to agonist. The third chapter investigated whether the ASM is intrinsically responsible for the bronchoprotective effect of deep inspirations (DIs). This study showed that simulated prior DIs can increase the compliance of the muscle to subsequent DIs, and although the effect on a single strip of muscle is small, the effect at the whole lung level may be sufficient to explain the bronchoprotective effect of DIs. The final chapter describes the molecular phenotype of ASM in asthma at both the gene and protein level. Proteins involved in contraction were found not to be significantly altered in asthmatics; however a host of proteins involved in cytoskeletal structure were changed and could explain why asthmatic ASM is stiffer and less responsive to DIs.

Text

2015-01-08

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/51862

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/