UBC Theses and Dissertations

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UBC Theses and Dissertations

Development and maintenance of force and stiffness in airway smooth muscle Norris, Brandon Anthony


The primary function of airway smooth muscle (ASM) is to contract upon stimulation. Mechanical manifestation of contraction includes development and maintenance of force and stiffness, and when the developed force is greater than the load on the muscle, shortening occurs. Dysfunction of ASM could lead to excessively stiff or narrowed airways. This thesis research is aimed at advancing our understanding of the basic mechanisms involved in the development and maintenance of force and stiffness in ASM and how these mechanical properties are regulated by enzymes and their associated signalling pathways. The research is also aimed at identifying new targets for asthma therapy with specific interventions that reduce airway stiffness and narrowing. Recently, stiffness of the passive components of ASM –unrelated to that stemming from attached myosin crossbridges - has been shown to be actively regulated by intracellular enzymes. Chapter 2 of this thesis shows that the passive components of the ASM can be activated to generate force and augment stiffness. This activation is cross-bridge independent, as the calcium within the ASM cells was removed and the phosphorylation of the regulatory myosin light chain was abolished. The activation could be prevented when Rho-kinase was inhibited. Rho-kinase is known to be actively involved in the cytoskeletal dynamics of ASM; therefore, it is reasonable to assume that the cytoskeletal network is at least partly responsible for the activation of the passive components in ASM. Chapter 3 of the thesis aimed to explain the biphasic response that occurs when a ramp stretch is applied to an activated ASM strip. By performing ramp stretches in different conditions, the two phases of the biphasic force response revealed an intricate relationship between the two contributors to muscle stiffness – the attached actomyosin crossbridges and the cytoskeleton. Results presented in both chapters of the thesis suggest that signalling pathways involving Rho-kinase is crucial for regulating the calcium dependent and independent ASM force and stiffness. This has provided a focus for future studies in identifying enzyme or structural protein targets for modulating ASM mechanical properties down stream of the Rho-kinase.

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