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Airway smooth muscle in health and disease

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Title: Airway smooth muscle in health and disease
Author: Chin, Leslie Yee Mann
Degree Doctor of Philosophy - PhD
Program Pathology
Copyright Date: 2010
Publicly Available in cIRcle 2010-08-23
Abstract: This thesis focuses on the structure and function of airway smooth muscle (ASM) in health and disease. By employing the use of structural analysis by electron microscopy, functional analysis by mechanical measurements, and biochemical analysis, this thesis provides valuable insight into ASM pathophysiology. The first two chapters focus on the mechanisms by which the contractile apparatus is arranged within the cell. The studies examined whether the actin filament lattice acts a scaffold to facilitate myosin filament assembly within contractile units and the contractile response to potassium chloride (KCl). The muscle was treated with cytochalasin D (CD), a known actin filament disrupter, but this provided little insight on whether the actin lattice guides myosin filament assembly, since CD had a limited effect on actin filaments but a significant effect on force. KCl was found to cause contraction of similar force to acetylcholine contraction, despite the presence of fewer myosin filaments. KCl likely caused depolymerization of myosin filaments upon activation and allowed for force generation by non-filamentous myosin molecules. In the last two studies, human ASM was sourced from the tracheas of whole lungs donated for medical research. From this tissue source it was shown that, unlike in previous human ASM studies, human muscle is similar to that of other mammalian species and capable of significant isotonic shortening. This finding lends support to the use of animal ASM models as a proxy for human ASM. This also was the first study to examine human ASM in the paradigm of mechanical plasticity, using in situ muscle length as a reference length instead of the traditional Lmax, and was the first to demonstrate length adaptation in human ASM. The mechanical properties of asthmatic ASM were found to differ from those of non-asthmatic ASM at several key measurements. Asthmatic ASM was found to have an altered length-tension relationship, increased passive tension, and maintained force better in response to a mechanical perturbation than non-asthmatic ASM. This last finding provides a possible mechanism by which asthmatic airways are more resistant to the bronchodilating effects of deep inspiration. Force generating capacity, shortening extent and velocity were not different.
URI: http://hdl.handle.net/2429/27650
Scholarly Level: Graduate

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