Chun Yong Seow

Professor

Research Classification

Biological and Biochemical Mechanisms
Asthma
Muscle
Respiratory System
Physiology

Research Interests

Airway smooth muscle
Contraction mechanism

Relevant Degree Programs

 

Research Methodology

biophysics
biochemistry
pharmacology
mathematical modeling

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Doctoral students
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Smooth muscle structure and function, contraction mechanism, lung mechanics, asthma

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
Mechanical and molecular contribution of airway smooth muscle to airway hyperresponsiveness in asthma (2015)

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.

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Airway smooth muscle in health and disease (2010)

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 thesisprovides valuable insight into ASM pathophysiology. The first two chapters focus on themechanisms by which the contractile apparatus is arranged within the cell. The studiesexamined whether the actin filament lattice acts a scaffold to facilitate myosin filamentassembly within contractile units and the contractile response to potassium chloride(KCl). The muscle was treated with cytochalasin D (CD), a known actin filamentdisrupter, but this provided little insight on whether the actin lattice guides myosinfilament assembly, since CD had a limited effect on actin filaments but a significanteffect on force. KCl was found to cause contraction of similar force to acetylcholinecontraction, despite the presence of fewer myosin filaments. KCl likely causeddepolymerization of myosin filaments upon activation and allowed for force generationby non-filamentous myosin molecules. In the last two studies, human ASM was sourcedfrom the tracheas of whole lungs donated for medical research. From this tissue source itwas shown that, unlike in previous human ASM studies, human muscle is similar to thatof other mammalian species and capable of significant isotonic shortening. This findinglends support to the use of animal ASM models as a proxy for human ASM. This alsowas 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 wasthe first to demonstrate length adaptation in human ASM. The mechanical properties ofasthmatic 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 mechanicalperturbation than non-asthmatic ASM. This last finding provides a possible mechanismby which asthmatic airways are more resistant to the bronchodilating effects of deepinspiration. Force generating capacity, shortening extent and velocity were not different.

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Master's Student Supervision (2010 - 2018)
The influence of interleukin-13 on force generation in airway smooth muscle tissue (2016)

Airway smooth muscle (ASM) has been implicated in the pathophysiology of asthma by contributing to excessive airway narrowing and Airway Hyperresponsiveness (AHR). Inflammation has also been suggested as a mechanism contributing to AHR. Levels of Interleukin-13 (IL-13), an inflammatory mediator, are increased in asthmatic sera and can alter the expression of specific contractile genes/proteins in cultured ASM cells. In cultured cells, IL-13 can cause increased ASM contractility and force generation in response to different contractile agonists such as acetylcholine (ACh), KCl, or histamine. However, there remains a lack of consensus regarding whether IL-13 can induce changes in mechanical properties of ASM tissue in response to all, or only some, contractile agonists. Our objective was to investigate the influence of IL-13 on the force generation of isolated ASM tissue in response to a variety of agonists. Ovine tracheal smooth muscle was isolated, bathed in Krebs solution, and then equilibrated using electrical field stimulation. To obtain baseline mechanical measurements, tissues were either contracted with a range of ACh concentrations, pre-stimulated with ACh then relaxed with progressively increasing doses of isoproterenol (ISO), or contracted with single a single concentration of KCl or histamine (n=5 per condition). Paired samples from each tissue were pinned at in situ length and incubated for 24h or 72h with or without IL-13 in serum-free DMEM. Responses were compared to their baseline measurements after incubation to determine the influence of IL-13. Compared to non-exposed tissues, IL-13 did not increase maximal force or sensitivity to a range of ACh concentrations after 24 or 72h (n=5 each), nor did it impede the relaxation of ASM induced by ISO after 24h (n=5). Likewise, response to KCl was not changed by IL-13 after 72h (n=5). Response to histamine was ~120% higher compared to control (t=72h) after treatment (% of baseline maximal force, n=5, p=0.03). These findings contrast with previous literature in ASM cell culture experiments. In tissue strips, IL-13 did not induce significant changes to ASM mechanics in response to ACh, ISO, or KCl. However, IL-13 did influence histamine-induced contractile response suggesting a potential avenue by which airway inflammation influences ASM contraction.

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Development and maintenance of force and stiffness in airway smooth muscle (2015)

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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Length distribution of myosin filaments in smooth muscle and implications in the structure and function of contractile units (2015)

Smooth muscle is an essential component of the walls of numerous hollow or tubular organs throughout the body, including blood vessels, airways, and the bladder. Proper physiological functioning of these organs relies heavily on the appropriate activation and contraction of the smooth muscle tissue. Pathophysiological conditions may arise from both excessive and insufficient smooth muscle contraction. Muscle function is closely associated with muscle structure. More specifically, during a contraction, cyclic interactions between myosin cross-bridges and actin filaments allow for muscle shortening and force generation. Myosin molecules from smooth muscle and non-muscle cells are known to self-assemble into side-polar filaments in vitro. However the in situ mechanism of filament assembly is not clear and the question of whether there is a unique length for myosin filaments in smooth muscle is still under debate. In this study we measured the lengths of 16,587 myosin filaments in three types of smooth muscle cells using serial electron microscopy (EM). Sheep airway and pulmonary arterial smooth muscle as well as rabbit carotid arterial smooth muscle were fixed for EM and serial ultra-thin (50-60 nm) sections were obtained. Myosin filaments were traced in consecutive sections to determine their lengths. The results indicate that there is not a single length for the myosin filaments; instead there is a wide variation in lengths. The plots of observation frequency versus myosin filament length follow an exponential decay pattern. The most significant finding of this study is that myosin filaments in smooth muscle do not have a uniform length and analysis suggests that the distribution of filament length is a result of a dynamic equilibrium between polymerization and de-polymerization of myosin molecules driven by predictable probabilities of the myosin dimers to bind with and dissociate from each other.

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