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Introduction
Chun Y Seow is a professor at the Department of Pathology and Laboratory Medicine, University of British Columbia - Vancouver. His laboratory is located at the UBC Centre for Heart Lung Innovation (formerly known as the James Hogg Research Centre). Chun does research in airway smooth muscle Cell Biology and Lung Physiology in health and asthma.
Current institution
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September 1996 - present
Publications
Publications (174)
Background
Understanding the characteristics of pulmonary resistance and elastance in relation to the location of airway narrowing, e.g., tracheal stenosis vs. intrapulmonary airway obstruction, will help us understand lung function characteristics and mechanisms related to different airway diseases.
Methods
In this study, we used ex vivo sheep lu...
Simple Summary
The effects of a rho-kinase inhibitor alone and in combination with a bronchodilator in the presence of a small-amplitude oscillatory strain on the mechanical properties of airway smooth muscle were described in this brief review. Findings from relevant studies provide a strong basis for human trials using rho-kinase alone or in comb...
Background
Deep inspiration (DI) has been shown to induce bronchodilation and bronchoprotection in bronchochallenged healthy subjects, but not in asthmatics. Strain-induced relaxation of airway smooth muscle (ASM) is considered one of the factors responsible for these effects. Other factors include the release or redistribution of pulmonary surfact...
The ability to generate force in large arteries is known to be augmented by cyclic strain that mimics the mechanically dynamic in vivo environment associated with blood pressure fluctuation experienced by these arteries. Cyclic strain does not induce a contractile response, like that observed in the myogenic response seen in small arteries, but pro...
Emphysema is one of the pathological hallmarks of chronic obstructive pulmonary disease. We have recently reported that radiofrequency therapy improves lung function in rodent models of emphysema. However, preclinical data using large animals is necessary for clinical translation. Here, we describe the work performed to establish a unilateral porci...
Dynamic regulation of myosin filaments is a crucial factor in the ability of airway smooth muscle (ASM) to adapt to a wide length range. Increased stability or robustness of myosin filaments may play a role in the pathophysiology of asthmatic airways. Biochemical techniques for the purification of myosin and associated regulatory proteins could hel...
The time course of smooth muscle contraction can be divided into two phases, the initial phase is associated with force development while the sustained phase is associated with force maintenance. Cumulative evidence suggests that the two phases are regulated by different signaling pathways, and that rho-kinase (ROCK) and protein kinase C (PKC) play...
Lung resistance (R L ) is determined by airway and parenchymal tissue resistance, as well as the degree of heterogeneity in airway constriction. Deep inspirations (DIs) are known to reverse experimentally induced increase in R L , but the mechanism is not entirely clear. The first step towards understanding the effect of DI is to determine how each...
Muscles convert chemical energy to mechanical work. Mechanical performance of a muscle is often assessed by the muscle’s ability to shorten and generate power over a range of loads or forces, characterized by the force–velocity and force–power relationships. The hyperbolic force–velocity relationship of muscle, for a long time, has been regarded as...
Lung resistance (R L ) and elastance (E L ) can be measured during positive or negative pressure ventilation. Whether the different modes of ventilation produce different R L and E L is still being debated. Although negative pressure ventilation (NPV) is more physiological, positive pressure ventilation (PPV) is more commonly used for treating resp...
Deep inspiration (DI)-induced bronchodilation is the first line of defense against bronchoconstriction in healthy subjects. A hallmark of asthma is the lack of this beneficial effect of DI. The mechanism underlying the bronchodilatory effect of DI is not clear. Understanding the mechanism will help us unravel the mystery of asthma pathophysiology....
Smooth muscle is an integral part of hollow organs. Many of them are constantly subjected to mechanical forces that alter organ shape and modify the properties of smooth muscle. To understand the molecular mechanisms underlying smooth muscle function in its dynamic mechanical environment, a new paradigm has emerged that depicts evanescence of myosi...
The principle of mechanopharmacology of airway smooth muscle (ASM) is based on the premise that physical agitation, such as pressure oscillation applied to an airway, is able to induce bronchodilation by reducing contractility and softening the cytoskeleton of ASM. Although the underlying mechanism is not entirely clear, there is evidence to sugges...
Myosin phosphatase‐Rho interacting protein (p116Rip) was originally found as a RhoA‐binding protein. Subsequent studies by us and others revealed that p116Rip facilitates myosin light chain phosphatase (MLCP) activity through direct and indirect manners. However, it is unclear how p116Rip regulates myosin phosphatase activity in cells. To elucidate...
The cyclic interaction between myosin crossbridges and actin filaments underlies smooth muscle contraction. Phosphorylation of the 20-kDa myosin light chain (MLC20) is a crucial step in activating the crossbridge cycle. Our current understanding of smooth muscle contraction is based on observed correlations among MLC20 phosphorylation, maximal shor...
Muscle contraction is caused by the action of myosin motors within the structural confines of contractile unit arrays. When the force generated by cyclic interactions between myosin crossbridges and actin filaments is greater than the average load shared by the crossbridges, sliding of the actin filaments occurs and the muscle shortens. The shorten...
Asthmatic airways are stiffer than normal. We have shown that the cytoskeletal passive stiffness of airway smooth muscle (ASM) can be regulated by intracellular signaling pathways, especially those associated with Rho kinase (ROCK). We have also shown that an oscillatory strain reduces the passive stiffness of ASM and its ability to generate force....
Background
Gene expression changes in the structural cells of the airways are thought to play a role in the development of asthma and airway hyperresponsiveness. This includes changes to smooth muscle contractile machinery and epithelial barrier integrity genes. We used a targeted gene expression arrays to identify changes in the expression and co-...
Progressive limb and girdle muscle atrophy leading to loss of ambulation is a hallmark of dysferlinopathies, which include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. However, animal models fail to fully reproduce the disease severity observed in humans, with Dysferlin-null (Dysf-/-) mice exhibiting minor muscle damage and weakness...
We relate changes of the airway wall to the response of the intact airway and the whole lung. We address how mechanical conditions and specific structural changes for an airway contribute to hyperresponsiveness resistant to deep inspiration. This review conveys that the origins of hyperresponsiveness do not devolve into an abnormality at single str...
Smooth muscle is able to function over a much broader length range than striated muscle. The ability to maintain contractility after a large length change is thought to be due to an adaptive process involving restructuring of the contractile apparatus to maximize overlap between the contractile filaments. The molecular mechanism for the length-adap...
Study of Force adpatation in young healthy humans
Bronchospasm induced in non-asthmatic human subjects can be easily reversed by a deep inspiration (DI) whereas bronchospasm that occurs spontaneously in asthmatic subjects cannot. This physiological effect of a DI has been attributed to the manner in which a DI causes airway smooth muscle (ASM) cells to stretch, but underlying molecular mechanisms–...
Fig A in S1 File. Primary ASM from zyxin-/-
mice express no zyxin. (A) Western blot of wild type and zyxin-/- primary ASM cells showing the absence of zyxin expression in zyxin-/- cells. (B) Candidate regulators of contractility and stress fiber function do not show altered levels of expression in zyxin-/- cells. Fig B in S1 File. Applying stretch...
Timelapse micrograph showing a zyxin-/- mouse embryonic fibroblast transfected with zyxin-GFP and Lifeact-mApple undergoing a transient stretch and release of 10%.
(MOV)
Zoomed region of S1 Movie.
(MOV)
[This corrects the article on p. 516 in vol. 7, PMID: 28082901.].
Objectives:
To better understand the effects of Double J (JJ) stenting on ureteral physiology and function.
Materials and methods:
In total, twenty-four pigs (24) were stented cystoscopically unilaterally for 48h, 1, 2, 4 and 7 wks. Controls consisted of un-stented animals (n=4) or the contralateral un-stented ureter in pigs. Ureters were harves...
Airway remodeling, a key feature of asthma, alters every layer of the airway wall but most strikingly the airway smooth muscle (ASM) layer. Airway remodeling in asthmatics contributes to fixed airflow obstruction and can amplify airway narrowing caused by ASM activation. Previous modeling studies have shown that the increase in ASM mass has the lar...
Vascular smooth muscle (VSM) is unique in its ability to maintain an intrinsic level of contractile force, known as tone. Vascular tone is believed to arise from the constitutive activity of membrane-bound L-type Ca²⁺ channels (LTCC). This study used a pharmacological agonist of LTCC, Bay K8644, to elicit a sustained, sub-maximal contraction in VSM...
Force adaptation, a process whereby sustained spasmogenic activation (viz., tone) of airway smooth muscle (ASM) increases its contractile capacity, has been reported in isolated ASM tissues in vitro, as well as in mice in vivo. The objective of the present study was to assess the effect of tone on airway responsiveness in humans. Ten healthy volunt...
Taking a big breath is known to reverse bronchoconstriction induced by bronchochallenge in healthy subjects; this bronchodilatory effect of deep inspiration (DI) is diminished in asthmatics. The mechanism underlying the DI effect is not clear. Observations from experiments using isolated airway smooth muscle (ASM) preparations and airway segments s...
The study of mechanobiology is now widespread. The impact of cell and tissue mechanics on cellular responses is well appreciated. However, knowledge of the impact of cell and tissue mechanics on pharmacological responsiveness, and its application to drug screening and mechanistic investigations, have been very limited in scope. We emphasize the nee...
Rationale: An asthma-like airway phenotype has been described in people with cystic fibrosis (CF). Whether these findings are directly due to loss of cystic fibrosis transmembrane conductance regulator (CFTR) function or secondary to chronic airway infection and/or inflammation has been difficult to determine. Objectives: Airway contractility is pr...
Airway smooth muscle (ASM) in vivo is constantly subjected to oscillatory strain due to tidal breathing and deep inspirations. ASM contractility is known to be adversely affected by strains, especially those of large amplitudes. Based on the cross-bridge model of contraction, it is likely that strain impairs force generation by disrupting actomyosi...
Vitronectin, a multifunctional glycoprotein, is involved in coagulation, inhibition of the formation of the membrane attack complex (MAC), cell adhesion and migration, wound healing, and tissue remodeling. The primary cellular source of vitronectin is hepatocytes; it is not known whether resident cells of airways produce vitronectin, even though th...
Airway smooth muscle (ASM) plays a central role in the excessive narrowing of the airway that characterizes the primary functional impairment in asthma. This phenomenon is known as airway hyper-responsiveness (AHR). Emerging evidence suggests that the development and maintenance of ASM force involves dynamic reorganization of the subcellular filame...
It has long been known that airway smooth muscle (ASM) contraction contributes significantly to the reversible airflow obstruction that defines asthma. It has also been postulated that phenotypic changes in ASM contribute to the airway hyper-responsiveness (AHR) that is a characteristic feature of asthma. Although there is agreement that the mass o...
The standard method for measuring the phosphorylation of the regulatory myosin light chain (MLC20) in smooth muscle is extraction of the light chain using a urea extraction buffer, urea–glycerol gel electrophoresis of the soluble portion of the extract (supernatant) and Western blot analysis. The undissolved portion of the tissue during extraction...
Deep inspirations (DIs) taken prior to an inhaled challenge with a spasmogen limit airway responsiveness in non-asthmatics. This phenomenon is called bronchoprotection and is severely impaired in asthmatics. The ability of DIs to prevent a decrease in FEV1 was initially attributed to inhibition of airway narrowing. However, DIs taken prior to metha...
Smooth muscle contraction can be divided into two phases: the initial contraction determines the amount of developed force and the second phase determines how well the force is maintained. The initial phase is primarily due to activation of actomyosin interaction and is relatively well understood, whereas the second phase remains poorly understood....
Rationale:
Airway narrowing is maintained for a prolonged period after acute bronchoconstriction in humans in the absence of deep inspirations (DIs).
Objectives:
To determine whether maintenance of airway smooth muscle (ASM) shortening is responsible for the persistence of airway narrowing in healthy subjects following transient methacholine (MC...
A characteristic feature of asthma is exaggerated airway narrowing, termed airway hyperresponsiveness (AHR) due to contraction of airway smooth muscle (ASM). Although smooth muscle-specific asthma susceptibility genes have been identified, it is not known whether asthmatic ASM is phenotypically different from non-asthmatic ASM in terms of subcellul...
# PAUSE FOR DEEP INSPIRATION {#article-title-2}
to the editor: The Viewpoint by Professor Lutchen is timely and appropriate ([3][1]). There is now uncertainty as to the importance of airway smooth muscle (ASM) dynamics to normal airway function and whether disruption in the airway-lung dynamic
Muscles shorten faster against light loads than they do against heavy loads. The hyperbolic equation first used by A.V. Hill over seven decades ago to illustrate the relationship between shortening velocity and load is still the predominant method used to characterize muscle performance, even though it has been regarded as purely empirical and lack...
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 myos...
The structurally dynamic cytoskeleton is important in many cell functions. Large gaps still exist in our knowledge regarding what regulates cytoskeletal dynamics and what underlies the structural plasticity. Because Rho-kinase is an upstream regulator of signaling events leading to phosphorylation of many cytoskeletal proteins in many cell types, w...
The lung is a dynamic organ and the oscillating stress applied to the airway wall during breathing maneuvers can decrease airway smooth muscle (ASM) contractility. However, it is unclear whether it is the stress or the attendant strain that is responsible for the decline of ASM force associated with breathing maneuvers, and whether tone can prevent...
Reduced airway distensibility due to increased airway stiffness is a characteristic of asthma. Airway stiffness is determined by the property and structural organization of the various elements of the airway wall, and is often divided into active and passive components. Active stiffness is thought to be associated with activation of muscle cells in...
Airway inflammation in patients with asthma exposes the airway smooth muscle (ASM) to a variety of spasmogens. These spasmogens increase ASM tone, which can lead to force adaptation. Length oscillations of ASM, which occur in vivo due to breathing maneuvers, can attenuate force adaptation. However, in the presence of tone, the force oscillations re...
The airway smooth muscle (ASM) layer within the airway wall modulates airway diameter and distensibility. Even in the relaxed state, the ASM layer possesses finite stiffness and limits the extent of airway distension by the radial force generated by parenchymal tethers and transmural pressure. Airway stiffness has often been attributed to passive e...
Airway smooth muscle (ASM) is the major effector of excessive airway narrowing in asthma. Changes in some of the mechanical properties of ASM could contribute to excessive narrowing and have not been systematically studied in human ASM from nonasthmatic and asthmatic subjects.
Human ASM strips (eight asthmatic and six nonasthmatic) were studied at...
Although the structure of the contractile unit in smooth muscle is poorly understood, some of the mechanical properties of the muscle suggest that a sliding-filament mechanism, similar to that in striated muscle, is also operative in smooth muscle. To test the applicability of this mechanism to smooth muscle function, we have constructed a mathemat...
Excessive narrowing of the airways due to airway smooth muscle (ASM) contraction is a major cause of asthma exacerbation. ASM is therefore a direct target for many drugs used in asthma therapy. The contractile mechanism of smooth muscle is not entirely clear. A major advance in the field in the last decade was the recognition and appreciation of th...
Excessive narrowing of the airways due to airway smooth muscle (ASM) contraction is a major cause of asthma exacerbation. ASM is therefore a direct target for many drugs used in asthma therapy. The contractile mechanism of smooth muscle is not entirely clear. A major advance in the field in the last decade was the recognition and appreciation of th...
The function of a complex system such as a smooth muscle cell is the result of the active interaction among molecules and molecular aggregates. Emergent macroscopic manifestations of these molecular interactions, such as the length-force relationship and its associated length adaptation, are well documented, but the molecular constituents and organ...
The wall of hollow organs of vertebrates is a unique structure able to generate active tension and maintain a nearly constant passive stiffness over a large volume range. These properties are predominantly attributable to the smooth muscle cells that line the organ wall. Although smooth muscle is known to possess plasticity (i.e., the ability to ad...
Airway smooth muscle (ASM) is able to generate maximal force under static conditions, and this isometric force can be maintained over a large length range due to length adaptation. The increased force at short muscle length could lead to excessive narrowing of the airways. Prolonged exposure of ASM to submaximal stimuli also increases the muscle's...
Tidal breathing, and especially deep breathing, is known to antagonise bronchoconstriction caused by airway smooth muscle (ASM) contraction; however, this bronchoprotective effect of breathing is impaired in asthma. Force fluctuations applied to contracted ASM in vitro cause it to relengthen, force-fluctuation-induced relengthening (FFIR). Given th...
Phosphorylation of myosin by myosin light chain kinase (MLCK) is essential for smooth muscle contraction. In this study we show that caldesmon (CaD) is also phosphorylated in vitro by MLCK. The phosphorylation is calcium- and calmodulin (CaM)-dependent and requires a MLCK concentration close to that found in vivo. On average, approximately 2 mol P(...
The amplitude of strain in airway smooth muscle (ASM) produced by oscillatory perturbations such as tidal breathing or deep inspiration (DI) influences the force loss in the muscle and is therefore a key determinant of the bronchoprotective and bronchodilatory effects of these breathing maneuvers. The stiffness of unstimulated ASM (passive stiffnes...
Airway smooth muscle (ASM) plays a vital role in the exaggerated airway narrowing seen in asthma. However, whether asthmatic ASM is mechanically different from nonasthmatic ASM is unclear. Much of our current understanding about ASM mechanics comes from measurements made in other species. Limited data on human ASM mechanics prevents proper comparis...
Breathing is known to functionally antagonize bronchoconstriction caused by airway muscle contraction. During breathing, tidal lung inflation generates force fluctuations that are transmitted to the contracted airway muscle. In vitro, experimental application of force fluctuations to contracted airway smooth muscle strips causes them to relengthen....
Stress and strain are omnipresent in the lung due to constant lung volume fluctuation associated with respiration, and they modulate the phenotype and function of all cells residing in the airways including the airway smooth muscle (ASM) cell. There is ample evidence that the ASM cell is very sensitive to its physical environment, and can alter its...
Airway smooth muscle (ASM) in individuals with asthma is continuously stimulated by spasmogens released as part of chronic airway inflammation. This chronic submaximal stimulation of ASM produces "tone," which may or may not narrow airways sufficiently to induce respiratory symptoms. However, when coupled with a bronchoprovocative challenge with a...
Ionic interactions between the plasma membrane (PM) and the sarcoplasmic reticulum (SR) play a crucial role in smooth muscle activation and homeostasis. The most common form of Ca2+ signalling seen in vascular smooth muscle of conduit arteries and capacitance veins consists of repetitive asynchronous Ca2+ waves. In the inferior vena cava of the rab...
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 c...
Asthma is an episodic respiratory syndrome caused by several pathogenic processes. This recurrent syndrome is associated with an accelerated decline in lung function and increase in airway obstruction over time. The reduced lung function is a consequence of tissue restructuring of all the components of the airway wall: 1) epithelium metaplasia; 2)...
Hypervasoconstriction is associated with pulmonary hypertension and dysfunction of the pulmonary arterial smooth muscle (PASM) is implicated. However, relatively little is known about the mechanical properties of PASM. Recent advances in our understanding of plastic adaptation in smooth muscle may shed light on the disease mechanism. In this study,...
Many types of smooth muscle, including airway smooth muscle (ASM), are capable of generating maximal force over a large length range due to length adaptation, which is a relatively rapid process in which smooth muscle regains contractility after experiencing a force decrease induced by length fluctuation. Although the underlying mechanism is unclea...
mphysematous and fibrotic remodelling of lung tissue associated with chronic obstructive pulmonary disease (COPD) is known to alter the mechanical properties of the parenchyma and the airways, as well as the mechanical interdependence between them. This is thought to contribute to increased airway resistance in COPD (1). Due to its dynamic nature,...
The phenomenon of length adaptation in airway smooth muscle (ASM) is well documented; however, the underlying mechanism is less clear. Evidence to date suggests that the adaptation involves reassembly of contractile filaments, leading to reconfiguration of the actin filament lattice and polymerization or depolymerization of the myosin filaments wit...
Airway hyperresponsiveness, particularly the ability of airways to narrow excessively in response to stimuli that normally cause little airway narrowing in nonasthmatic subjects, is a characteristic feature of asthma and the basis of its symptoms. Although airway hyperresponsiveness may be partly the result of alterations in the contractile phenoty...
The sliding filament theory of contraction that was developed for striated muscle is generally believed to be also applicable to smooth muscle. However, the well-organized myofilament lattice (i.e., the sarcomeric structure) found in striated muscle has never been clearly delineated in smooth muscle. There is evidence that the myofilament lattice i...
