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Subject Medical and Demographic Data
Source publication
Rationale:
Airway smooth muscle (ASM) plays a key role in airway hyperresponsiveness (AHR) but it is unclear whether its contractility is intrinsically changed in asthma.
Objectives:
To investigate whether key parameters of ASM contractility are altered in subjects with asthma.
Methods:
Human trachea and main bronchi were dissected free of epi...
Citations
... Yet, the contribution of ASM defects in asthmatic hyperresponsiveness is still unclear and a matter of vivid debates (Seow and Fredberg 2001;Mitzner 2004Mitzner , 2008Ameredes 2007;DuBois 2007;Ford 2007;Fredberg 2007;Irvin 2007;Panettiere 2007;Permutt 2007;Seow et al. 2007;Mead 2007aMead , 2007bBossé et al. 2012Bossé et al. , 2013Gunst and Panettieri 2012;Pare and Mitzner 2012b). While isolated ASM cells from asthmatics seem hypercontractile (Ma et al. 2002;Matsumoto et al. 2007;Sutcliffe et al. 2012;An et al. 2016;Galior et al. 2018), the bulk of evidence in studies measuring ASM at the scale of the tissue or the organ have shown no or inconsistent changes in contractility (Chin et al. 2012;Noble et al. 2013;Wright et al. 2013;Ijpma et al. 2015Ijpma et al. , 2020, and even more often a decreased sensitivity to methacholine (Goldie et al. 1986;Van Koppen et al. 1988; Fig. 1. The structure of the smooth muscle (in black) in human small airways. ...
... Reprinted by permission from the publisher (the American Physiological Society) and the authors. Whicker et al. 1988;Bai 1990Bai , 1991Ijpma et al. 2015Ijpma et al. , 2020. Another viable possibility is that hypercontractility would be acquired, perhaps in a reversible fashion, due to in vivo alterations seen in asthma. ...
Research on airway smooth muscle has traditionally focused on its putative detrimental role in asthma, emphasizing on how its shortening narrows the airway lumen, without much consideration about its potential role in subserving the function of the entire respiratory system. New experimental evidence on mice suggests that not only the smooth muscle is required to sustain life postnatally, but its stiffening effect on the lung tissue also protects against excessive airway narrowing and, most importantly, against small airway narrowing heterogeneity and closure. These results suggest that the smooth muscle plays an vital role in the lung periphery, essentially safeguarding alveolar ventilation by preventing small airway closure. These results also shed light on perplexing clinical observations, such as the long-standing doubts about the safety of bronchodilators. Since there seems to be an optimal level of smooth muscle contraction, at least in small airways, the therapeutic goal of maximizing the relaxation of the smooth muscle in asthma needs to be revisited. A bronchodilator with an excessive potency for inhibiting smooth muscle contraction, and that is still potent at concentrations reaching the lung periphery, may foster airway closure and air trapping, resulting in no net gain or even a decline in lung function.
... While the physiological purpose of the airway smooth muscle is still debated (Mitzner, 2004(Mitzner, , 2007Seow and Fredberg, 2001;Ameredes, 2007;Bossé et al., 2012;DuBois, 2007;Ford, 2007;Fredberg, 2007;Gunst and Panettieri, 2012;Irvin, 2007;Mead, 2007c2007a, 2007bMead, 2007c2007a, , 2008Panettiere, 2007;Pare and Mitzner, 2012;Permutt, 2007;Seow et al., 2007;Mead, 2007c2007c), its contractile activation with a spasmogen triggers force, shortening and many other changes in mechanics, such as stiffening (Chin et al., 2010;Ijpma et al., 2015Ijpma et al., , 2020Noble et al., 2007;Gazzola et al., 2016;Fredberg et al., 1997). When these changes occur in vivo, they translate into altered mechanics of the airway wall and the lung (Mitzner et al., 1992;Boucher et al., 2022;Chapman et al., 2014), with the potential to influence airway caliber and lung function. ...
... Many contractile readouts other than isometric force can be measured in vitro (Chin et al., 2010;Ijpma et al., 2015Ijpma et al., , 2020Noble et al., 2007;Gazzola et al., 2016;Fredberg et al., 1997). They include, inter alias, shortening, stiffness, elastance, resistance, and the ability to relax in response to a bronchodilator. ...
... The contractile readouts being measured in a given experimental setting are often context-dependent and are often restricted to one per study. Comparison between studies are also difficult because different preparations (e.g., tracheal strips, bronchial rings, precision-cut lung slices, isolated cells,…) from different species are used in distinct experimental settings (Chin et al., 2010;Ijpma et al., 2015Ijpma et al., , 2020Noble et al., 2007;Gazzola et al., 2016;Fredberg et al., 1997;Donovan et al., 2015;Ma et al., 2002;An et al., Fig. 1. Concentration-response of porcine tracheal strips in the isometric condition. ...
... Additionally, in asthmatic subjects, fast re-narrowing of the airways has been observed following DI-induced bronchodilation [21], suggesting that asthmatic ASM may be different from healthy ASM in its response to strain, although shortening velocity and active isometric force of tracheal smooth muscle from human asthmatics was found not to be different from that from non-asthmatics [22,23]. However, a more recent finding indicates an increase in reactivity of intra-lobal bronchi from human asthmatics compared with those of non-asthmatics [23]. ...
... Additionally, in asthmatic subjects, fast re-narrowing of the airways has been observed following DI-induced bronchodilation [21], suggesting that asthmatic ASM may be different from healthy ASM in its response to strain, although shortening velocity and active isometric force of tracheal smooth muscle from human asthmatics was found not to be different from that from non-asthmatics [22,23]. However, a more recent finding indicates an increase in reactivity of intra-lobal bronchi from human asthmatics compared with those of non-asthmatics [23]. The difference in ASM between asthmatics and non-asthmatics may also lie in their "robustness", in that the asthmatic muscle's contractility is less affected by mechanical strain [22], such as that associated with DIs. ...
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 surfactant, alteration in mucus plugs, and changes in airway heterogeneity.
Main body
The present review is focused on the DI effect on ASM function, based on recent findings from ex vivo sheep lung experiments showing a large change in airway diameter during a DI. The amount of stretch on the airways, when applied to isolated airway rings in vitro, caused a substantial decrease in ASM contractility that takes many minutes to recover. When challenged with a bronchoconstrictor, the increase in pulmonary resistance in the ex vivo ovine lungs is mostly due to the increase in airway resistance.
Conclusions
Although non-ASM related factors cannot be excluded, the large strain on the airways associated with a DI substantially reduces ASM contractility and thus can account for most of the bronchodilatory and bronchoprotective effects of DI.
... It is then possible to focus on each variable independently of one another by studying either isometric or isotonic contractions. Changes in tissue tension (i.e., force) are measured by exposing the strip to contractile or relaxing agonists, or an electric field stimulation (EFS) (Ijpma et al., 2015). Assessing tissue changes in tensile force in response to gradually increasing concentrations of a drug or agonist gives a dose-response curve that has been used to compare differences in ASM responsiveness (see above) (O'Byrne and Inman, 2003). ...
... Assessing tissue changes in tensile force in response to gradually increasing concentrations of a drug or agonist gives a dose-response curve that has been used to compare differences in ASM responsiveness (see above) (O'Byrne and Inman, 2003). Using the quick-release technique (described below), it is possible to determine the shortening velocity (Seow and Stephens, 1986;Bullimore et al., 2010;Ijpma et al., 2015). Important parameters of muscle mechanics include force, stress, length, and shortening velocity. ...
... However, further careful stereology studies did not confirm any difference in matrix proteins between asthmatic and control ASM (James et al., 2012). Thus, to study ASM responses that are otherwise influenced by ASM mass, muscle force is normalized to the cross-sectional area which is referred to as stress (Ijpma et al., 2015). ...
Known to have affected around 340 million people across the world in 2018, asthma is a prevalent chronic inflammatory disease of the airways. The symptoms such as wheezing, dyspnea, chest tightness, and cough reflect episodes of reversible airway obstruction. Asthma is a heterogeneous disease that varies in clinical presentation, severity, and pathobiology, but consistently features airway hyperresponsiveness (AHR)—excessive airway narrowing due to an exaggerated response of the airways to various stimuli. Airway smooth muscle (ASM) is the major effector of exaggerated airway narrowing and AHR and many factors may contribute to its altered function in asthma. These include genetic predispositions, early life exposure to viruses, pollutants and allergens that lead to chronic exposure to inflammatory cells and mediators, altered innervation, airway structural cell remodeling, and airway mechanical stress. Early studies aiming to address the dysfunctional nature of ASM in the etiology and pathogenesis of asthma have been inconclusive due to the methodological limitations in assessing the intrapulmonary airways, the site of asthma. The study of the trachealis, although convenient, has been misleading as it has shown no alterations in asthma and it is not as exposed to inflammatory cells as intrapulmonary ASM. Furthermore, the cartilage rings offer protection against stress and strain of repeated contractions. More recent strategies that allow for the isolation of viable intrapulmonary ASM tissue reveal significant mechanical differences between asthmatic and non-asthmatic tissues. This review will thus summarize the latest techniques used to study ASM mechanics within its environment and in isolation, identify the potential causes of the discrepancy between the ASM of the extra- and intrapulmonary airways, and address future directions that may lead to an improved understanding of ASM hypercontractility in asthma.
... The validity of our findings thus rests on the assumption that the ASM from the trachea is appropriate to assess the overall contractility and that the ASM from other airways are similarly affected by HDM. Previous studies comparing ASM derived from the trachea versus lower airways have generally found no differences in contractility (Gunst and Stropp, 1988;Jiang and Stephens, 1990;Ijpma et al., 2015). However, ASM from different locations within the airway tree are sometimes, but not always (Ijpma et al., 2015), differently affected in asthma (Ijpma et al., 2020), heaves (Matusovsky et al., 2016), and murine model of asthma (Donovan et al., 2013). ...
... Previous studies comparing ASM derived from the trachea versus lower airways have generally found no differences in contractility (Gunst and Stropp, 1988;Jiang and Stephens, 1990;Ijpma et al., 2015). However, ASM from different locations within the airway tree are sometimes, but not always (Ijpma et al., 2015), differently affected in asthma (Ijpma et al., 2020), heaves (Matusovsky et al., 2016), and murine model of asthma (Donovan et al., 2013). More precisely, while asthma (or asthma-like conditions) is sometimes associated with increased contractility of the peripheral airways but not with changes in tracheal contractility (Matusovsky et al., 2016;Ijpma et al., 2020), it is sometimes associated with increased contractility of the trachea and a decreased contractility of peripheral airways (Donovan et al., 2013). ...
The contractility of airway smooth muscle (ASM) is labile. Although this feature can greatly modulate the degree of airway responsiveness in vivo, the extent by which ASM’s contractility is affected by pulmonary allergic inflammation has never been compared between strains of mice exhibiting a different susceptibility to develop airway hyperresponsiveness (AHR). Herein, female C57BL/6 and BALB/c mice were treated intranasally with either saline or house dust mite (HDM) once daily for 10 consecutive days to induce pulmonary allergic inflammation. The doses of HDM were twice greater in the less susceptible C57BL/6 strain. All outcomes, including ASM contractility, were measured 24 h after the last HDM exposure. As expected, while BALB/c mice exposed to HDM became hyperresponsive to a nebulized challenge with methacholine in vivo, C57BL/6 mice remained normoresponsive. The lack of AHR in C57BL/6 mice occurred despite exhibiting more than twice as much inflammation than BALB/c mice in bronchoalveolar lavages, as well as similar degrees of inflammatory cell infiltrates within the lung tissue, goblet cell hyperplasia and thickening of the epithelium. There was no enlargement of ASM caused by HDM exposure in either strain. Unexpectedly, however, excised tracheas derived from C57BL/6 mice exposed to HDM demonstrated a decreased contractility in response to both methacholine and potassium chloride, while tracheas from BALB/c mice remained normocontractile following HDM exposure. These results suggest that the lack of AHR in C57BL/6 mice, at least in an acute model of HDM-induced pulmonary allergic inflammation, is due to an acquired ASM hypocontractility.
... An early hypothesis of the mechanism of the AHR observed in patients with asthma, was that the ASM intrinsically generates higher contractile force and therefore could narrow the airways more easily. In the studies of the larger airways of people with asthma there is conflicting evidence regarding the difference in maximal contractile force between patients with and without asthma [109][110][111][112][113][114]. The majority of these studies showed no difference between groups with and without asthma. ...
Small airways (<2 mm in diameter) are probably involved across almost all asthma severities and they show proportionally more structural and functional abnormalities with increasing asthma severity. The structural and functional alterations of the epithelium, extracellular matrix and airway smooth muscle in small airways of people with asthma have been described over many years using in vitro studies, animal models or imaging and modelling methods. The purpose of this review was to provide an overview of these observations and to outline several potential pathophysiological mechanisms regarding the role of small airways in asthma.
... There is evidence in asthma that ASM is increased in mass by both hypertrophy (increased cell size) and hyperplasia (increased cell number) (5,229). However, it appears that the strength of contraction (corrected for muscle area, at least in central airways) is not increased, and the velocity of shortening is normal (58,125). Furthermore, increased basal tone in ASM is associated with increased AHR and the reduced ability to bronchodilate in response to a deep breath (87). ...
This article will discuss in detail the pathophysiology of asthma from the point of view of lung mechanics. In particular, we will explain how asthma is more than just airflow limitation resulting from airway narrowing but in fact involves multiple consequences of airway narrowing, including ventilation heterogeneity, airway closure, and airway hyperresponsiveness. In addition, the relationship between the airway and surrounding lung parenchyma is thought to be critically important in asthma, especially as related to the response to deep inspiration. Furthermore, dynamic changes in lung mechanics over time may yield important information about asthma stability, as well as potentially provide a window into future disease control. All of these features of mechanical properties of the lung in asthma will be explained by providing evidence from multiple investigative methods, including not only traditional pulmonary function testing but also more sophisticated techniques such as forced oscillation, multiple breath nitrogen washout, and different imaging modalities. Throughout the article, we will link the lung mechanical features of asthma to clinical manifestations of asthma symptoms, severity, and control. © 2020 American Physiological Society. Compr Physiol 10:975-1007, 2020.
... Evidence suggests that ASM show a significant degree of plasticity and do not have a force-response curve typical of skeletal muscle. Asthmatic ASM does not appear to generate greater forces for a given stimulus than that from nonasthmatics (260,261). Krishnan et al. suggested that asthma represents "freezing" of smooth muscle (262), but "freezing" only appears to occur during viral infections when airways obstruction is relatively fixed. During poorly controlled asthma, the variability in caliber is greatly enhanced by specific and nonspecific constrictor stimuli, quite the reverse of being "frozen." ...
The defining feature of asthma is loss of normal post-natal homeostatic control of airways smooth muscle (ASM). This is the key feature that distinguishes asthma from all other forms of respiratory disease. Failure to focus on impaired ASM homeostasis largely explains our failure to find a cure and contributes to the widespread excessive morbidity associated with the condition despite the presence of effective therapies. The mechanisms responsible for destabilizing the normal tight control of ASM and hence airways caliber in post-natal life are unknown but it is clear that atopic inflammation is neither necessary nor sufficient. Loss of homeostasis results in excessive ASM contraction which, in those with poor control, is manifest by variations in airflow resistance over short periods of time. During viral exacerbations, the ability to respond to bronchodilators is partially or almost completely lost, resulting in ASM being “locked down” in a contracted state. Corticosteroids appear to restore normal or near normal homeostasis in those with poor control and restore bronchodilator responsiveness during exacerbations. The mechanism of action of corticosteroids is unknown and the assumption that their action is solely due to “anti-inflammatory” effects needs to be challenged. ASM, in evolutionary terms, dates to the earliest land dwelling creatures that required muscle to empty primitive lungs. ASM appears very early in embryonic development and active peristalsis is essential for the formation of the lungs. However, in post-natal life its only role appears to be to maintain airways in a configuration that minimizes resistance to airflow and dead space. In health, significant constriction is actively prevented, presumably through classic negative feedback loops. Disruption of this robust homeostatic control can develop at any age and results in asthma. In order to develop a cure, we need to move from our current focus on immunology and inflammatory pathways to work that will lead to an understanding of the mechanisms that contribute to ASM stability in health and how this is disrupted to cause asthma. This requires a radical change in the focus of most of “asthma research.”
... As alluded above, defects in ASM's contractile properties other than the stress-generating capacity may contribute to impaired bron-chodilation in vivo, including increased amount and velocity of shortening, increased stiffness, increased ability to tolerate/ recover from oscillating stress, and impaired ability to relax. Again, all of those contractile properties have been compared between asthmatic and nonasthmatic ASM, and no consistent differences were found, at least when the tissues were isolated from the "sick" environment and studied in vitro (14,26). ...
The shortening of airway smooth muscle (ASM) is greatly affected by time. This is because stimuli affecting ASM shortening, such as bronchoactive molecules or the strain inflicted by breathing maneuvers, not only alter quick biochemical processes regulating contraction but also slower processes that allow ASM to adapt to an ever changing length. Little attention has been given to the effect of time on ASM shortening. The present study investigates the effect of changing the time interval between simulated deep inspirations (DIs) on ASM shortening and its responsiveness to simulated DIs. Excised tracheal strips from sheep were mounted in organ baths and either activated with methacholine or relaxed with isoproterenol. They were then subjected to simulated DIs by imposing swings in distending stress emulating a transmural pressure from 5 to 30 cmH 2 O. The simulated DIs were intercalated by 2, 5, 10 or 30 min. In between simulated DIs, the distending stress was either fixed or oscillating to simulate tidal breathing. The results show that while shortening was increased by prolonging the interval between simulated DIs, the bronchodilator effect of simulated DIs ( i.e., the elongation of the strip post- versus pre-DI) was not affected and the rate of re-shortening post-simulated DIs was decreased. As the frequency with which DIs are taken increases upon bronchoconstriction, our results may be relevant to typical alterations observed in asthma, such as an increased rate of re-narrowing post-DI.
... Tracheal ASM is a commonly studied tissue due to its relative thickness and ease of dissection. Contractile properties of the tracheal ASM in asthma are consistent with studies performed on large bronchi (Ijpma et al., 2015). There is however some evidence from horses with heaves (an innate model of asthma) to suggest that in the context of disease, peripheral airways behave differently to more proximally located airways (Matusovsky et al., 2016). ...
Developmental abnormalities of airways may impact susceptibility to asthma in later life. We used a maternal hypoxia-induced mouse model of intrauterine growth restriction (IUGR) to examine changes in mechanical properties of the airway wall. Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11 to GD 17.5 (IUGR; term, GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A control group of pregnant mice were housed under normoxic conditions throughout pregnancy. At 8 weeks postnatal age, offspring were euthanized and a tracheasectomy performed. Tracheal segments were studied in organ baths to measure active airway smooth muscle (ASM) stress to carbachol and assess passive mechanical properties (stiffness) from stress-strain curves. In a separate group of anesthetized offspring, the forced oscillation technique was used to examine airway mechanics from relative changes in airway conductance during slow inflation and deflation between 0 and 20 cmH2O transrespiratory pressure. From predicted radius-pressure loops, storage and loss moduli and hysteresivity were calculated. IUGR offspring were lighter at birth (p < 0.05) and remained lighter at 8 weeks of age (p < 0.05) compared with Controls. Maximal stress was reduced in male IUGR offspring compared with Controls (p < 0.05), but not in females. Sensitivity to contractile agonist was not affected by IUGR or sex. Compared with the Control group, airways from IUGR animals were stiffer in vitro (p < 0.05). In vivo, airway hysteresivity (p < 0.05) was increased in the IUGR group, but there was no difference in storage or loss moduli between groups. In summary, the effects of IUGR persist to the mature airway wall, where there are clear abnormalities to ASM contractile properties and passive wall mechanics. We propose that mechanical abnormalities of the airway wall acquired through disrupted fetal growth impact susceptibility to disease.
