Role Of Airway Smooth Muscle Research Articles

Local targeting of TSLP: feat or defeat

The physiological role of airway smooth muscle remains highly elusive given the poor overall understanding of the regulatory elements and their influence in healthy humans [1]. Paradoxically, the pathophysiological contribution of airway smooth muscle contraction to asthma is better understood than the physiological role of this contraction in non-asthmatics: early and late asthmatic responses highlight immediate-immune cell-free and delayed-immune cell-dependent bronchoconstriction, respectively [2]. Reducing the late asthmatic response with the inhaled anti-TSLP antibody ecleralimab raises more questions than providing answers <https://bit.ly/3vOkEIN> We thank David Manley for revising the English in this editorial.

Role of Airway Smooth Muscle in Inflammation Related to Asthma and COPD.

Airway smooth muscle contributes to both contractility and inflammation in the pathophysiology of asthma and COPD. Airway smooth muscle cells can change the degree of a variety of functions, including contraction, proliferation, migration, and the secretion of inflammatory mediators (phenotype plasticity). Airflow limitation, airway hyperresponsiveness, β2-adrenergic desensitization, and airway remodeling, which are fundamental characteristic features of these diseases, are caused by phenotype changes in airway smooth muscle cells. Alterations between contractile and hyper-contractile, synthetic/proliferative phenotypes result from Ca2+ dynamics and Ca2+ sensitization. Modulation of Ca2+ dynamics through the large-conductance Ca2+-activated K+ channel/L-type voltage-dependent Ca2+ channel linkage and of Ca2+ sensitization through the RhoA/Rho-kinase pathway contributes not only to alterations in the contractile phenotype involved in airflow limitation, airway hyperresponsiveness, and β2-adrenergic desensitization but also to alteration of the synthetic/proliferative phenotype involved in airway remodeling. These Ca2+ signal pathways are also associated with synergistic effects due to allosteric modulation between β2-adrenergic agonists and muscarinic antagonists. Therefore, airway smooth muscle may be a target tissue in the therapy for these diseases. Moreover, the phenotype changing in airway smooth muscle cells with focuses on Ca2+ signaling may provide novel strategies for research and development of effective remedies against both bronchoconstriction and inflammation.

S100A4 is secreted by airway smooth muscle tissues and activates inflammatory signaling pathways via receptors for advanced glycation end products.

S100A4 is a low-molecular-mass (12 kDa) EF-hand Ca2+-binding S100 protein that is expressed in a broad range of normal tissue and cell types. S100A4 can be secreted from some cells to act in an autocrine or paracrine fashion on target cells and tissues. S100A4 has been reported in the extracellular fluids of subjects with several inflammatory diseases, including asthma. Airway smooth muscle plays a critical role in airway inflammation by synthesizing and secreting inflammatory cytokines. We hypothesized that S100A4 may play an immunomodulatory role in airway smooth muscle. Trachealis smooth muscle tissues were stimulated with recombinant His-S100A4, and the effects on inflammatory responses were evaluated. S100A4 induced the activation of Akt and NF-κB and stimulated eotaxin secretion. It also increased the expression of RAGE and endogenous S100A4 in airway tissues. Stimulation of airway smooth muscle tissues with IL-13 or TNF-α induced the secretion of S100A4 from the tissues and promoted the expression of endogenous receptors for advanced glycation end products (RAGE) and S100A4. The role of RAGE in mediating the responses to S100A4A was evaluated by expressing a mutant nonfunctional RAGE (RAGEΔcyto) in tracheal muscle tissues and by treating tissues with a RAGE inhibitor. S100A4 did not activate NF-κB or Akt in tissues that were expressing RAGEΔcyto or treated with a RAGE inhibitor, indicating that S100A4 mediates its effects by acting on RAGE. Our results demonstrate that inflammatory mediators stimulate the synthesis and secretion of S100A4 in airway smooth muscle tissues and that extracellular S100A4 acts via RAGE to mediate airway smooth muscle inflammation.

Generation and Role of Oscillatory Contractions in Mouse Airway Smooth Muscle

Background/Aims: Tetraethylammonium chloride (TEA) induces oscillatory contractions in mouse airway smooth muscle (ASM); however, the generation and maintenance of oscillatory contractions and their role in ASM are unclear. Methods: In this study, oscillations of ASM contraction and intracellular Ca²⁺ were measured using force measuring and Ca²⁺ imaging technique, respectively. TEA, nifedipine, niflumic acid, acetylcholine chloride, lithium chloride, KB-R7943, ouabain, 2-Aminoethoxydiphenyl borate, thapsigargin, tetrodotoxin, and ryanodine were used to assess the mechanism of oscillatory contractions. Results: TEA induced depolarization, resulting in activation of L-type voltage-dependent Ca²⁺ channels (LVDCCs) and voltage-dependent Na⁺ (V_Na) channels. The former mediated Ca²⁺ influx to trigger a contraction and the latter mediated Na⁺ entry to enhance the contraction via activating LVDCCs. Meanwhile, increased Ca²⁺-activated Cl^- channels, inducing depolarization that resulted in contraction through LVDCCs. In addition, the contraction was enhanced by intracellular Ca²⁺ release from Ca²⁺ stores mediated by inositol (1,4,5)-trisphosphate receptors (IP₃Rs). These pathways together produce the contractile phase of the oscillatory contractions. Furthermore, the increased Ca²⁺ activated the Na⁺-Ca²⁺ exchanger (NCX), which transferred Ca²⁺ out of and Na⁺ into the cells. The former induced relaxation and the latter activated Na⁺/K⁺-ATPase that induced hypopolarization to inactivate LVDCCs causing further relaxation. This can also explain the relaxant phase of the oscillatory contractions. Moreover, the depolarization induced by V_Na channels and NCX might be greater than the hypopolarization caused by Na⁺/K⁺-ATPase alone, inducing LVDCC activation and resulting in further contraction. Conclusions: These data indicate that the TEA-induced oscillatory contractions were cooperatively produced by LVDCCs, V_Na channels, Ca²⁺-activated Cl^- channels, NCX, Na⁺/K⁺ ATPase, IP₃Rs-mediated Ca²⁺ release, and extracellular Ca²⁺.

Bronchial thermoplasty and the role of airway smooth muscle: are we on the right direction?

Asthma is characterized by inflammation of the airways that includes eosinophils, basal membrane thickening, epithelial sloughing, vascular changes, smooth muscle hypertrophy and hyperplasia, and mucous gland hyperplasia. Recently, there have been studies on the role of hypersensitivity and inflammation in asthma, but the role of bronchial smooth muscle remains unclear. Bronchial thermoplasty is an endoscopic procedure that is approved by the US Food and Drug Administration (FDA) for the treatment of severe refractory asthma, based on the local delivery of radio frequency at 65°C to the airways, with the aim of controlling bronchospasm through a reduction of airway smooth muscle (ASM). Several recent studies have shown significant improvement in clinical outcomes of bronchial thermoplasty for asthma, including symptom control, reduction in exacerbation and hospitalization rates, improved quality of life, and reduction in number of working days or school days lost due to asthma. Data from these recent studies have shown reduction in ASM following bronchial thermoplasty and changes in inflammation patterns. It has also been argued that bronchial thermoplasty may have modulating effects on neuroendocrine epithelial cells, bronchial nerve endings, TRPV1 nerve receptors, and type-C unmyelinated fibers in the bronchial mucosa. This may involve interrupting the central and local reflexes responsible for the activation of bronchospasm in the presence of bronchial hyperreactivity. Several questions remain regarding the use of bronchial thermoplasty, mechanism of action, selection of appropriate patients, and long-term effects. In this review, the role of ASM in the pathogenesis of asthma and the key aspects of bronchial thermoplasty are discussed, with a focus on the potential clinical effects of this promising procedure, beyond the reduction in ASM.

Nelumbo nucifera leaves extracts inhibit mouse airway smooth muscle contraction

BackgroundAlkaloids extracted from lotus leaves (AELL) can relax vascular smooth muscle. However, whether AELL has a similar relaxant role on airway smooth muscle (ASM) remains unknown. This study aimed to explore the relaxant property of AELL on ASM and the underlying mechanism.MethodsAlkaloids were extracted from dried lotus leaves using the high temperature rotary evaporation extraction method. The effects of AELL on mouse ASM tension were studied using force measuring and patch-clamp techniques.ResultsIt was found that AELL inhibited the high K+ or acetylcholine chloride (ACh)-induced precontraction of mouse tracheal rings by 64.8 ± 2.9%, or 48.8 ± 4.7%, respectively. The inhibition was statistically significant and performed in a dose-dependent manner. Furthermore, AELL-induced smooth muscle relaxation was partially mediated by blocking voltage-dependent Ca2+ channels (VDCC) and non-selective cation channels (NSCC).ConclusionAELL, which plays a relaxant role in ASM, might be a new complementary treatment to treat abnormal contractions of the trachea and asthma.

TLR3 activation increases chemokine expression in human fetal airway smooth muscle cells.

Viral infections, such as respiratory syncytial virus and rhinovirus, adversely affect neonatal and pediatric populations, resulting in significant lung morbidity, including acute asthma exacerbation. Studies in adults have demonstrated that human airway smooth muscle (ASM) cells modulate inflammation through their ability to secrete inflammatory cytokines and chemokines. The role of ASM in the developing airway during infection remains undefined. In our study, we used human fetal ASM cells as an in vitro model to examine the effect of Toll-like receptor (TLR) agonists on chemokine secretion. We found that fetal ASM express multiple TLRs, including TLR3 and TLR4, which are implicated in the pathogenesis of respiratory syncytial virus and rhinovirus infection. Cells were treated with TLR agonists, polyinosinic-polycytidylic acid [poly(I:C)] (TLR3 agonist), lipopolysaccharide (TLR4 agonist), or R848 (TLR7/8 agonist), and IL-8 and chemokine (C-C motif) ligand 5 (CCL5) secretion were evaluated. Interestingly, poly(I:C), but neither lipopolysaccharide nor R848, increased IL-8 and chemokine (C-C motif) ligand 5 secretion. Examination of signaling pathways suggested that the poly(I:C) effects in fetal ASM involve TLR and ERK signaling, in addition to another major inflammatory pathway, NF-κB. Moreover, there are variations between fetal and adult ASM with respect to poly(I:C) effects on signaling pathways. Pharmacological inhibition suggested that ERK pathways mediate poly(I:C) effects. Overall, our data show that poly(I:C) initiates activation of proinflammatory pathways in developing ASM, which may contribute to immune responses to infection and exacerbation of asthma.

17β-Aminoestrogens induce guinea pig airway smooth muscle hyperresponsiveness through L-type Ca2+ channels activation

Therapy with estrogens is frequently used in menopausal women and as hormonal contraception. Because of its thrombotic effects, long term estrogen administration used in hormonal replacement therapy (HRT) and contraception could represent a health hazard. In this regard, 17β-aminoestrogens such as aminoestrol, butolame and pentolame have shown promising HRT potential, because they have a weak agonist estrogenic action and antithrombotic activity. Additionally, estrogens play a protective role in airway smooth muscle, but the effect of 17β-aminoestrogens on the airway smooth muscle has not been tested yet. In guinea pig tracheal smooth muscle pentolame and butolame induced hyperresponsiveness to histamine (His), carbachol (Cch) and KCl. Interestingly, aminoestrol did not show this effect at the highest concentration studied, it even lowered the contraction induced by Cch. The hyperresponsiveness induced by pentolame to His was abolished by nifedipine. In single tracheal myocytes, KCl induced an increment in the intracellular Ca2+ concentration [Ca2+]i, pentolame also showed an increase in [Ca2+]i and the addition of KCl in the plateau of this rise further significantly augmented the [Ca2+]i response. Additionally, in patch clamp experiments pentolame increased the L-type Ca2+ currents. Thus, 17β-aminoestrogens such as pentolame and butolame, but not aminoestrol, activate L-type Ca2+ channel to induced hyperresponsiveness to Cch, His and KCl in guinea pig tracheal smooth muscle. Due to its lack of effect on airways and to its anticoagulant characteristics, aminoestrol seems to be the best alternative in the HRT among the 17β-aminoestrogens studied.

The ROAD to a focused view of airway smooth muscle and inflammatory cells in asthmatic sensitization: a tribute to Newman Stephens.

The ROAD to a focused view of airway smooth muscle and inflammatory cells in asthmatic sensitization: a tribute to Newman Stephens.

Smooth Muscle Hypercontractility in Airway Hyperresponsiveness: Innate, Acquired, or Nonexistent?

Asthma symptoms are triggered or exacerbated by a range of environmental factors, such as allergens, viruses, fungi, exercise, aspirin, pollutants, and occupational irritants and sensitizers. While traditionally considering an intrinsic disease, in more recent years asthma has been viewed by many as a genetically associated environmental lung disorder with a heterogeneous pathogenesis. With the exception of the severe cases, the diagnostic signature of asthma is the reversibility of airway obstruction by agents that relax airway smooth muscle (ASM), which attests to the importance of this tissue in the pathobiology of the airflow obstruction. Most asthmatic individuals are hyperresponsive to bronchoprovocative challenge with a spasmogen (i.e., bronchoconstrictor agonist such as methacholine or histamine). Airway hyperresponsiveness (AHR) in asthmatic patients can either result from “hyperreactive airways” characterized by an excessive airway narrowing or “hyperexcitability,” where the airways become excessively sensitive to very low doses of constrictor agonists. It is believed that the abnormal narrowing of the airways (hyperreactivity) is responsible for most of the morbidity and mortality due to asthma. In either case, the role of ASM in the development of AHR remains to be further investigated. The controversial questions that remain to be answered are whether AHR seen in asthmatic patients is due to functional changes in the ASM and whether those changes actually lead a “hypercontractile” phenotype. This special issue aims to shed light on what seems to be a perdurable debate as to whether the hypercontractility of ASM characterizes AHR, whether this hypercontractile phenotype exists, and whether it is innate or acquired. Notwithstanding the potentially important associative role of airway inflammation, this special issue addresses different viewpoints by experts in the field that relate to newly identified contractile properties of ASM that may contribute to AHR when perturbed and also considers the latest advances in the search for better asthma treatments that directly target the ASM. C. D. Pascoe and coworkers set the stage for the ongoing debate by providing an enlighten historical perspective on the role that has been attributed to ASM in the pathobiology of asthma and AHR. The authors reference monographs that date backs to the 16th century and then describe pivotal developments made more recently that offer tentative links between the airway dysfunction seen in asthma and certain recognized features of ASM observed ex vivo. They also point out the rapid gain of interest and the increasing amount of research pursued in this area in the past few years.

Counterpoint: Alterations in airway smooth muscle phenotype do not cause airway hyperresponsiveness in asthma

We have been assigned the task of showing that “alterations in airway smooth muscle phenotype DO NOT cause the airways hyperresponsiveness of asthma.” In the following paragraphs we will briefly review the overwhelming lack of evidence that any fundamental change in the intrinsic properties of

Beyond the Immune System: The Role of Resident Cells in Asthma and COPD

Beyond the Immune System: The Role of Resident Cells in Asthma and COPD

S8-3 Caveolae and regulation of airway smooth muscle function(The role of airway smooth muscle in pathogenesis asthma)

S8-3 Caveolae and regulation of airway smooth muscle function(The role of airway smooth muscle in pathogenesis asthma)

S8-4 Bronchial Thermoplasty : A Novel Treatment for Severe Asthma(The role of airway smooth muscle in pathogenesis asthma)

S8-4 Bronchial Thermoplasty : A Novel Treatment for Severe Asthma(The role of airway smooth muscle in pathogenesis asthma)

The Pivotal Role of Airway Smooth Muscle in Asthma Pathophysiology

Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function.

Noninflammatory mechanisms of airway hyper-responsiveness in bronchial asthma: an overview

Airway hyper-responsiveness (AHR) is a cardinal feature of asthma. Its absence has been considered useful in excluding asthma, whereas it may be present in other diseases such as atopic rhinitis and chronic obstructive pulmonary disease. AHR is often considered an epiphenomenon of airway inflammation. Actually, the response of airways to constrictor stimuli is modulated by a complex array of factors, some facilitating and others opposing airway narrowing. Thus, it has been suggested that AHR, and perhaps asthma, might be present even without or before the development of airway inflammation. We begin this review by highlighting some terminological and methodological issues concerning the measurement of AHR. Then we describe the neurohumoral mechanisms controlling airway tone. Finally, the pivotal role of airway smooth muscle and internal and external modulation of airway caliber in vivo are discussed in detail.

Asthma: where is it going?

Asthma is characterized by reversible airway obstruction, airway hyperresponsiveness, and airway inflammation. Although our understanding of its pathophysiological mechanisms continues to evolve, the relative contributions of airway hyperresponsiveness and inflammation are still debated. The first mechanism identified as important for asthma was bronchial hyperresponsiveness. In a second step, asthma was recognized also as an inflammatory disease, with chronic inflammation inducing structural changes or remodeling. However, persistence of airway dysfunction despite inflammatory control is observed in chronic severe asthma of both adults and children. More recently, a potential role for epithelial-mesenchymal communication or transition is emerging, with epithelial injury often resulting in a self-sustaining phenotype of wound repair modulation by activation/reactivation of the epithelial-mesenchymal trophic unit, suggesting that chronic asthma can be more than an inflammatory disease. It is noteworthy that the gene-environmental interactions critical for the development of a full asthma phenotype involve processes similar to those occurring in branching morphogenesis. In addition, a central role for airway smooth muscle in the pathogenesis of the disease has been explored, highlighting its secretory function as well as different intrinsic properties compared to normal subjects. These new concepts can potentially shed light on the mechanisms underlying some asthma phenotypes and improve our understanding of the disease in terms of the therapeutic strategies to be applied. How we understand asthma and its mechanisms along time will be the focus of this overview.

Treating asthma means treating airway smooth muscle cells

Asthma is characterised by airway hyperresponsiveness, airway inflammation and airway remodelling. Airway smooth muscle cells are known to be the main effector cells of airway narrowing. In the present paper, studies will be discussed that have led to a novel view of the role of airway smooth muscle in the pathogenesis of asthma in which airway hyperresponsiveness, remodelling and inflammation are, at least in part, attributable to airway smooth muscle. Furthermore, how this new view may lead to a change in the phenotyping and treatment of patients with asthma will be discussed.

Airway Smooth Muscle Cell as an Inflammatory Cell: Lessons Learned from Interferon Signaling Pathways

The present article will describe the potential role of airway smooth muscle (ASM) in mediating both deleterious/beneficial effects of interferons (IFNs) in asthma. First described as beneficial in treating the main features of asthma, the interplay between IFNs and ASM could explain their deleterious actions recently described in a number of different studies. Through multiple mechanisms, including the suppression of steroid action, the synergistic pro-inflammatory actions when combined with other cytokines, and the modulation of calcium metabolism, IFNs are now seen as critical mediators in the pathogenesis of asthma.

Airway smooth muscle relaxation is impaired in mice lacking the p47phox subunit of NAD(P)H oxidase.

NAD(P)H oxidase is one of the critical enzymes mediating cellular production of reactive oxygen species and has a central role in airway smooth muscle (ASM) cell proliferation. Since reactive oxygen species also affect ASM contractile response, we hypothesized a regulatory role of NAD(P)H oxidase in ASM contractility. We therefore studied ASM function in wild-type mice (C57BL/6J) and mice deficient in a component (p47phox) of NAD(P)H oxidase. In histological sections of the trachea, we found that the area occupied by ASM was 17% more in p47(phox-/-) than in wild-type mice. After correcting for the difference in ASM content, we found that force generation did not vary between the two genotypes. Similarly, their ASM shortening velocity, maximal power, and sensitivity to acetylcholine, as well as airway responsiveness to methacholine in vivo, were not significantly different. The main finding of this study was a significantly reduced ASM relaxation in p47phox-/- compared with wild-type mice both during the stimulus and after the end of stimulation. The tension relaxation attained at the 20th second of electric field stimulation was, respectively, 17.6 +/- 2.4 and 9.2 +/- 2.3% in null and wild-type mice (P <0.01 by t-test). Similar significant differences were found in the rate of tension relaxation and the time required to reduce tension by one-half. Our data suggest that NAD(P)H oxidase may have a role in the structural arrangement and mechanical properties of the airway tissue. Most importantly, we report the first evidence that the p47phox subunit of NAD(P)H oxidase plays a role in ASM relaxation.