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1.  Airway Smooth Muscle Hypercontractility in Asthma 
Journal of Allergy  2013;2013:185971.
In recent years, asthma has been defined primarily as an inflammatory disorder with emphasis on inflammation being the principle underlying pathophysiological characteristic driving airway obstruction and remodelling. Morphological abnormalities of asthmatic airway smooth muscle (ASM), the primary structure responsible for airway obstruction seen in asthma, have long been described, but surprisingly, until recently, relatively small number of studies investigated whether asthmatic ASM was also fundamentally different in its functional properties. Evidence from recent studies done on single ASM cells and on ASM-impregnated gel cultures have shown that asthmatic ASM is intrinsically hypercontractile. Several elements of the ASM contraction apparatus in asthmatics and in animal models of asthma have been found to be different from nonasthmatics. These differences include some regulatory contractile proteins and also some components of both the calcium-dependent and calcium-independent contraction signalling pathways. Furthermore, oxidative stress was also found to be heightened in asthmatic ASM and contributes to hypercontractility. Understanding the abnormalities and mechanisms driving asthmatic ASM hypercontractility provides a great potential for the development of new targeted drugs, other than the conventional current anti-inflammatory and bronchodilator therapies, to address the desperate unmet need especially in patients with severe and persistent asthma.
doi:10.1155/2013/185971
PMCID: PMC3613096  PMID: 23577039
2.  Airway Smooth Muscle Dynamics and Hyperresponsiveness: In and outside the Clinic 
Journal of Allergy  2012;2012:157047.
The primary functional abnormality in asthma is airway hyperresponsiveness (AHR)—excessive airway narrowing to bronchoconstrictor stimuli. Our understanding of the underlying mechanism(s) producing AHR is incomplete. While structure-function relationships have been evoked to explain AHR (e.g., increased airway smooth muscle (ASM) mass in asthma) more recently there has been a focus on how the dynamic mechanical environment of the lung impacts airway responsiveness in health and disease. The effects of breathing movements such as deep inspiration reveal innate protective mechanisms in healthy individuals that are likely mediated by dynamic ASM stretch but which may be impaired in asthmatic patients and thereby facilitate AHR. This perspective considers the evidence for and against a role of dynamic ASM stretch in limiting the capacity of airways to narrow excessively. We propose that lung function measured after bronchial provocation in the laboratory and changes in lung function perceived by the patient in everyday life may be quite different in their dependence on dynamic ASM stretch.
doi:10.1155/2012/157047
PMCID: PMC3483736  PMID: 23118774
3.  The laminin β1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma 
Respiratory Research  2010;11(1):170.
Background
Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hyper)contractile phenotype is dependent on laminin, which can be inhibited by the laminin-competing peptide Tyr-Ile-Gly-Ser-Arg (YIGSR). The role of laminins in ASM remodelling in chronic asthma in vivo, however, has not yet been established.
Methods
Using an established guinea pig model of allergic asthma, we investigated the effects of topical treatment of the airways with YIGSR on features of airway remodelling induced by repeated allergen challenge, including ASM hyperplasia and hypercontractility, inflammation and fibrosis. Human ASM cells were used to investigate the direct effects of YIGSR on ASM proliferation in vitro.
Results
Topical administration of YIGSR attenuated allergen-induced ASM hyperplasia and pulmonary expression of the proliferative marker proliferating cell nuclear antigen (PCNA). Treatment with YIGSR also increased both the expression of sm-MHC and ASM contractility in saline- and allergen-challenged animals; this suggests that treatment with the laminin-competing peptide YIGSR mimics rather than inhibits laminin function in vivo. In addition, treatment with YIGSR increased allergen-induced fibrosis and submucosal eosinophilia. Immobilized YIGSR concentration-dependently reduced PDGF-induced proliferation of cultured ASM to a similar extent as laminin-coated culture plates. Notably, the effects of both immobilized YIGSR and laminin were antagonized by soluble YIGSR.
Conclusion
These results indicate that the laminin-competing peptide YIGSR promotes a contractile, hypoproliferative ASM phenotype in vivo, an effect that appears to be linked to the microenvironment in which the cells are exposed to the peptide.
doi:10.1186/1465-9921-11-170
PMCID: PMC3013082  PMID: 21129174
4.  Myosin, Transgelin, and Myosin Light Chain Kinase 
Rationale: Airway smooth muscle (SM) of patients with asthma exhibits a greater velocity of shortening (Vmax) than that of normal subjects, and this is thought to contribute to airway hyperresponsiveness. A greater Vmax can result from increased myosin activation. This has been reported in sensitized human airway SM and in models of asthma. A faster Vmax can also result from the expression of specific contractile proteins that promote faster cross-bridge cycling. This possibility has never been addressed in asthma.
Objectives: We tested the hypothesis that the expression of genes coding for SM contractile proteins is altered in asthmatic airways and contributes to their increased Vmax.
Methods: We quantified the expression of several genes that code for SM contractile proteins in mild allergic asthmatic and control human airway endobronchial biopsies. The function of these contractile proteins was tested using the in vitro motility assay.
Measurements and Main Results: We observed an increased expression of the fast myosin heavy chain isoform, transgelin, and myosin light chain kinase in patients with asthma. Immunohistochemistry demonstrated the expression of these genes at the protein level. To address the functional significance of this overexpression, we purified tracheal myosin from the hyperresponsive Fisher rats, which also overexpress the fast myosin heavy chain isoform as compared with the normoresponsive Lewis rats, and found a faster rate of actin filament propulsion. Conversely, transgelin did not alter the rate of actin filament propulsion.
Conclusions: Selective overexpression of airway smooth muscle genes in asthmatic airways leads to increased Vmax, thus contributing to the airway hyperresponsiveness observed in asthma.
doi:10.1164/rccm.200609-1367OC
PMCID: PMC2633053  PMID: 19011151
asthma; airway hyperresponsiveness; gene expression; smooth muscle; myosin
5.  Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma 
Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.
As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.
Anti-inflammatory therapy, however, does not “cure” asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.
In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.
doi:10.1183/09031936.00112606
PMCID: PMC2527453  PMID: 17470619
Airway mechanics; interdependence; lung function; muscle adaptation; muscle contraction; parenchyma
6.  Role of Abl in airway hyperresponsiveness and airway remodeling 
Respiratory Research  2013;14(1):105.
Background
Asthma is a chronic disease that is characterized by airway hyperresponsiveness and airway remodeling. The underlying mechanisms that mediate the pathological processes are not fully understood. Abl is a non-receptor protein tyrosine kinase that has a role in the regulation of smooth muscle contraction and smooth muscle cell proliferation in vitro. The role of Abl in airway hyperresponsiveness and airway remodeling in vivo is largely unknown.
Methods
To evaluate the role of Abl in asthma pathology, we assessed the expression of Abl in airway tissues from the ovalbumin sensitized and challenged mouse model, and human asthmatic airway smooth muscle cells. In addition, we generated conditional knockout mice in which Abl expression in smooth muscle was disrupted, and then evaluated the effects of Abl conditional knockout on airway resistance, smooth muscle mass, cell proliferation, IL-13 and CCL2 in the mouse model of asthma. Furthermore, we determined the effects of the Abl pharmacological inhibitors imatinib and GNF-5 on these processes in the animal model of asthma.
Results
The expression of Abl was upregulated in airway tissues of the animal model of asthma and in airway smooth muscle cells of patients with severe asthma. Conditional knockout of Abl attenuated airway resistance, smooth muscle mass and staining of proliferating cell nuclear antigen in the airway of mice sensitized and challenged with ovalbumin. Interestingly, conditional knockout of Abl did not affect the levels of IL-13 and CCL2 in bronchoalveolar lavage fluid of animals treated with ovalbumin. However, treatment with imatinib and GNF-5 inhibited the ovalbumin-induced increase in IL-13 and CCL2 as well as airway resistance and smooth muscle growth in animals.
Conclusions
These results suggest that the altered expression of Abl in airway smooth muscle may play a critical role in the development of airway hyperresponsiveness and airway remodeling in asthma. Our findings support the concept that Abl may be a novel target for the development of new therapy to treat asthma.
doi:10.1186/1465-9921-14-105
PMCID: PMC3852349  PMID: 24112389
Airway hyperresponsiveness; Airway remodeling; Tyrosine kinase; Airway smooth muscle
7.  The Pivotal Role of Airway Smooth Muscle in Asthma Pathophysiology 
Journal of Allergy  2011;2011:742710.
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.
doi:10.1155/2011/742710
PMCID: PMC3246780  PMID: 22220184
8.  TARGETING THE AIRWAY SMOOTH MUSCLE FOR ASTHMA TREATMENT 
Asthma is a complex respiratory disease whose incidence has increased worldwide in the last decade. There is currently no cure for asthma. While bronchodilator and anti-inflammatory medications are effective medicines in some asthmatic patients, it is clear that an unmet therapeutic need persists for a subpopulation of individuals with severe asthma. This chronic lung disease is characterized by airflow limitation and lung inflammation and remodeling that includes increased airway smooth muscle (ASM) mass. In addition to its contractile properties, the ASM also contributes to the inflammatory process by producing active mediators, modifying the extracellular matrix composition, and interacting with inflammatory cells. These undesirable functions make interventions aimed at reducing ASM abundance an attractive strategy for novel asthma therapies. There are at least three mechanisms that could limit the accumulation of smooth muscle – decreased cell proliferation, augmented cell apoptosis, and reduced cell migration into the smooth muscle layer. Inhibitors of the mevalonate pathway or statins hold promise for asthma because they exhibit anti-inflammatory, anti-migratory, and anti-proliferative effects in pre-clinical and clinical studies, and they can target the SM. This review will discuss current knowledge of ASM biology and identify gaps in the field in order to stimulate future investigations of the cellular mechanisms controlling ASM overabundance in asthma. Targeting ASM has the potential to be an innovative venue of treatment for patients with asthma.
doi:10.1016/j.trsl.2009.06.008
PMCID: PMC2764304  PMID: 19766960
airway smooth muscle; asthma; contractile; cytokine; hyperplasia; hypertrophy; inflammation; mevalonate; progenitor cells; statins; TGF beta; translational
9.  Airway remodelling in asthma: role for mechanical forces 
Asia Pacific Allergy  2014;4(1):19-24.
Asthma is a chronic airway inflammatory disease with functional and structural changes, leading to bronchial hyperresponsiveness and airflow obstruction. Airway structural changes or airway remodelling consist of epithelial injury, goblet cell hyperplasia, subepithelial layer thickening, airway smooth muscle hyperplasia and angiogenesis. These changes were previously considered as a consequence of chronic airway inflammation. Even though inhaled corticosteroids can suppress airway inflammation, the natural history of asthma is still unaltered after inhaled corticosteroid treatment. As such there is increasing evidence for the role of mechanical forces within the asthmatic airway contributing to airway structural changes.
doi:10.5415/apallergy.2014.4.1.19
PMCID: PMC3921863  PMID: 24527406
Asthma; Airway remodelling; Mechanical forces
10.  Airway Wall Expression of OX40/OX40L and Interleukin-4 in Asthma 
Chest  2010;137(4):797-804.
Background:
The costimulatory molecule OX40 and its ligand, OX40L, mediate key aspects of allergic airway inflammation in animal models of asthma, including eosinophilic airway inflammation, airway hyperresponsiveness, and T helper 2 polarization. We sought to examine OX40/OX40L and interleukin (IL)-4 expression in asthma across severities.
Methods:
Bronchial biopsies were obtained from 27 subjects with asthma (mild Global Initiative for Asthma [GINA] 1 [n = 10], moderate GINA 2-3 [n = 7], and severe GINA 4-5 [n = 10]) and 13 healthy controls. The number of OX40+, OX40L+, IL-4+, and IL-4 receptor α (IL-4Rα)+ cells in the lamina propria and airway smooth muscle (ASM) bundle and the intensity of IL-4Rα+ expression by the ASM were assessed.
Results:
The number of OX40+, OX40L+, and IL-4+ cells in the lamina propria and OX40+ and IL-4+ cells in the ASM bundle was significantly increased in subjects with mild asthma, but not in those with moderate or severe asthma, compared with healthy controls. In the subjects with asthma, OX40/OX40L expression was positively correlated with the number of eosinophils and IL-4+ cells in the lamina propria. The number of IL-4Rα+ cells in the lamina propria was significantly increased in moderate-to-severe disease, but not in mild asthma, compared with controls. IL-4Rα expression by the ASM bundle was not different among groups.
Conclusions:
OX40/OX40L expression is increased in the bronchial submucosa in mild asthma, but not in moderate-to-severe disease, and is related to the degree of tissue eosinophilia and IL-4 expression. Whether these costimulatory molecules have a role as targets for asthma requires further investigation.
doi:10.1378/chest.09-1839
PMCID: PMC2851558  PMID: 20139223
11.  Expression of IL-4 Receptor alpha on smooth muscle cells is not necessary for development of experimental allergic asthma 
Background
Airflow in the lungs of patients with allergic asthma is impaired by excessive mucus production and airway smooth muscle contractions. Elevated levels of the cytokines IL-4 and IL-13 are associated with this pathology. In vitro studies have suggested that IL-4 receptor alpha (IL-4Rα) signalling on smooth muscle cells is critical for airway inflammation and airway hyperresponsiveness.
Objective
In order to define the contribution of IL-4 and IL-13 to the onset of asthmatic pathology the role of their key receptor IL-4Rα in smooth muscle cells was examined in vivo.
Methods
By using transgenic SMC-MHCcreIL-4Rα−/lox mice deficient for IL-4Rα in smooth muscle cells, in vivo effects of impaired IL-4Rα signalling in smooth muscle cells on the outcome of asthmatic disease were investigated for the first time. Allergic asthma was introduced in mice by repeated sensitisation with ovalbumin/aluminium hydroxide on days 0, 7 and 14 followed by intranasal allergen challenge on days 21–23. Mice were investigated for the presence of airway hyperresponsiveness, airway inflammation, allergen specific antibody production, Th2 type cytokine responses and lung pathology.
Results
Airway hyperresponsiveness, airway inflammation, mucus production, Th2 cytokine production and specific antibody responses were unaffected in SMC-MHCcreIL-4Rα−/lox mice when compared to control animals.
Conclusion
The impairment of IL-4Rα on smooth muscle cells had no effect on major aetiological markers of allergic asthma. These findings suggest that IL-4Rα responsiveness in airway smooth muscle cells during the early phase of allergic asthma is not, as suggested, necessary for the outcome of the disease.
Clinical Implications
Therapies targeting the IL-4Rα might have no direct effect on smooth muscle cells in an allergic asthma response.
doi:10.1016/j.jaci.2010.04.028
PMCID: PMC2917502  PMID: 20579713
Smooth muscle cell; Allergy; Asthma; Cytokine Receptors; IL-4; IL-13; gene-deficient mice
12.  Glutathione Redox Control of Asthma: From Molecular Mechanisms to Therapeutic Opportunities 
Antioxidants & Redox Signaling  2012;17(2):375-408.
Abstract
Asthma is a chronic inflammatory disorder of the airways associated with airway hyper-responsiveness and airflow limitation in response to specific triggers. Whereas inflammation is important for tissue regeneration and wound healing, the profound and sustained inflammatory response associated with asthma may result in airway remodeling that involves smooth muscle hypertrophy, epithelial goblet-cell hyperplasia, and permanent deposition of airway extracellular matrix proteins. Although the specific mechanisms responsible for asthma are still being unraveled, free radicals such as reactive oxygen species and reactive nitrogen species are important mediators of airway tissue damage that are increased in subjects with asthma. There is also a growing body of literature implicating disturbances in oxidation/reduction (redox) reactions and impaired antioxidant defenses as a risk factor for asthma development and asthma severity. Ultimately, these redox-related perturbations result in a vicious cycle of airway inflammation and injury that is not always amenable to current asthma therapy, particularly in cases of severe asthma. This review will discuss disruptions of redox signaling and control in asthma with a focus on the thiol, glutathione, and reduced (thiol) form (GSH). First, GSH synthesis, GSH distribution, and GSH function and homeostasis are discussed. We then review the literature related to GSH redox balance in health and asthma, with an emphasis on human studies. Finally, therapeutic opportunities to restore the GSH redox balance in subjects with asthma are discussed. Antioxid. Redox Signal. 17, 375–408.
I. Introduction and Conceptual Framework
II. Glutathione Synthesis
III. Distribution of Glutathione in the Body
IV. Glutathione Function and Homeostasis
A. Glutathione as a cysteine reservoir
B. Xenobiotic conjugation and detoxification
C. Free radical scavenging
D. Maintenance of thiol equilibrium
E. Protein S-glutathionylation
F. Regulation of cell surface proteins
G. Protection against nitrosative stress from RNS
V. Glutathione Redox Balance in Health
A. Intracellular glutathione redox status
B. Plasma glutathione redox status
C. Epithelial lining fluid glutathione redox status
VI. Glutathione Redox Balance in Asthma
A. Airway glutathione concentrations in asthma, measured invasively
B. Airway glutathione concentrations in asthma, measured noninvasively
C. Systemic glutathione concentrations in asthma
D. Glutathione redox balance in asthma: Effect of corticosteroids
VII. Other Glutathione-Related Proteins and Redox Systems in Asthma
A. Glutathione peroxidases
B. Glutathione reductases
C. Glutathione-S-transferases
D. Nitrosoglutathione
E. Thioredoxins
F. Glutaredoxins
G. Peroxiredoxins
VIII. Physiological and Biological Implications of Altered Glutathione Redox Balance in Asthma
IX. Altered Glutathione Redox Balance in Asthma: Therapeutic Opportunities
A. Glutathione and glutathione-ethyl esters
B. Cysteine precursors
C. Dietary interventions
1. Selenium
2. Whey protein
3. Sulfur amino acids
4. B vitamins
5. Glutamine and glycine
X. Clinical Implications and Future Directions
doi:10.1089/ars.2011.4198
PMCID: PMC3353819  PMID: 22304503
13.  Airway TGFβ1 and oxidant stress in children with severe asthma: Association with airflow limitation 
Background
Transforming growth factor beta-1 (TGFβ1) is thought to play a role in airway remodeling in asthma. TGFβ1 expression may be mediated by an excessive burden of reactive oxygen species and oxidant stress.
Objective
Given the profound airway oxidant stress we have previously observed in children with severe asthma, we sought to: 1) quantify TGFβ1 protein and mRNA gene expression in the airways of children with mild-to-moderate and severe atopic asthma; and to 2) determine the relationship of airway TGFβ1 concentrations to oxidant burden (i.e., lipid peroxidation), Th2-mediated eosinophilic inflammation, and airflow limitation.
Methods
Bronchoalveolar lavage fluid was collected from 68 atopic children with asthma (severe asthma, n = 28) and 12 atopic adult controls. Airway TGFβ1 expression and activation were assessed in relation to airway IL-13, 8-isoprostane, and malondialdehyde concentrations. The relationship of airway TGFβ1 expression to airflow limitation in children with asthma was also assessed.
Results
Children with severe asthma had higher total airway concentrations of TGFβ1 that were associated with increased protein and mRNA expression of TGFβ1 in airway macrophages and an increase in the lipid peroxidation biomarkers 8-isoprostanes and malondialdehyde. TGFβ1 activation was also greater in children with severe asthma and was associated with higher airway 8-isoprostane, malondialdehyde and IL-13 concentrations. Total airway TGFβ1 concentrations were further associated with airflow limitation.
Conclusions
Children with severe asthma have increased airway TGFβ1 expression and activation associated with an increased airway oxidant burden. Oxidant stress may mediate the effects of TGFβ1 and promote airway remodeling in children with severe asthma.
doi:10.1016/j.jaci.2011.11.037
PMCID: PMC3268912  PMID: 22206775
Airway remodeling; Asthma; Children; Lung function; Oxidant stress; Transforming growth factor beta-1
14.  Breath Formate Is a Marker of Airway S-Nitrosothiol Depletion in Severe Asthma 
PLoS ONE  2010;5(7):e11919.
Background
Children with severe asthma have poor symptom control and elevated markers of airway oxidative and nitrosative stress. Paradoxically, they have decreased airway levels of S-nitrosothiols (SNOs), a class of endogenous airway smooth muscle relaxants. This deficiency results from increased activity of an enzyme that both reduces SNOs to ammonia and oxidizes formaldehyde to formic acid, a volatile carboxylic acid that is more easily detected in exhaled breath condensate (EBC) than SNOs. We therefore hypothesize that depletion of airway SNOs is related to asthma pathology, and breath formate concentration may be a proxy measure of SNO catabolism.
Methods and Findings
We collected EBC samples from children and adolescents, including 38 with severe asthma, 46 with mild-to-moderate asthma and 16 healthy adolescent controls, and the concentration of ionic constituents was quantified using ion chromatography. The concentrations of EBC components with volatile conjugates were log-normally distributed. Formate was the principal ion that displayed a significant difference between asthma status classifications. The mean EBC formate concentration was 40% higher in samples collected from all asthmatics than from healthy controls (mean = 5.7 µM, mean±standard deviation = 3.1−10.3 µM vs. 4.0, 2.8−5.8 µM, p = 0.05). EBC formate was higher in severe asthmatics than in mild-to-moderate asthmatics (6.8, 3.7−12.3 µM vs. 4.9, 2.8−8.7 µM, p = 0.012). In addition, formate concentration was negatively correlated with methacholine PC20 (r = −0.39, p = 0.002, asthmatics only), and positively correlated with the NO-derived ion nitrite (r = 0.46, p<0.0001) as well as with total serum IgE (r = 0.28, p = 0.016, asthmatics only). Furthermore, formate was not significantly correlated with other volatile organic acids nor with inhaled corticosteroid dose.
Conclusions
We conclude that EBC formate concentration is significantly higher in the breath of children with asthma than in those without asthma. In addition, amongst asthmatics, formate is elevated in the breath of those with severe asthma compared to those with mild-to-moderate asthma. We suggest that this difference is related to asthma pathology and may be a product of increased catabolism of endogenous S-nitrosothiols.
doi:10.1371/journal.pone.0011919
PMCID: PMC2912922  PMID: 20689836
15.  Link between vitamin D and airway remodeling 
In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma.
doi:10.2147/JAA.S46944
PMCID: PMC3979801
vitamin D; asthma; airway remodeling; airway smooth muscle; supplementation
16.  Transforming Growth Factor-β Induces Airway Smooth Muscle Hypertrophy 
Although smooth muscle hypertrophy is present in asthmatic airways, little is known about the biochemical pathways regulating airway smooth muscle protein synthesis, cell size, or accumulation of contractile apparatus proteins. We sought to develop a model of airway smooth muscle hypertrophy in primary cells using a physiologically relevant stimulus. We hypothesized that transforming growth factor (TGF)-β induces hypertrophy in primary bronchial smooth muscle cells. Primary human bronchial smooth muscle cells isolated from unacceptable lung donor tissue were studied. Cells were seeded on uncoated plastic dishes at 50% confluence and TGF-β was added. Experiments were performed in the absence of serum. TGF-β increased cell size and total protein synthesis, expression of α-smooth muscle actin and smooth muscle myosin heavy chain, formation of actomyosin filaments, and cell shortening to acetylcholine. Further, TGF-β increased airway smooth muscle α-actin synthesis in the presence of the transcriptional inhibitor actinomycin D, evidence that translational control is a physiologically important element of the observed hypertrophy. TGF-β induced the phosphorylation of eukaryotic translation initiation factor-4E–binding protein, a signaling event specifically involved in translational control. Finally, two inhibitors of 4E-binding protein phosphorylation, the phosphoinositol 3-kinase inhibitor LY294002 and a phosphorylation site mutant of 4E-binding protein-1 that dominantly inhibits eukaryotic initiation factor-4E, each blocked TGF-β– induced α-actin expression and cell enlargement. We conclude that TGF-β induces hypertrophy of primary bronchial smooth muscle cells. Further, phosphorylation of 4E-binding protein is required for the observed hypertrophy.
doi:10.1165/rcmb.2005-0166OC
PMCID: PMC2644185  PMID: 16239645
4E-binding protein; α-smooth muscle actin; eukaryotic initiation factor-4E; mammalian target of rapamycin (mTOR); phosphatidylinositol 3-kinase
17.  Airway remodelling in asthma: From benchside to clinical practice 
Airway remodelling refers to the structural changes that occur in both large and small airways relevant to miscellaneous diseases including asthma. In asthma, airway structural changes include subepithelial fibrosis, increased smooth muscle mass, gland enlargement, neovascularization and epithelial alterations. Although controversial, airway remodelling is commonly attributed to an underlying chronic inflammatory process. These remodelling changes contribute to thickening of airway walls and, consequently, lead to airway narrowing, bronchial hyper-responsiveness, airway edema and mucous hypersecretion. Airway remodelling is associated with poor clinical outcomes among asthmatic patients. Early diagnosis and prevention of airway remodelling has the potential to decrease disease severity, improve control and prevent disease expression. The relationship between structural changes and clinical and functional abnormalities clearly deserves further investigation. The present review briefly describes the characteristic features of airway remodelling observed in asthma, its clinical consequences and relevance for physicians, and its modulation by therapeutic approaches used in the treatment of asthmatic patients.
PMCID: PMC2933777  PMID: 20808979
Allergy; Asthma; Remodelling; Rhinitis
18.  Inflammation of bronchial smooth muscle in allergic asthma 
Thorax  2007;62(1):8-15.
Background
Recent observations in asthma suggest that bronchial smooth muscle is infiltrated by inflammatory cells including mast cells. Such an infiltration may contribute to airway remodelling that is partly due to an increase in smooth muscle mass. Whether muscle increase is the result of smooth muscle cell hypertrophy remains controversial and has not been studied by ultrastructural analysis. A morphometric analysis of airway smooth muscle (ASM) was undertaken in asthmatic patients using electron microscopy to examine the interactions between ASM cells and inflammatory cells.
Methods
ASM specimens were obtained from 14 asthmatic subjects and nine non‐asthmatic controls undergoing fibreoptic endoscopy. Inflammatory cell counts were assessed by immunohistochemistry, and ultrastructural parameters were measured using electron microscopy in a blinded fashion on smooth muscle cells and inflammatory cells.
Results
ASM from asthmatic patients was infiltrated by an increased number of mast cells and lymphocytes. Smooth muscle cells and their basal lamina were thicker in asthmatic patients (9.5 (0.8) and 1.4 (0.2) μm) than in controls (6.7 (0.4) and 0.7 (0.1) μm). In asthmatics the extracellular matrix was frequently organised in large amounts between ASM cells. Myofibroblasts within smooth muscle bundles were only observed in asthmatics, some of them displaying a close contact with ASM cells.
Conclusion
In asthma, airway myositis is characterised by a direct interaction between ASM cells and mast cells and lymphocytes. Smooth muscle remodelling was present, including cell hypertrophy and abnormal extracellular matrix deposition moulding ASM cells.
doi:10.1136/thx.2006.062141
PMCID: PMC2111285  PMID: 17189531
asthma; smooth muscle; inflammation; mast cell; myofibroblast
19.  Transforming Growth Factor-β and Nuclear Factor E2–related Factor 2 Regulate Antioxidant Responses in Airway Smooth Muscle Cells 
Rationale: Aberrant airway smooth muscle cell (ASMC) function and overexpression of transforming growth factor (TGF)-β, which modulates ASMC proliferative and inflammatory function and induces oxidant release, are features of asthma. Nuclear factor E2-related factor 2 (Nrf2) activates antioxidant genes conferring protection against oxidative stress.
Objectives: To determine the role of Nrf2 in ASMCs and its modulation by TGF-β, and compare Nrf2 activity in ASMCs from subjects with severe and nonsevere asthma and healthy subjects.
Methods: ASMCs were cultured from airways of subjects without asthma, and from airway biopsies from patients with severe and nonsevere asthma. We studied Nrf2 activation on antioxidant gene expression and proliferation, the effect of TGF-β on Nrf2 transcriptional activity, and the impact of Nrf2 activation on TGF-β–mediated proliferation and IL-6 release. Nrf2–antioxidant response elements binding and Nrf2-dependent antioxidant gene expression was determined in asthmatic ASMCs.
Measurements and Main Results: Activation of Nrf2 led to up-regulation of the antioxidant genes heme oxygenase (HO)-1, NAD(P)H:quinone oxidoreductase, and manganese superoxide dismutase, and a reduction in proliferation. TGF-β reduced Nrf2-mediated antioxidant gene transcription through induction of activating transcription factor-3 expression. Nrf2 activation attenuated TGF-β–mediated reduction in HO-1, ASMC proliferation, and IL-6 release. Nrf2–antioxidant response elements binding was reduced in ASMCs from patients with severe asthma compared with ASMCs from patients with nonsevere asthma and normal subjects. HO-1 expression was reduced in ASMCs from patients with both nonsevere and severe asthma compared with healthy subjects.
Conclusions: Nrf2 regulates antioxidant responses and proliferation in ASMCs and is inactivated by TGF-β. Nrf2 reduction may underlie compromised antioxidant protection and aberrant ASM function in asthma.
doi:10.1164/rccm.201011-1780OC
PMCID: PMC3402549  PMID: 21799075
asthma; airway smooth muscle; nuclear factor E2-related factor 2; transforming growth factor-β; antioxidant
20.  Airway Smooth Muscle in Asthma: Just a Target for Bronchodilation? 
Clinics in chest medicine  2012;33(3):543-558.
Synopsis
Airway smooth muscle (ASM) has long been recognized as the main cell type responsible for bronchial hyperresponsiveness. It has thus been considered as a target for bronchodilation. In asthma however, there is a complex relationship between ASM and inflammatory cells such as mast cells and T lymphocytes. Moreover, the increased ASM mass in the asthmatic airways is one of the key features of airway remodeling. This article aims to review the main concepts about the three possible roles of ASM in asthma including (i) contractile tone, (ii) inflammatory response and (iii) remodeling.
doi:10.1016/j.ccm.2012.05.002
PMCID: PMC3431506  PMID: 22929101
Bronchodilators; Hyperresponsiveness; Inflammation; Remodeling; Smooth muscle
21.  Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma 
Rationale: Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation in mild to moderate asthma. However, whether FeNO levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by FeNO levels would identify a more reactive, at-risk asthma phenotype.
Methods: FeNO and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 nonsevere) and 49 healthy subjects enrolled in the Severe Asthma Research Program.
Measurements and Main Results: FeNO levels were similar among patients with severe and nonsevere asthma. The proportion of individuals with high FeNO levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high FeNO had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High FeNO identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care.
Conclusions: Grouping of asthma by FeNO provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.
doi:10.1164/rccm.200905-0695OC
PMCID: PMC2874447  PMID: 20133930
nitric oxide; severe asthma; phenotype; airway reactivity; exhaled breath
22.  Autocrine interaction between IL-5 and IL-1β mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle 
Journal of Clinical Investigation  1999;104(5):657-667.
T-helper type 2 (Th2) cytokines have been implicated in the pathogenesis of the pulmonary inflammatory response and altered bronchial responsiveness in allergic asthma. To elucidate the mechanism of Th2-dependent mediation of altered airway responsiveness in the atopic asthmatic state, the expression and actions of specific cytokines were examined in isolated rabbit and human airway smooth muscle (ASM) tissues and cultured cells passively sensitized with sera from atopic asthmatic patients or nonatopic/nonasthmatic (control) subjects. Relative to control tissues, the atopic asthmatic sensitized ASM exhibited significantly enhanced maximal isometric contractility to acetylcholine and attenuated relaxation responses to isoproterenol. These proasthmatic changes in agonist responsiveness were ablated by pretreating the atopic sensitized tissues with either an IL-5 receptor blocking antibody (IL-5ra) or the human recombinant IL-1 receptor antagonist (IL-1ra), whereas an IL-4 neutralizing antibody had no effect. Moreover, relative to controls, atopic asthmatic sensitized ASM cells demonstrated an initial, early (after 3 hours of incubation) increased mRNA expression and protein release of IL-5. This was followed (after 6 hours of incubation) by an enhanced mRNA expression and release of IL-1β protein, an effect that was inhibited in sensitized cells pretreated with IL-5ra. Extended studies demonstrated that naive ASM exposed to exogenously administered IL-5 exhibited an induced upregulated mRNA expression and protein release of IL-1β associated with proasthmatic-like changes in ASM constrictor and relaxant responsiveness, and that these effects were ablated in tissues pretreated with IL-1ra. Taken together, these observations provide new evidence that (a) the Th2 cytokine IL-5 and the pleiotropic proinflammatory cytokine IL-1β are endogenously released by atopic asthmatic sensitized ASM and mechanistically interact to mediate the proasthmatic perturbations in ASM responsiveness; and (b) the nature of this interaction is given by an initial endogenous release of IL-5, which then acts to induce the autologous release of IL-1β by the sensitized ASM itself, resulting in its autocrine manifestation of the proasthmatic phenotype.
PMCID: PMC408541  PMID: 10487780
23.  Correlation of Systemic Superoxide Dismutase Deficiency to Airflow Obstruction in Asthma 
Rationale: Increased oxidative stress and decreased superoxide dismutase (SOD) activity in the asthmatic airway are correlated to airflow limitation and hyperreactivity. We hypothesized that asthmatic individuals with higher levels of oxidative stress may have greater loss of SOD activity, which would be reflected systemically in loss of circulating SOD activity and clinically by development of severe asthma and/or worsening airflow limitation. Methods: To investigate this, serum SOD activity and proteins, the glutathione peroxidase/glutathione antioxidant system, and oxidatively modified amino acids were measured in subjects with asthma and healthy control subjects. Results: SOD activity, but not Mn-SOD or Cu,Zn-SOD protein, was lower in asthmatic serum as compared with control, and activity loss was significantly related to airflow limitation. Further, serum SOD activity demonstrated an inverse correlation with circulating levels of 3-bromotyrosine, a posttranslational modification of proteins produced by the eosinophil peroxidase system of eosinophils. Exposure of purified Cu,Zn-SOD to physiologically relevant levels of eosinophil peroxidase-generated reactive brominating species, reactive nitrogen species, or tyrosyl radicals in vitro confirmed that eosinophil-derived oxidative pathways promote enzyme inactivation. Conclusion: These findings are consistent with greater oxidant stress in asthma leading to greater inactivation of SOD, which likely amplifies inflammation and progressive airflow obstruction.
doi:10.1164/rccm.200502-180OC
PMCID: PMC2718470  PMID: 15883124
asthma; superoxide dismutase; glutathione; pulmonary functions; peroxidase
24.  Neurotrophins in bronchial asthma 
Respiratory Research  2001;2(5):265-268.
Allergic bronchial asthma (BA) is characterized by chronic airway inflammation, development of airway hyperreactivity and recurrent reversible airway obstruction. T-helper 2 cells and their products have been shown to play an important role in this process. In contrast, the mechanisms by which immune cells interact with the cells residing in lung and airways, such as neurons, epithelial or smooth muscle cells, still remains uncertain. Sensory and motor neurons innervating the lung exhibit a great degree of functional plasticity in BA defined as 'neuronal plasticity'. These neurons control development of airway hyperresponsiveness and acute inflammatory responses, resulting in the concept of 'neurogenic inflammation'. Such quantitative and/or qualitative changes in neuronal functions are mediated to a great extent by a family of cytokines, the neurotrophins, which in turn are produced by activated immune cells, among others in BA. We have therefore developed the concept that neurotrophins such as nerve growth factor and brain-derived neurotrophic factor link pathogenic events in BA to dysfunctions of the immune and nervous system.
doi:10.1186/rr66
PMCID: PMC59513  PMID: 11686893
bronchial asthma; neurogenic inflammation; neuronal plasticity; neurotrophins
25.  S-Nitrosoglutathione Reductase 
Rationale: Nitric oxide bioactivity, mediated through the formation of S-nitrosothiols (SNOs), has a significant effect on bronchomotor tone. S-Nitrosoglutathione is an endogenous bronchodilator that is decreased in children with asthmatic respiratory failure and in adults with asthma undergoing segmental airway challenge. Recently we showed that S-nitrosoglutathione reductase (GSNOR) regulates endogenous SNOs. Mice with genetic deletion of GSNOR are protected from airway hyperresponsivity in an allergic asthma model.
Objectives: We hypothesized that GSNOR is increased in human asthma and correlates with lung SNO content and airway reactivity.
Methods: We recruited 36 subjects with mild asthma with FEV1 88.5 ± 2.3% predicted and 34 healthy control subjects with FEV1 100.7 ± 2.5% predicted. Bronchoalveolar lavage (BAL) was performed in all subjects. Cell counts, differentials, GSNOR activity, and SNO levels were determined in BAL.
Measurements and Main Results: SNO content was decreased in asthmatic BAL compared with control BAL and correlated inversely with GSNOR expression in BAL cell lysates. Furthermore, GSNOR activity measured from BAL samples was significantly increased in subjects with asthma compared with control subjects and correlated inversely with the provocative concentration of methacholine causing a 20% decrease in FEV1.
Conclusions: These findings suggest that GSNOR is an important regulator of airway SNO content and airways hyperresponsiveness in human asthma.
doi:10.1164/rccm.200901-0158OC
PMCID: PMC2724715  PMID: 19395503
asthma; S-nitrosoglutathione reductase; S-nitrosothiols; airway hyperresponsiveness

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