Mast Cells Promote Airway Smooth Muscle Cell Differentiation via Autocrine Up-Regulation of TGF-β1

Woodman, Lucy; Siddiqui, Salman; Cruse, Glenn; Sutcliffe, Amanda; Saunders, Ruth; Kaur, Davinder; Bradding, Peter; Brightling, Christopher

doi:10.4049/jimmunol.181.7.5001

Cited by 115 publications

(121 citation statements)

References 39 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…TGF-b1 induces the expression of SM22, calponin, a-SMA, MLCK, and Ca 21 pathway proteins in HASM cells, subsequently mediating enhancements in cell stiffness, actin-cytoskeleton reorganization, and contractility (87,104,105). In addition, mast cell-derived TGF-b1 may modulate the phenotype of HASM cells, promoting their differentiation into a more contractile phenotype and subsequently enhancing agonist-induced contraction (106).…”

Section: Contraction Cell Shortening and Cytoskeletal Motorsmentioning

confidence: 99%

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Ojiaku

Yoo

Panettieri

2017

Am J Respir Cell Mol Biol

106

View full text Add to dashboard Cite

The pathogenesis of asthma includes a complex interplay among airway inflammation, hyperresponsiveness, and remodeling. Current evidence suggests that airway structural cells, including bronchial smooth muscle cells, myofibroblasts, fibroblasts, and epithelial cells, mediate all three aspects of asthma pathogenesis. Although studies show a connection between airway remodeling and changes in bronchomotor tone, the relationship between the two remains unclear. Transforming growth factor b1 (TGF-b1), a growth factor elevated in the airway of patients with asthma, plays a role in airway remodeling and in the shortening of various airway structural cells. However, the role of TGF-b1 in mediating airway hyperresponsiveness remains unclear. In this review, we summarize the literature addressing the role of TGF-b1 in airway remodeling and shortening. Through our review, we aim to further elucidate the role of TGF-b1 in asthma pathogenesis and the link between airway remodeling and airway hyperresponsiveness in asthma and to define TGF-b1 as a potential therapeutic target for reducing asthma morbidity and mortality.

show abstract

Section: Contraction Cell Shortening and Cytoskeletal Motorsmentioning

confidence: 99%

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Ojiaku

Yoo

Panettieri

2017

Am J Respir Cell Mol Biol

106

View full text Add to dashboard Cite

show abstract

“…ASMs were stained with rabbit polyclonal anti-NOX4 (Abcam, Cambridge, UK), anti-NOX 1-3 and 5 (Insight Biotechnology, Wembley, UK) indirectly labeled with fluorescein isothiocyanate (FITC; Dako), or a-smooth muscle actin-FITC direct conjugate (Sigma Gillingham, Dorset, UK), or bradykinin B2 receptor indirectly labeled with FITC (BD, Oxford, UK) or isotype controls (Dako) and assessed by flow cytometry (BD FACScan; BD), as previously described (22). ASMs were stained for immunofluorescence with rabbit polyclonal NOX1-5 or anti-superoxide dismutase (SOD)2 (Abcam) or isotype controls, indirectly labeled with FITC, and counterstained with 49,69-diamidino-2 phenylindole (Sigma).…”

Section: Flow Cytometry and Immunofluorescencementioning

confidence: 99%

Increased Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Expression Mediates Intrinsic Airway Smooth Muscle Hypercontractility in Asthma

Sutcliffe

Hollins²,

Gomez³

et al. 2012

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

Rationale: Asthma is characterized by disordered airway physiology as a consequence of increased airway smooth muscle contractility. The underlying cause of this hypercontractility is poorly understood. Objectives: We sought to investigate whether the burden of oxidative stress in airway smooth muscle in asthma is heightened and mediated by an intrinsic abnormality promoting hypercontractility. Methods: We examined the oxidative stress burden of airway smooth muscle in bronchial biopsies and primary cells from subjects with asthma and healthy controls. We determined the expression of targets implicated in the control of oxidative stress in airway smooth muscle and their role in contractility. Measurements and Main Results: We found that the oxidative stress burden in the airway smooth muscle in individuals with asthma is heightened and related to the degree of airflow obstruction and airway hyperresponsiveness. This was independent of the asthmatic environment as in vitro primary airway smooth muscle from individuals with asthma compared with healthy controls demonstrated increased oxidative stress-induced DNA damage together with an increased production of reactive oxygen species. Genome-wide microarray of primary airway smooth muscle identified increased messenger RNA expression in asthma of NADPH oxidase (NOX) subtype 4. This NOX4 overexpression in asthma was supported by quantitative polymerase chain reaction, confirmed at the protein level. Airway smooth muscle from individuals with asthma exhibited increased agonist-induced contraction. This was abrogated by NOX4 small interfering RNA knockdown and the pharmacological inhibitors diphenyleneiodonium and apocynin. Conclusions: Our findings support a critical role for NOX4 overexpression in asthma in the promotion of oxidative stress and consequent airway smooth muscle hypercontractility. This implicates NOX4 as a potential novel target for asthma therapy.Keywords: asthma; airway smooth muscle; airway hyperresponsiveness; NOX4; SOD2 Asthma affects over 300 million people worldwide. Importantly, asthma control is suboptimal in about half of sufferers, and 10% are refractory to current antiinflammatory and bronchodilator therapies (1, 2). There is therefore an urgent need for new therapies. Asthma is characterized by variable airflow obstruction and airway hyperresponsiveness as a consequence of increased airway smooth muscle contractility (1, 2). This heightened airway smooth muscle (ASM) contraction is considered to be largely due to the local asthmatic milieu with infiltration by inflammatory cells, in particular eosinophils and T cells, into the submucosa (2-4), to mast cells in the ASM bundle (4, 5), and to up-regulation of Th2 cytokines (6, 7).Interestingly, there is an increasing body of evidence that ASM is fundamentally altered in asthma compared with healthy controls, suggesting that abnormalities in these structural cells may also play a critical role in the development of the abnormal physiology in asthma and may contribute to the persistent airway ...

show abstract

“…For example, vascular SMCs display reduced levels of contractile filaments following injury to the vessel wall, adopting the so-called synthetic phenotype characterized by an overabundance of rough endoplasmic reticulum (3). On the other hand, recent studies have shown an exaggerated SMC contractile phenotype thought to contribute to disease progression (4,5).…”

mentioning

confidence: 99%

The Smooth Muscle Cell-restricted KCNMB1 Ion Channel Subunit Is a Direct Transcriptional Target of Serum Response Factor and Myocardin

Long

Tharp

Georger

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Large conductance calcium-activated potassium (MaxiK) channels play a pivotal role in maintaining normal arterial tone by regulating the excitation-contraction coupling process. MaxiK channels comprise ␣ and ␤ subunits encoded by Kcnma and the cell-restricted Kcnmb genes, respectively. Although the functionality of MaxiK channel subunits has been well studied, the molecular regulation of their transcription and modulation in smooth muscle cells (SMCs) is incomplete. Using several model systems, we demonstrate down-regulation of Kcnmb1 mRNA upon SMC phenotypic modulation in vitro and in vivo. As part of a broad effort to define all functional CArG elements in the genome (i.e. the CArGome), we discovered two conserved CArG boxes located in the proximal promoter and first intron of the human KCNMB1 gene. Gel shift and chromatin immunoprecipitation assays confirmed serum response factor (SRF) binding to both CArG elements. A luciferase assay showed myocardin (MYOCD)-mediated transactivation of the KCNMB1 promoter in a CArG element-dependent manner. In vivo analysis of the human KCNMB1 promoter disclosed activity in embryonic heart and aortic SMCs; mutation of both conserved CArG elements completely abolished in vivo promoter activity. Forced expression of MYOCD increased Kcnmb1 expression in a variety of rodent and human non-SMC lines with no effect on expression of the Kcnma1 subunit. Conversely, knockdown of Srf resulted in decreases of endogenous Kcnmb1. Functional studies demonstrated MYOCD-induced, iberiotoxin-sensitive potassium currents in porcine coronary SMCs. These results reveal the first ion channel subunit as a direct target of SRF-MYOCD transactivation, providing further insight into the role of MYOCD as a master regulator of the SMC contractile phenotype. Smooth muscle cells (SMCs)2 are of crucial importance in maintaining normal structural and contractile integrity of various organs and tissues throughout the vertebrate body. Unlike skeletal and cardiac muscle cells, which largely undergo irreversible terminal differentiation, SMCs have the inherent ability to alter their differentiated state in response to diverse stimulatory cues. This process of SMC phenotypic modulation is a hallmark of several human pathological conditions, including vascular occlusive disease, asthma, intestinal and bladder obstruction, and Alzheimer disease. SMC phenotypic modulation is often defined in terms of unique molecular signatures of gene expression involved with contraction and cytoskeletal architecture as well as extracellular matrix remodeling (1, 2). For example, vascular SMCs display reduced levels of contractile filaments following injury to the vessel wall, adopting the so-called synthetic phenotype characterized by an overabundance of rough endoplasmic reticulum (3). On the other hand, recent studies have shown an exaggerated SMC contractile phenotype thought to contribute to disease progression (4, 5).The majority of SMC-restricted genes contain one or more conserved CArG elements that bind the widely express...

show abstract

Mast Cells Promote Airway Smooth Muscle Cell Differentiation via Autocrine Up-Regulation of TGF-β1

Cited by 115 publications

References 39 publications

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Increased Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Expression Mediates Intrinsic Airway Smooth Muscle Hypercontractility in Asthma

The Smooth Muscle Cell-restricted KCNMB1 Ion Channel Subunit Is a Direct Transcriptional Target of Serum Response Factor and Myocardin

Contact Info

Product

Resources

About