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

Baroffio, Michele; Barisione, Giovanni; Crimi, Emanuele; Brusasco, Vito

doi:10.1177/1753465809343595

Cited by 35 publications

(29 citation statements)

References 116 publications

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“…AHR is often considered an epiphenomenon of airway inflammation. However, recent studies revealed that ASMCs showed asthmatic phenotypes, even in the absence of the inflammation (4,5,6). Our findings show that asthmatic ASMCs are epigenetically modulated, and such epigenetic alterations …”

Section: Discussionsupporting

confidence: 47%

“…Antiinflammatory therapy is currently the primary medication for asthma, and studies of AHR have been prevalently focused on inflammatory cells, mediators, and immune responses (3). However, accumulating evidence shows that AHR may also present in patients with asthma without inflammation, suggesting that airway inflammation cannot fully explain the mechanisms underlying AHR (4)(5)(6). Therefore, noninflammatory AHR mechanisms should not be overlooked, and require additional in-depth investigations.…”

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confidence: 99%

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Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

Lin

Shang

Mitzner

et al. 2016

Am J Respir Cell Mol Biol

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Airway hyperresponsiveness (AHR) is a hallmark feature in asthma characterized by exaggerated airway contractile response to stimuli due to increased airway sensitivity and chronic airway remodeling. We have previously shown that allergen-induced AHR in mice is associated with aberrant DNA methylation in the lung genome, suggesting that AHR could be epigenetically regulated, and these changes might predispose the animals to asthma. Previous studies demonstrated that overexpression of phosphodiesterase 4D (PDE4D) is associated with increased AHR. However, epigenetic regulation of this gene in asthmatic airway smooth muscle cells (ASMCs) has not been examined. In this study, we aimed to examine the relationship between epigenetic regulation of PDE4D and ASMC phenotypes. We identified CpG site-specific hypomethylation at PDE4D promoter in human asthmatic ASMCs. We next used methylated oligonucleotides to introduce CpG site-specific methylation at PDE4D promoter and examined its effect on ASMCs. We showed that PDE4D methylation decreased cell proliferation and migration of asthmatic ASMCs. We further elucidated that methylated PDE4D decreased PDE4D expression in asthmatic ASMCs, increased cAMP level, and inhibited the aberrant increase in Ca 21 level. Moreover, PDE4D methylation reduced the phosphorylation level of downstream effectors of Ca 21 signaling, including myosin light chain kinase and p38. Taken together, our findings demonstrate that gene-specific epigenetic changes may predispose ASMCs to asthma through alterations in cell phenotypes. Modulation of ASMC phenotypes by methylated PDE4D oligonucleotides can reverse the aberrant ASMC functions to normal phenotypes. This has provided new insight to the development of novel therapeutic options for this debilitative disease.

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Section: Discussionsupporting

confidence: 47%

mentioning

confidence: 99%

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

Lin

Shang

Mitzner

et al. 2016

Am J Respir Cell Mol Biol

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“…Airway smooth muscle (ASM) cells are the major resident cells in airways, and their dysfunction has been implicated as contributing to AHR (24)(25)(26)(27). It is known that the reversal potential for chloride in smooth muscle cells is about -20 mV, and thus activation of Cl (Ca) channels depolarizes the membrane, leading to contraction (28).…”

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

The Transmembrane Protein 16A Ca²⁺-activated Cl⁻ Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness

Zhang

Li²,

Zhao

et al. 2013

Am J Respir Crit Care Med

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Rationale: Asthma is a chronic inflammatory disorder with a characteristic of airway hyperresponsiveness (AHR). Ca 21 -activated Cl 2 [Cl (Ca) ] channels are inferred to be involved in AHR, yet their molecular nature and the cell type they act within to mediate this response remain unknown. Objectives: Transmembrane protein 16A (TMEM16A) and TMEM16B are Cl (Ca) channels, and activation of Cl (Ca) channels in airway smooth muscle (ASM) contributes to agonist-induced airway contraction. We hypothesized that Tmem16a and/or Tmem16b encode Cl (Ca) channels in ASM and mediate AHR. Methods:We assessed the expression of the TMEM16 family, and the effects of niflumic acid and benzbromarone on AHR and airway contraction, in an ovalbumin-sensitized mouse model of chronic asthma. We also cloned TMEM16A from ASM and examined the Cl 2 currents it produced in HEK293 cells. We further studied the impacts of TMEM16A deletion on Ca 21 agonist-induced cell shortening, and on Cl (Ca) (Ca) currents, and weakens caffeine-and methacholineinduced cell shortening. Conclusions: Tmem16a encodes Cl (Ca) channels in ASM and contributes to Ca 21 agonist-induced contraction. In addition, up-regulation of TMEM16A and its augmented activation contribute to AHR in an ovalbumin-sensitized mouse model of chronic asthma. TMEM16A may represent a potential therapeutic target for asthma.Keywords: TMEM16A; airway smooth muscle; airway hyperresponsiveness Asthma, affecting 300 million people worldwide, is characterized by chronic inflammation, mucus overproduction, reversible airway obstruction, and airway hyperresponsiveness (AHR). AHR is a heightened tendency to airway narrowing in response to nonspecific contractile agents, and underlies much of the pathology of asthmatic symptoms. Although intensively studied, the cellular and molecular mechanisms underlying AHR remain only partially understood and controversial. A number of studies have implied that Ca 21 -activated Cl 2 [Cl (Ca) ] channels are involved in AHR. Gene expression profile studies have consistently revealed that type 3 Cl (Ca) channels (mCLCA3) are highly upregulated in mouse models of asthma (1-6), and hCLCA1, the human counterpart of mCLCA3, is significantly more abundant in the airway epithelium of patients with asthma (4, 7, 8). Moreover, suppressing the expression of mCLCA3 or hCLCA1 by antisense or its function by niflumic acid, a relatively selective inhibitor of Cl (Ca) channels, prevents allergen-or helper T-cell type 2 (Th2) cytokine (e.g., IL-13)-induced mucus overproduction and AHR (5, 9-11). Not surprisingly, mCLCA3/hCLCA1 Supported by the National Natural Science Foundation of China (grant 31272311) (to M.-S.Z.) and the Natural Science Foundation of Zhejiang Province (Y2100346) (to H.L.), and by U.S. National Heart, Lung, and Blood Institute grant HL73875 (to R.Z.G.).Author Contributions: C.-H.Z., Y.L., W.Z., and H.L. performed research; B.D.H. provided TMEM16A null mice; L.M.L. performed data analysis and edited the paper; M.-S.Z. designed and supervised the stu...

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“…It is also likely that bronchoconstriction in this population occurs as a result of breathing at low lung volumes. [11][12][13][14] Perhaps a more important feature of spinal shock in this population is reduced reflex-mediated sympathetic input to the adrenal gland. 15 This results in a low level of circulating catecholamines and is responsible for the haemodynamic instability observed in acute tetraplegia.…”

Section: Resultsmentioning

confidence: 99%

The use of bronchodilators in people with recently acquired tetraplegia: a randomised cross-over trial

et al. 2012

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Study design: A within-participant, double-blind, cross-over, randomised control trial. Objectives: To determine the short-term effects of bronchodilator therapy on respiratory function in people with recently acquired motor complete tetraplegia. Setting: Hospital, Australia. Methods: A total of 12 people with recently acquired tetraplegia were randomised to receive either a one-off dose of a bronchodilator followed by an equivalent dose of a placebo propellant between 1 day and 1 week later or visa versa. The three outcomes were forced expiratory volume in 1 s (FEV1), peak expiratory flow rate (PEF) and forced vital capacity (FVC). These were measured while supine by a blinded assessor 10 and 30 min after treatment. Data were analysed on 11 participants and reported as percentage of predicted. Results: The FEV1, FVC and PEF mean between-group differences (95% confidence interval) at 10 min post treatment were 7.3% (2.7-11.9%; P ¼ 0.003), 5.5% (1.6-9.4%; P ¼ 0.008) and 20.1% (1.1-40.4%; P ¼ 0.039). Similar effects were observed at 30 min for FVC and FEV1 but not for PEF. Conclusion: Bronchodilator therapy has a beneficial effect on FEV1, FVC and PEF in participants with recently acquired tetraplegia.

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

Cited by 35 publications

References 116 publications

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

The Transmembrane Protein 16A Ca²⁺-activated Cl⁻ Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness

The use of bronchodilators in people with recently acquired tetraplegia: a randomised cross-over trial

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

Cited by 35 publications

References 116 publications

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

The Transmembrane Protein 16A Ca2+-activated Cl− Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness

The use of bronchodilators in people with recently acquired tetraplegia: a randomised cross-over trial

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The Transmembrane Protein 16A Ca²⁺-activated Cl⁻ Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness