Airway Smooth Muscle Hyperproliferation Is Regulated by MicroRNA-221 in Severe Asthma

Perry, Mark M.; Baker, Josie; Gibeon, David; Adcock, Ian M.; Chung, Kian Fan

doi:10.1165/rcmb.2013-0067oc

Cited by 135 publications

(141 citation statements)

References 48 publications

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“…Asthmatic ASMCs showed increased histone H3K18 acetylation, and enhanced binding of p300 at the CXCL8 promoter as compared with nonasthmatic ASMCs. On the other hand, ASMCs showed alteration in expression of specific microRNAs in proinflammatory milieu, resulting in aberrant expression of genes modulating ASMC proliferation, hypertrophy, and contractility (15)(16)(17)(18). Furthermore, DNA methylation is the best-studied epigenetic mechanisms in asthma studies.…”

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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 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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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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“…MiRNAs may regulate up to one-third of all protein coding genes in the human genome (46), and the relevance of miRNAs in asthma has been previously implied in studies of their expression in human asthma and animal models of allergic airway inflammation (47)(48)(49)(50)(51)(52). We performed miRNA microarrays on AMs from healthy subjects and patients with asthma, and performed bioinformatics analyses followed by qPCR confirmation of the in silico results.…”

Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 7 Is Reduced in Severe Asthma and Linked to an Altered MicroRNA Profile

Rupani

Martínez-Nuñez

Dennison

et al. 2016

Am J Respir Crit Care Med

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Rationale: Asthma is one of the most common chronic diseases worldwide, and individuals with severe asthma experience recurrent exacerbations. Exacerbations are predominantly viral associated and have been linked to defective airway IFN responses. Ascertaining the molecular mechanisms underlying this deficiency is a major research goal to identify new therapeutic targets.Objectives: We investigated the hypothesis that reduced Toll-like receptor 7 (TLR7)-derived signaling drove the impaired IFN responses to rhinovirus by asthmatic alveolar macrophages (AMs); the molecular mechanisms underlying this deficiency were explored.Methods: AMs were recovered from bronchoalveolar lavage from healthy subjects and patients with severe asthma. Expression of pattern-recognition receptors and microRNAs was evaluated by quantitative polymerase chain reaction and Western blotting. A TLR7-luciferase reporter construct was created to evaluate binding of microRNAs to the 39 untranslated region of TLR7. IFN production was measured by quantitative polymerase chain reaction and ELISA.Measurements and Main Results: The expression of TLR7 was significantly reduced in severe asthma AMs and was associated with reduced rhinovirus and imiquimod-induced IFN responses by these cells compared with healthy AMs. Severe asthma AMs also expressed increased levels of three microRNAs, which we showed were able to directly reduce TLR7 expression. Ex vivo knockdown of these microRNAs restored TLR7 expression with concomitant augmentation of virus-induced IFN production.Conclusions: In severe asthma, TLR7 deficiency drives impaired innate immune responses to virus by AMs. Blocking a group of microRNAs that are up-regulated in these cells can restore antiviral innate responses, providing a novel approach for therapy in asthma.

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“…In human ASM (HASM) cells, TGF-b1 both induces proliferation (81) and inhibits mitogen-induced proliferation (82) through different pathways. In addition, TGF-b1 induces greater proliferation in HASM cells from patients with severe asthma as compared with those from patients with nonsevere asthma (83), suggesting that the effects of TGF-b1 on structural cell proliferation may depend on disease state.…”

Section: Airway Remodeling and Proliferationmentioning

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

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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.

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Airway Smooth Muscle Hyperproliferation Is Regulated by MicroRNA-221 in Severe Asthma

Cited by 135 publications

References 48 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

Toll-like Receptor 7 Is Reduced in Severe Asthma and Linked to an Altered MicroRNA Profile

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

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