Mild and Moderate Asthma Is Associated with Airway Goblet Cell Hyperplasia and Abnormalities in  Mucin Gene Expression

Ordoñez, Claudia L.; Khashayar, Ramin; Wong, Hofer; Ferrando, Ron; Wu, Reen; Hyde, Dallas M.; Hotchkiss, Jon A.; Zhang, Yifan; Novikov, A A; Dolganov, Gregory; Fahy, John V.

doi:10.1164/ajrccm.163.2.2004039

Cited by 514 publications

(396 citation statements)

References 33 publications

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“…Proof of this concept could lead to novel therapeutic strategies targeting, for example, lung macrophages and/or their released factor(s) to prevent bronchial MUC5AC þ GCH in mild and moderate asthmatic patients. 5 MUC5B immophenotype was consistently induced in HBEC challenged with supernatant from LPS-treated MDM carrying high levels of TNF-a; by a mix of cytokines mimicking LPS-treated MDM supernatant; and by TNF-a alone at levels from LPS-treated MDM supernatant. Therefore, our data demonstrate that TNF-a at levels released by LPStreated MDM was able to induce MUC5B, suggesting that LPS-stimulated macrophages may generate MUC5B þ GCH.…”

Section: Discussionmentioning

confidence: 93%

“…3 In baseline conditions of chronic inflammatory respiratory disorders, MUC5B and/or MUC5AC are increased in different compartments of the respiratory tract. [3][4][5][6] For example, MUC5B and MUC5AC are augmented in small airway lumen and epithelium from patients with advanced CF; 4 GCH related only with increased MUC5AC phenotype has been reported in bronchus from mild and moderate asthmatic patients; 5 and abnormally high amounts of MUC5B and MUC5AC are present in the sputum from individuals with COPD, MUC5B being the predominant mucin. 6 MUC5B and MUC5AC can be upregulated when human bronchus epithelial cells (HBEC) are cultured with retinoic acid, interleukin (IL)-6, IL-17, and neuroregulin1b1.…”

Section: Abstract: Airways; Cytokines; Lps; Lung Inflammation; Tnf-alphamentioning

confidence: 99%

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Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Silva

Berčík

2012

Laboratory Investigation

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Airway goblet cell hyperplasia (GCH)-detectable by mucin staining-and abnormal macrophage infiltrate are pathological features present in many chronic respiratory disorders. However, it is unknown if both factors are associated. Using in-vivo and in-vitro models, we investigated whether macrophages are related with GCH and changes in mucin immunophenotypes. Lung sections from Sprague-Dawley rats treated for 48 h with one intra-tracheal dose of PBS or LPS (n ¼ 4-6 per group) were immunophenotyped for rat-goblet cells, immune, and proliferation markers. Human monocytederived macrophages (MDM) were pre-treated with or without LPS, immunophenotyped, and their supernatant, as well as cytokines at levels equivalent to supernatant were used to challenge primary culture of normal human bronchus epithelial cells (HBEC) in air-liquid interface, followed by MUC5B and MUC5AC mucin immunostaining. An association between increased bronchiolar goblet cells and terminal-bronchiolar proliferative epithelial cells confirmed the presence of GCH in our LPS rat model, which was related with augmented bronchiolar CD68 macrophage infiltration. The in-vitro experiments have shown that MUC5AC phenotype was inhibited when HBEC were challenged with supernatant from MDM pre-treated with or without LPS. In contrast, TNF-a and interleukin-1b at levels equivalent to supernatant from LPS-treated MDM increased MUC5AC. MUC5B was induced by LPS, supernatant from LPS-treated MDM, a mix of cytokines including TNF-a and TNF-a alone at levels present in supernatant from LPS-treated MDM. We demonstrated that macrophages are related with bronchiolar GCH, and that they induced MUC5B and inhibited MUC5AC in HBEC, suggesting a role for them in the pathogenesis of airway MUC5B-related GCH. KEYWORDS: airways; cytokines; LPS; lung inflammation; TNF-alphaMucus is a gel that covers the airway epithelium and is constituted by different glycoproteins called mucins, which are secreted by goblet cells from submucosal glands and the airway epithelium. 1 Mucus dissolves noxious gases and entraps foreign particles and pathogens, facilitating their clearance by mucociliary transport as a mechanism of innate defense. 2 However, in chronic inflammatory respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), there is a pathological goblet cell hyperplasia (GCH) and mucus hypersecretion that can generate airway occlusion, associated with morbidity and death. 1 The main gel-forming mucins found in human airways are MUC5B and MUC5AC. 1 In healthy individuals, low levels of MUC5B and MUC5AC can be detected in mucus; although MUC5B is mainly present in the submucosal glands and MUC5AC is predominantly distributed in the airway epithelium. 3 In baseline conditions of chronic inflammatory respiratory disorders, MUC5B and/or MUC5AC are increased in different compartments of the respiratory tract. [3][4][5][6] For example, MUC5B and MUC5AC are augmented in small airway lumen and epithelium from patients with advanced CF; 4 GC...

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Section: Discussionmentioning

confidence: 93%

Section: Abstract: Airways; Cytokines; Lps; Lung Inflammation; Tnf-alphamentioning

confidence: 99%

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Silva

Berčík

2012

Laboratory Investigation

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“…Obstruction of the airways with mucus is a potentially fatal feature of asthma. Therefore, factors that regulate the abundance of mucin-secreting cells and mucus secretion have been proposed as potential targets for treating asthma (25)(26)(27). Interestingly, immunofluorescence shows that TMEM16A is strongly expressed in Muc5AC-positive mucous cells in the OVA asthmatic mouse models ( Fig.…”

Section: Tmem16a Is Preferentially Expressed In Secretory Cells In Asmentioning

confidence: 99%

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Huang

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

310

342

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Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calciumactivated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.A sthma is a significant cause of morbidity and mortality worldwide, and the prevalence of this disease is increasing among all age, sex, and racial groups. Characteristic features of asthma include inflammation, subepithelial fibrosis, hyperplasia of mucus-producing cells, accumulation of mucus within airway lumens, hyperplasia of airway smooth muscle (ASM), and ASM hyperresponsiveness. Together, these symptoms impair lung function by limiting the flow of gases to and from the alveoli in the distal lung.The current standard of care for asthma involves inhaled corticosteroids for the management of inflammation combined with long-acting agonists of β2-adrenergic receptors. Despite this treatment, lung function is not improved in 30-45% of asthmatic patients, and exacerbations continue to be a major problem (reviewed in ref. 1). Asthma can be divided into at least two distinct molecular phenotypes defined by the degree of Th2 inflammation (2, 3). Cytokines, including IL-4 and IL-13, promote airway epithelial mucous cell metaplasia, subepithelial fibrosis, and hyperplasia of smooth muscle in Th2-high asthmatics, and these patients generally show improved lung function with inhaled corticosteroid therapy. A greater understanding of this heterogeneity and the molecular and physiological events that lead to airway remodeling might lead to improved diagnosis and treatment.Calcium-activated chloride channels (CaCCs) have been ascribed numerous cellular functions (reviewed in refs. 4 and 5), among these are epithelial fluid secretion and smooth muscle contraction, both of which contribute to the progression and severity of asthma. Moreover, calcium-activated chloride currents in the airway epithelium are enhanced by the Th2 cytokines IL-4 and IL-13, as well as IFN-γ (6). For these reasons, CaCC is an attractive potential therapeutic target for asthma (7). However, the study of CaCC was impeded by lack of information about the gene(s) encoding this channel. It was only relatively recently that TMEM16A (transmembrane p...

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“…In the lungs, goblet cell hyperplasia/ metaplasia of surface epithelial cells in inflammatory diseases correlate closely with increases in the expression of MUC5AC messages (62,63). Although surface goblet cells express other mucin genes (14,(64)(65)(66), MUC5AC is probably this cell type's most specific marker. Numerous reports have shown that inflammatory cytokines (e.g., TNF-α, IL-1β, IL-4, IL-6, IL-9, IL-13, IL-17), bacterial products (e.g., LPS, LTA, peptidoglycans, flagellin), growth factors (e.g., EGF, TGF-α, RA, thyroid hormones), proteases [e.g., neutrophil elastase (NE)], environmental pollutants (e.g., cigarette smoke extracts, acrolein, ozone), and viral mediators (e.g., respiratory syncytial virus, rhinovirus) can prominently stimulate MUC5AC expression either in vitro or in vivo on airway epithelial cells (Figure 1, middle).…”

Section: Muc5ac Expression and Regulationmentioning

confidence: 99%

Regulation of Airway Mucin Gene Expression

Thai

Loukoianov

Wachi

et al. 2008

Annu. Rev. Physiol.

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193

223

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Mucins are important components that exert a variety of functions in cell-cell interaction, epidermal growth factor receptor signaling, and airways protection. In the conducting airways of the lungs, mucins are the major contributor to the viscoelastic property of mucous secretion, which is the major barrier to trapping inhaled microbial organism, particulates, and oxidative pollutants. The homeostasis of mucin production is an important feature in conducting airways for the maintenance of mucociliary function. Aberrant mucin secretion and accumulation in airway lumen are clinical hallmarks associated with various lung diseases, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, and lung cancer. Among 20 known mucin genes identified, 11 of them have been verified at either the mRNA and/or protein level in airways. The regulation of mucin genes is complicated, as are the mediators and signaling pathways. This review summarizes the current view on the mediators, the signaling pathways, and the transcriptional units that are involved in the regulation of airway mucin gene expression. In addition, we also point out essential features of epigenetic mechanisms for the regulation of these genes.

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Mild and Moderate Asthma Is Associated with Airway Goblet Cell Hyperplasia and Abnormalities in Mucin Gene Expression

Cited by 514 publications

References 33 publications

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Regulation of Airway Mucin Gene Expression

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