Mucin genes have different expression patterns in healthy and diseased upper airway mucosa

Martínez-Antón, Asunción; DeBolós, C.; Garrido, Marta; Roca‐Ferrer, Jordi; Barranco, Carlos; Alobid, Isam; Xaubet, Antoni; Picado, César; Mullol, Joaquim

doi:10.1111/j.1365-2222.2006.02451.x

Cited by 96 publications

(86 citation statements)

References 44 publications

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“…In our previous study, we found that MUC8 mRNA levels were up-regulated in human nasal polyps epithelium whereas MUC5AC gene was not Yoon et al, 2002]. This is coincident with recently reported studies in which MUC8 expression was highly increased in all studied epithelia and glands of nasal polyp samples compared with the expression of the other major mucin genes, MUC5AC and MUC5B, which are moderately expressed in nasal polyps [Martinez-Anton et al, 2006. These studies raised the possibility that MUC8 plays a major role in the airway mucosa and its over-expression is related to mucus hypersecretion.…”

supporting

confidence: 82%

AP2α is essential for MUC8 gene expression in human airway epithelial cells

Moon

Kim

Choi

et al. 2010

J of Cellular Biochemistry

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Mucins are high molecular weight proteins that make up the major components of mucus. Hypersecretion of mucus is a feature of several chronic inflammatory airway diseases. MUC8 is an important component of airway mucus, and its gene expression is upregulated in nasal polyp epithelium. Little is known about the molecular mechanisms of MUC8 gene expression. We first observed overexpression of activator protein-2 alpha (AP2 alpha) in human nasal polyp epithelium. We hypothesized that AP2 alpha overexpression in nasal polyp epithelium correlates closely with MUC8 gene expression. We demonstrated that phorbol 12-myristate 13-acetate (PMA) treatment of the airway epithelial cell line NCI-H292 increases MUC8 gene and AP2 alpha expression. In this study, we sought to determine which signal pathway is involved in PMA-induced MUC8 gene expression. The results show that the protein kinase C and mitogen-activating protein/ERK kinase (MAPK) pathways modulate MUC8 gene expression. PD98059 or ERK1/2 siRNA and RO-31-8220 or PKC siRNA significantly suppress AP2 alpha as well as MUC8 gene expression in PMA-treated cells. To verify the role of AP2 alpha, we specifically knocked down AP2 alpha expression with siRNA. A significant AP2 alpha knock-down inhibited PMA-induced MUC8 gene expression. While dominant negative AP2 alpha decreased PMA-induced MUC8 gene expression, overexpressing wildtype AP2 alpha increased MUC8 gene expression. Furthermore, using lentiviral vectors for RNA interference in human nasal polyp epithelial cells, we confirmed an essential role for AP2 alpha in MUC8 gene expression. From these results, we concluded that PMA induces MUC8 gene expression through a mechanism involving PKC, ERK1/2, and AP2 alpha activation in human airway epithelial cells.

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supporting

confidence: 82%

AP2α is essential for MUC8 gene expression in human airway epithelial cells

Moon

Kim

Choi

et al. 2010

J of Cellular Biochemistry

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“…The role of MUC8 in the airways is also poorly understood, and, to date, there are no data suggesting that it is altered in lung disease. Expression of MUC8 glycoprotein in upper airways (nasal mucosa and nasal polyps) has been shown to be quite variable and not altered in CF, asthma, or allergic rhinitis (44). The cell surface mucins MUC1, MUC4, and MUC16 are present in both the periciliary and mucus layers of the ASL and are detected in human sputum, accounting for 10% of its mucin content, with the remaining consisting of the gel-forming mucins MUC5AC and MUC5B (56).…”

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis and the relationship between mucin and chloride secretion by cultures of human airway gland mucous cells

Finkbeiner

Zlock

Morikawa

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Ϫ and mucin secretion in cultures of non-CF and CF human tracheobronchial gland mucous (HTGM and CFTGM, respectively) cells. Biochemical studies showed that HTMG cells secreted typical airway mucins, and immunohistochemical studies showed that these cells expressed MUC1, MUC4, MUC5B, MUC8, MUC13, MUC16, and MUC20. Effects of cumulative doses of methacholine (MCh), phenylephrine (Phe), isoproterenol (Iso), and ATP on mucin and Cl Ϫ secretion were studied on HTGM and CFTGM cultures. Baseline mucin secretion was not significantly altered in CFTGM cells, and the increases in mucin secretion induced by mediators were unaltered (Iso, Phe) or slightly decreased (MCh, ATP). Across mediators, there was no correlation between the maximal increases in Cl Ϫ secretion and mucin secretion. In HTGM cells, the Cl Ϫ channel blocker, diphenylamine-2-carboxylic acid, greatly inhibited Cl Ϫ secretion but did not alter mucin release. In HTGM cells, mediators (10 Ϫ5 M) increased mucin secretion in the rank order ATP Ͼ Phe ϭ Iso Ͼ MCh. They increased Cl Ϫ secretion in the sequence ATP Ͼ MCh Ϸ Iso Ͼ Phe. The responses in Cl Ϫ secretion to MCh, ATP, and Phe were unaltered by CF, but the response to Iso was greatly reduced. We conclude that mucin secretion by cultures of human tracheobronchial gland cells is independent of Cl Ϫ secretion, at baseline, and is unaltered in CF; that the ratio of Cl Ϫ secretion to mucus secretion varies markedly depending on mediator; and that secretions induced by stimulation of ␤-adrenergic receptors will be abnormally concentrated in CF.

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“…MUC5AC together with MUC5B are the major contributors to the rheological properties and the structure of the mucus. [46][47][48] MUC2, however, is found concurrent irritation of the nasal mucosa. 2,49) The composition of normal mucus is altered depending on the relative contribution to the secretions of these different cellular sources and the disease stage of the subject.…”

Section: Mucinmentioning

confidence: 99%

The Effect of Cilia and the Mucociliary Clearance on Successful Drug Delivery

Gizurarson

2015

Biological & Pharmaceutical Bulletin

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Nasal mucociliary clearance is one of the most important factors affecting nasal delivery of drugs and vaccines. This is also the most important physiological defense mechanism inside the nasal cavity. It removes inhaled (and delivered) particles, microbes and substances trapped in the mucus. Almost all inhaled particles are trapped in the mucus carpet and transported with a rate of 8-10 mm/h toward the pharynx. This transport is conducted by the ciliated cells, which contain about 100-250 motile cellular appendages called cilia, 0.3 µm wide and 5 µm in length that beat about 1000 times every minute or 12-15 Hz. For efficient mucociliary clearance, the interaction between the cilia and the nasal mucus needs to be well structured, where the mucus layer is a tri-layer: an upper gel layer that floats on the lower, more aqueous solution, called the periciliary liquid layer and a third layer of surfactants between these two main layers. Pharmacokinetic calculations of the mucociliary clearance show that this mechanism may account for a substantial difference in bioavailability following nasal delivery. If the formulation irritates the nasal mucosa, this mechanism will cause the irritant to be rapidly diluted, followed by increased clearance, and swallowed. The result is a much shorter duration inside the nasal cavity and therefore less nasal bioavailability.

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Mucin genes have different expression patterns in healthy and diseased upper airway mucosa

Abstract: These results suggest that NP have a different pattern of mucin expression than healthy NM and that CF polyps (increased MUC5B) and AC polyps (decreased MUC2) have a different mucin expression pattern than bilateral NP.

Cited by 96 publications

References 44 publications

AP2α is essential for MUC8 gene expression in human airway epithelial cells

AP2α is essential for MUC8 gene expression in human airway epithelial cells

Cystic fibrosis and the relationship between mucin and chloride secretion by cultures of human airway gland mucous cells

The Effect of Cilia and the Mucociliary Clearance on Successful Drug Delivery

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