Upregulation of MUC8 and Downregulation of MUC5AC by Inflammatory Mediators in Human Nasal Polyps and Cultured Nasal Epithelium

Polyps are believed to be the source of mucus hypersecretion in chronic inflammation of the sinus. However, it is not clear which mucins are responsible for the hypersecretion of mucus by nasal polyps. We describe the over-expression of MUC8 mRNA in nasal polyps and the upregulation of MUC8 mRNA expression and downregulation of MUC5AC mRNA expression by inflammatory mediators. We found that the level of MUC8 mRNA, but not the level of MUC5AC mRNA, increased in nasal polyps. We also found that there was an increase in intracellular mucin in nasal polyps, compared to the normal nasal inferior turbinate. A mixture of inflammatory mediators increased MUC8 mRNA expression and decreased MUC5AC mRNA expression in cultured normal human nasal epithelial cells. Among inflammatory mediators, IL-4 is responsible for the decrease in MUC5AC mRNA and MUC5AC mucin secretion. These results indicate that MUC8 may be one of the major mucins secreted from the polyp epithelium and that it may play an important role in the pathogenesis of mucus hypersecretion in chronic sinusitis with polyps.     

Upregulation of MUC8 and downregulation of MUC5AC by inflammatory mediators in human nasal polyps and cultured nasal epithelium

Polyps are believed to be the source of mucus hypersecretion in chronic inflammation of the sinus. However, it is not clear which mucins are responsible for the hypersecretion of mucus by nasal polyps. We describe the over-expression of MUC8 mRNA in nasal polyps and the upregulation of MUC8 mRNA expression and downregulation of MUC5AC mRNA expression by inflammatory mediators. We found that the level of MUC8 mRNA, but not the level of MUC5AC mRNA, increased in nasal polyps. We also found that there was an increase in intracellular mucin in nasal polyps, compared to the normal nasal inferior turbinate. A mixture of inflammatory mediators increased MUC8 mRNA expression and decreased MUC5AC mRNA expression in cultured normal human nasal epithelial cells. Among inflammatory mediators, IL-4 is responsible for the decrease in MUC5AC mRNA and MUC5AC mucin secretion. These results indicate that MUC8 may be one of the major mucins secreted from the polyp epithelium and that it may play an important role in the pathogenesis of mucus hypersecretion in chronic sinusitis with polyps.     

Immunohistochemical analyses of MUC5AC mucin expression in sinus mucosa of children with sinusitis and controls

OBJECTIVES: The purpose of this study was to analyze MUC5AC protein expression in sinus mucosal specimens of children with and without chronic sinusitis. METHODS: Morphometric, histologic, and immunohistochemical analyses were carried out on sinus mucosa of 7 children with chronic sinusitis and 6 children without sinusitis. RESULTS: MUC5AC protein was expressed in a subset of goblet cells in the surface epithelium, but not in the submucosal glands in either pediatric population. The number of goblet cells that expressed MUC5AC mucin was not significantly different in patients with and without chronic sinusitis. All specimens had similar numbers of goblet cells in the surface epithelium. CONCLUSIONS: The data demonstrate that neither goblet cell hyperplasia nor increased MUC5AC expression occurs in the sinus mucosa of children with chronic sinusitis. This suggests that in contrast to asthma, in which goblet cell hyperplasia is present in the lower respiratory tract, mucus hypersecretion in pediatric chronic sinusitis may involve other secretory cells, eg, submucosal glandular cells, and mucins secreted by these glandular cells.     

Mucin gene expression in nasal polyps

CONCLUSIONS: A large set of mucin genes is expressed in nasal polyps. The expression pattern is complex and may reflect the wide spectrum of variables involved in polyp formation and progression. Prospective studies including subgroups of nasal polyps and involving substantial numbers of cases in each subgroup will be required to elucidate these variables and to understand how they affect mucus secretion. OBJECTIVE: At present, 15 of the 19 known mucin genes are expressed in the human airways. Nasal polyps might be expected to have a mucin expression pattern comparable to that of the airways. The aim of this study was to investigate mucin expression in nasal polyps. MATERIAL AND METHODS: Nasal polyp samples were obtained from 20 patients during functional endoscopic sinus surgery. Normal (control) sphenoid sinus mucosa was obtained from patients undergoing trans-sphenoid hypophysectomy. The expression of eight mucin genes (MUC1-4, -5AC, -5B, -6 and -7) was studied by in situ hybridization utilizing digoxigenin-labelled oligonucleotide probes. RESULTS: MUC6 and -7 were not expressed in sphenoid sinus mucosa, while all the studied mucin genes were expressed in nasal polyps. Expression patterns varied widely between individual polyps. The predominant epithelial mucin genes were MUC4, -5AC and -3, while MUC5B and -7 were mainly of glandular origin. MUC1, -2 and -6 were weakly expressed. The major alteration in gene expression in nasal polyps was found in the submucosal glands. MUC4 and -5AC represent a major component of both submucosal glands and epithelial cells in nasal polyps.     

Expression of MUC5AC mRNA in the goblet cells of human nasal mucosa

OBJECTIVES/HYPOTHESIS: Mucus hypersecretion is a common feature in chronic sinusitis with polyps. Because mucus hypersecretion is commonly accompanied by goblet cell hyperplasia, it is important to identify which mucin gene mRNAs are expressed in the goblet cells of the surface epithelium in the human airway. This study aims to investigate the pattern of expression of MUC5AC messenger RNA (mRNA) in the goblet cells of human nasal mucosa. METHODS: Six nasal polyps, five inferior turbinate mucosa specimens, and three normal-appearing mucosa specimens of the posterior ethmoid sinus were obtained. Each of the specimens was cut into 10-microm-thick serial frozen sections, and in situ hybridization of MUC5AC mRNA was performed with an oligonucleotide probe. Alcian blue (pH 2.5)-periodic acid-Schiff (AB-PAS) staining was performed on the serial sections. RESULTS: In human nasal polyps, MUC5AC mRNA was expressed in the cytoplasm of most of the goblet cells. However, in the inferior turbinate, MUC5AC mRNA was expressed in only some of the goblet cells. On the contrary, in the normal-appearing mucosa of the posterior ethmoid sinus, MUC5AC mRNA was barely expressed in the goblet cells. Furthermore, MUC5AC mRNA was mainly expressed in some of the PAS-positive goblet cells. CONCLUSIONS: Only a portion of the goblet cells in the human nasal mucosa expressed MUC5AC mRNA. This result suggests that surface goblet cells might have other mucin genes, in addition to MUC2 and MUC5AC.     

Upper airway mucin gene expression: a review

INTRODUCTION: The gel-like properties of mucus depend primarily on its content of mucins. The protein backbones of mucins are encoded by mucin genes. Of the currently known 20 mucin genes that encode protein backbone of mucins, 16 have been identified in the airways. METHOD: We explored the current knowledge about upper airway mucin expression in health and disease conditions using a Medline search. We have also studied upper airway mucin gene expression and compared our results with the results from other studies. RESULTS: MUC5AC, MUC5B, and MUC2 are the principal gel-forming mucins secreted in the airway. However, the spectrum of mucin expression in chronic upper airway diseases such as nasal polyps, chronic sinusitis, middle ear effusion, and cystic fibrosis is generally wide and variable. DISCUSSION: The wide spectrum of upper airway mucin expression is possibly caused by various anatomic and histologic features as well as physiologic and pathologic variables. These variables have not been fully explored yet, and the majority of airway mucin expression studies used small numbers of samples. CONCLUSION: Studies including adequate numbers of samples (patients) are more likely to reveal a clearer profile and more precise expression patterns. Generating a clear profile of mucin expression patterns in health and disease requires the analysis of different variables, which can alter that expression. It is also essential to understand the various molecular mechanisms controlling mucin gene and protein expression. This could lead to the invention of novel therapeutic modalities to treat upper airway diseases.     

Distribution of respiratory mucin proteins in human nasal mucosa

OBJECTIVES/HYPOTHESIS: The upper respiratory tract is involved in many acute and chronic respiratory tract diseases that present with the symptom of mucus hypersecretion. Mucin genes that encode for the backbone of glycoproteins contribute to the viscoelastic property of airway mucus. We examined the cellular expression and distribution of two major respiratory mucus-forming glycoproteins, MUC5AC and MUC5B, in normal human nasal tissues. METHODS: Immunohistochemical analysis using polyclonal antibodies against the mucins MUC5AC and MUC5B was performed in normal human nasal tissues. RESULTS: An abundant staining of submucosal mucus gland and epithelial goblet cells for MUC5B was found. Immunohistochemical analysis of MUC5AC showed staining of surface epithelium goblet cells, whereas there was no staining of glandular cells. Comparison of the expression to lower airways revealed a similar pattern of expression of both mucins. CONCLUSIONS: The data in the present study demonstrated the localization of the two major respiratory mucin proteins in human nasal mucosa with a similar distribution of expression of MUC5AC and MUC5B in normal upper and lower airways. Mucin protein expression parallels that of mucin messenger RNA expression.     

MUC5B secretion is up-regulated in sinusitis compared with controls

BACKGROUND: The mucus that lines the airway epithelium provides a barrier against pathogenic and noxious agents and participates in the innate mucosal response to inflammation and infection. Mucins are the major components of mucus and the macromolecules that impart rheologic properties to airway mucus. Airway mucus is overproduced in chronic rhinosinusitis (CRS). Biochemical and biophysical characterization of mucus in CRS and in normal airways will elucidate important aspects of CRS pathophysiology and allow the design of targeted medical treatments. The aim of this study was to estimate secretion of sinus mucus mucins in healthy individuals and CRS and correlate them with mucus biophysical properties. METHODS: Twenty-seven sinus mucus samples from 21 patients were collected (14 subjects with CRS undergoing sinus surgery as part of their treatment and 7 control subjects undergoing hypophysectomy without sinonasal disease). Biophysical properties of the mucus were measured by rheometry. ELISA was done to estimate MUC5AC and MUC5B mucin content in comparison with standards, i.e., porcine gastric mucin (MUC5AC) and human salivary mucin (MUC5B). RESULTS: MUC5B secretion +/- SEM was 0.49 +/- 0.16 microg/mL (n = 14) and 0.17 +/- 0.05 microg/mL (n = 7) and MUC5AC secretion +/- SEM was 1.26 +/- 0.26 microg/mL (n = 14) and 1.46 +/- 0.61 microg/mL (n = 7) in chronic sinusitis and control subjects, respectively. There was linear correlation between viscosity and mucin content in the control group but not in the CRS group. CONCLUSION: MUC5B secretion is significantly up-regulated in CRS compared with control subjects (p = 0.04). Correlation between viscosity and mucin content was lost in CRS. This is likely to have important implications for future therapies in CRS.     

Open-type congenital cholesteatoma: differential diagnosis for conductive hearing loss with a normal tympanic membrane

Conclusions

A large set of mucin genes is expressed in nasal polyps. The expression pattern is complex and may reflect the wide spectrum of variables involved in polyp formation and progression. Prospective studies including subgroups of nasal polyps and involving substantial numbers of cases in each subgroup will be required to elucidate these variables and to understand how they affect mucus secretion.

Objective

At present, 15 of the 19 known mucin genes are expressed in the human airways. Nasal polyps might be expected to have a mucin expression pattern comparable to that of the airways. The aim of this study was to investigate mucin expression in nasal polyps.

Material and methods

Nasal polyp samples were obtained from 20 patients during functional endoscopic sinus surgery. Normal (control) sphenoid sinus mucosa was obtained from patients undergoing trans-sphenoid hypophysectomy. The expression of eight mucin genes (MUC1–4, -5AC, -5B, -6 and -7) was studied by in situ hybridization utilizing digoxigenin-labelled oligonucleotide probes.

Results

MUC6 and -7 were not expressed in sphenoid sinus mucosa, while all the studied mucin genes were expressed in nasal polyps. Expression patterns varied widely between individual polyps. The predominant epithelial mucin genes were MUC4, -5AC and -3, while MUC5B and -7 were mainly of glandular origin. MUC1, -2 and -6 were weakly expressed. The major alteration in gene expression in nasal polyps was found in the submucosal glands. MUC4 and -5AC represent a major component of both submucosal glands and epithelial cells in nasal polyps.     

Mucin gene expression in hypertrophic adenoids

CONCLUSION: Membrane-bound mucin MUC4 represents the predominant mucin expressed in the adenoid epithelium followed by MUC5AC (gel-forming mucin). This may suggest that membrane-bound mucins could be involved in pathogen binding and immunological stimulation. OBJECTIVES: The aim of this study was to investigate mucin expression in hypertrophic adenoids. MATERIALS AND METHODS: Adenoidal samples were obtained from 12 children. The expression of eight mucin genes, MUC1-4, MUC5AC, 5B, 6 and 7 was studied by in situ hybridization utilizing digoxigenin-labelled oligonucleotide probes. RESULTS: The dominant mucin genes were MUC4, 3 and 5AC, while MUC1, 2, 5B and 7 were sparsely expressed and MUC6 was not expressed. Expression patterns were very different from those in the upper airways. Most samples expressed two membrane-bound mucins (MUC4 and 3) and one secretory mucin (MUC5AC).     

Expression of mucin genes in chronic ethmoiditis

We have investigated the profiles of MUC genes expressed in chronic ethmoiditis mucosa and normal ethmoid mucosa using RT-PCR, and the morphology of chronic ethmoiditis by a combination of light and electron microscope was observed. In the light- and electron-microscopic studies, chronic ethmoiditis mucosa revealed increased numbers of goblet cells with higher production of mucus in comparison to normal ethmoid mucosa. RT-PCR of cDNAs from three normal ethmoid mucosa revealed the same pattern of mucin gene expression, such as MUC5AC and MUC8. However, RT-PCR of cDNAs from eight chronic ethmoiditis mucosa showed the expression of two MUC1, six MUC4, eight MUC5AC, five MUC5B, seven MUC7, and eight MUC8. MUC2 and MUC6 were not detected. These results suggest that MUC4, MUC5AC, MUC5B, MUC7, and MUC8 are major mucins in the ethmoid mucosa and are up-regulated by chronic inflammation.     

Localization and expression of MUC5B and MUC7 mucins in pediatric sinus mucosa

OBJECTIVES: The purpose of this study was to analyze the secretory cell population and distribution of MUC5B and MUC7 mucins in the sinus mucosa of pediatric patients with and without chronic rhinosinusitis (CRS). METHODS: Sinus mucosal specimens were collected at surgery in a pediatric tertiary care facility. Histologic, immunohistochemical, and morphometric analyses were performed on sinus mucosa of 20 children with CRS and 7 children without CRS. RESULTS: A significant increase in the area of submucosal glands was evident in the sinus mucosa of children with CRS as compared to controls. MUC5B and MUC7 mucins were expressed in the submucosal glands, as well as in goblet cells, in the sinus mucosa of both populations. No differences in MUC5B or MUC7 expression were observed when mucin expression was normalized to glandular area. CONCLUSIONS: Children with CRS have an increased number of submucosal glands, indicating that glandular mucins contribute to mucus overproduction in CRS. MUC5B and MUC7 mucins, which have previously been considered only glandular mucins, are also expressed in goblet cells in the sinus mucosa.     

黏蛋白在鼻息肉及变应性鼻炎中的基因表达水平的研究

目的：探讨5种人黏蛋白基因（MUC2、MUC5AC、MUC5B、MUC18、MUC19）在鼻息肉和变应性鼻炎中的基因表达水平及临床意义。方法：采用RT-PCR及实时荧光定量RT-PCR,检测35例鼻息肉、18例变应性鼻炎患者下鼻甲及18例正常人黏蛋白基因（MUCS）在下鼻甲黏膜上皮的基因表达水平。结果：RT-PCR及实时荧光定量RT-PCR的结果表明,MUC5AC、MUC5B在鼻息肉组和变应性鼻炎组中的表达高于对照组（P〈0.05）,鼻息肉组与变应性鼻炎组及对照组间表达差异均无统计学意义（P〉0.05）。MUC2、MUC18在3组中的表达差异无统计学意义（P〉0.05）。MUC19在变应性鼻炎组中的表达高于鼻息肉组和对照组（P〈0.05或P〈0.01）。结论：MUC5AC和MUC5B在鼻息肉、变应性鼻炎的黏液过度分泌过程中具有重要意义;MUC19在变应性鼻炎的黏液过度分泌过程中也有重要意义,但是对鼻息肉患者的黏液分泌没有明显作用;未发现MUC2、MUC18在变应性鼻炎的黏液过度分泌过程中起明显作用。