What does mucin have to do with lung disease?

doi:10.1016/S1526-0550(02)00007-0

Paediatric Respiratory Reviews

Volume 3, Issue 2, June 2002, Pages 98-103

https://doi.org/10.1016/S1526-0550(02)00007-0 Get rights and content

Abstract

Mucin glycoproteins are a major macromolecular component of mucus. Mucins are large, heavily glycosylated glycoproteins that are expressed in two major forms: the membrane-tethered mucins and the secreted mucins. In the airways, MUC1 and MUC4 are the predominant membrane-tethered mucins that are present on epithelial cell surfaces; MUC5AC, MUC5B and MUC2 are the predominant secreted mucins that contribute to the mucus gel. Although the role of MUC1 and MUC4 in the airway is not known, they may function as receptors or receptor ligands and activate intracellular signalling cascades affecting epithelial functions. Several inflammatory mediators increase expression of the secreted mucin genes, MUC5AC and MUC2. Furthermore, overexpression of MUC5AC, MUC5B and MUC2 correlates strongly with secretory cell hyperplasia and metaplasia in human and murine airways. The insights gleaned from the investigations of mucin function and gene regulation should be useful for elucidating the cellular mechanisms leading to airway remodelling and mucus obstruction.

Section snippets

INTRODUCTION

Airway mucus forms a protective barrier between the respiratory tract epithelium and the environment. Mucus is composed mainly of water and ions with 5% of the content due to proteins secreted by airway cells, including mucin glycoproteins, lysozyme, lactoferrin, defensins, kallikrein, antiproteases, secretory component, serum transudate proteins, IgA, IgG, proteoglycans and lipids.1., 2. Mucus participates in heat and water exchange in the respiratory tract³ and binds particles and bacteria,

MUCIN GLYCOPROTEINS (MUCINS)

The mucins are large glycoproteins, ranging in size from several hundred to several thousand kDa. They are heavily glycosylated with heterogeneous O-linked oligosaccharides that comprise 50–80% of the molecular mass. Mucins are secreted from goblet cells and from mucous and serous cells in submucosal glands. Because of their complex structure, mucins have been difficult to isolate and identify biochemically.⁶ Molecular genetic approaches have significantly advanced the field resulting in the

RESPIRATORY TRACT MUCINS

In the normal human adult lung, at least eight MUC genes, MUC1, 2, 4, 5AC, 5B, 7, 8 and 13, are expressed as mRNA.²² Using in situ hybridisation, the normal expression pattern of different MUC genes is somewhat restricted to specific cell types in the lower and upper respiratory tract epithelium.²³ MUC1 and MUC4 are present in all superficial airway epithelial cells. MUC2 is present at low levels in superficial epithelial cells. MUC5AC is predominantly expressed in goblet cells. MUC5B is

MUCIN EXPRESSION IN AIRWAY DISEASES

What role do mucins play in the pathogenesis of lung disease? It has long been recognised by clinicians that mucus obstruction of the airways is a major cause of morbidity and mortality in several chronic inflammatory airway diseases such as chronic bronchitis, asthma and cystic fibrosis (CF). Chronic mucus hypersecretion is associated with a decline in pulmonary function and morbidity in chronic obstructive pulmonary disease.²⁶ Sputum production and associated mucus obstruction of airways

IN VIVO MODELS OF AIRWAY DISEASES

In asthma, chronic bronchitis and cystic fibrosis, mucin overproduction has been linked to secretory cell hyperplasia. To further investigate the mechanisms of secretory cell metaplasia/hyperplasia and mucin overproduction, in vivo models have been exploited. Several inflammatory mediators relevant to asthma have been shown to induce goblet cell metaplasia and increase Muc gene expression in murine airway epithelium. Following sensitisation to ovalbumin and an ovalbumin challenge, murine

MUCIN GENE REGULATION BY INFLAMMATORY MEDIATORS

The consistent association between goblet cell metaplasia and increased mucin expression provides a strong rationale for investigating the molecular mechanisms of mucin gene regulation in the lung. For these studies, in vitro models of airway epithelial cells have been used.36., 41. Several respiratory tract carcinoma cell lines express both mRNA and glycoproteins of the major respiratory tract mucins, MUC2, MUC5AC and MUC5B. Specifically, NCI-H292 (a mucoepidermoid carcinoma) has been used to

CONCLUSION

Chronic inflammatory airways diseases have the common pathological findings of secretory cell hyperplasia and mucus obstruction of the airways. The mucin glycoproteins, major macromolecular components of mucus, are overexpressed in the airways of patients with asthma, cystic fibrosis and chronic bronchitis. The increased expression of secreted, gel-forming mucins, MUC2, MUC5AC and MUC5B, occurs in concert with secretory cell hyperplasia in both humans and in vivo rodent models of asthma.

PRACTICE POINTS

•
Mucin glycoproteins are a major macromolecular component of airway mucus.
•
Both membrane-tethered and secreted, gel-forming mucin (MUC) genes are expressed in the airway.
•
Inflammatory mediators increase mRNA expression of the secreted mucins, MUC2 and MUC5AC.
•
Increased expression of MUC2, MUC5AC and MUC5B are associated with secretory cell hyperplasia and metaplasia in the airways.

RESEARCH DIRECTIONS

•
Investigation of the regulation of MUC1 and MUC4 mRNA and glycoprotein expression in the lung.
•
Evaluation of the relationship between mucin expression and secretory cell hyperplasia.
•
Determination of the functions of membrane-tethered and secreted mucins in the airways.
•
Correlation of chronic inflammatory airway disease phenotypes and altered MUC expression.

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Qufeng Xuanbi Formula inhibited benzo[a]pyrene-induced aggravated asthma airway mucus secretion by AhR/ROS/ERK pathway
2024, Journal of Ethnopharmacology
Excessive secretion of airway mucus may be an important pathological factor of air pollution-induced acute asthma attacks. Treatment of airway mucus hypersecretion improves asthma aggravated by air pollutants. Qufeng Xuanbi Formula (QFXBF) has been used to treat asthma for more than 30 years. However, whether QFXBF inhibits asthmatic mucus secretion exacerbated by air pollutants has not yet been established.
This study aimed to evaluate the effect of QFXBF on airway mucus secretion and the mechanism of action in an air pollutant benzo[a]pyrene (BaP)-induced mouse model of aggravated asthma.
Ovalbumin (OVA) and BaP co-exposure were used to establish the aggravated asthma model. The average enhanced pause (Penh), serum OVA-specific IgE, and changes in lung histopathology were determined. 16HBE cells exposed to BaP, treatment with QFXBF, arylhydrocarbon receptor (AhR) signal antagonist SR1, reactive oxygen species (ROS) antagonist NAC, or extracellular signal-regulated kinase (ERK1/2) signal antagonist U0126 were established to investigate the effect of QFXBF on BaP-induced mucus secretion and its target. The mRNA and protein expression levels of MUC5AC in the lung tissue and 16HBE cells were examined. We also studied the effect of QFXBF on ROS production. Finally, the protein expression of AhR, phospho-extracellular signal-regulated kinases (p-ERK1/2), and ERK1/2 in 16HBE cells and lung tissues was determined by western blotting.
Administration of QFXBF significantly alleviated the pathological symptoms, including Penh, serum OVA-specific IgE, and changes in lung histopathology in a BaP-induced mouse model of aggravated asthma. QFXBF inhibited MUC5AC expression in asthmatic mice and 16HBE cells exposed to BaP. ROS production, AhR expression, and ERK1/2 phosphorylation were significantly increased in BaP-induced asthmatic mice and 16HBE cells. Signaling pathway inhibitors StemRegenin 1 (SR1), NAC, and U0126 significantly inhibitedBaP-induced MUC5AC expression in 16HBE cells. SR1 reversed Bap-induced ROS production and ERK activation, and NAC inhibited Bap-induced ERK activation. In addition, QFXBF regulated AhR signaling, inhibited ROS production, reversed ERK activation, and downregulated mucus secretion to improve asthma aggravated by air pollutant BaP.
QFXBF can ameliorate mucus secretion in BaP-induced aggravated asthmatic mice and 16HBE cells, and the specific mechanism may be related to the inhibition of the AhR/ROS/ERK signaling pathway.
Therapeutic implementation in arterial thrombosis with pulmonary administration of fucoidan microparticles containing acetylsalicylic acid
2022, International Journal of Pharmaceutics
Citation Excerpt :
MP/F4M showed higher free mucin (7.99 ± 0.12; 8.2 ± 0.41; 9.24 ± 0.24 and 9.45 ± 0.53 mg mL−1) in all the mucin concentrations tested (200, 250, 300 and 350 mg mL−1, respectively) when compared to the control (MP/wF4M – Microparticles without HPMC) (12.53 ± 0.18; 10.99 ± 0.00; 11.12 ± 0.06 and 12.87 ± 0.06 mg mL−1, respectively) (Supplementary Information Fig. S6). It is essential for a delayed-release formulation for pulmonary administration to resist the pulmonary clearance and interact with negatively charged mucin, the major component of lung mucus (Voynow, 2002). These results showed that isolated ASA was fast-washed (low permeation/adsorption), mainly due to its negative charge.
Several antithrombotic drugs are available to treat cardiovascular diseases due to its high mortality and morbidity worldwide. Despite these, severe adverse effects that can lead to treatment withdrawal have been described, highlighting the importance of new therapies. Thus, this work describes the development of fucoidan microparticles containing acetylsalicylic acid (MP/F4M) for pulmonary delivery and in vitro, ex vivo, and in vivo evaluation. Microparticles were prepared via spray-drying and characterized in vitro (mucoadhesive properties, coagulation time, platelet aggregation, adhesion, and hemolysis) followed by ex vivo platelet aggregation, in vivo arterial thrombosis, and hemorrhagic profile. The formulation physicochemical characterization showed suitable characteristics along with delayed drug release, increased breathable particle fraction, and high washability resistance as well as antiplatelet activity and enhanced platelet adhesion in vitro. In in vivo assays, MP/F4M protected against arterial thrombosis, without changes in the hemorrhagic profile. Finally, no lung changes were observed after prolonged pulmonary administration, whereas isolated ASA led to an inflammatory response. In conclusion, pulmonary administration of fucoidan microparticles with an antiplatelet drug may be an alternative therapy to treat cardiovascular diseases, opening the field for different formulations.
Benzo(a)pyrene induces MUC5AC expression through the AhR/mitochondrial ROS/ERK pathway in airway epithelial cells
2021, Ecotoxicology and Environmental Safety
Citation Excerpt :
Excessive secretion of a high concentration of mucus in the respiratory tract often leads to fluid embolism, which leads to abnormal gas exchange and ultimately respiratory failure. This phenomenon is particularly obvious in cases of severe and fatal diseases (Voynow, 2002). Mucin is encoded by many specific MUC genes.
Benzo(a)pyrene (BaP) is a ubiquitous air pollutants, and BaP exposure leads to a risk of respiratory diseases. The oversecretion of airway mucus and high expression of mucin 5AC (MUC5AC) are associated with common respiratory disorders caused by air pollution. We aimed to investigate the effect of BaP on MUC5AC expression, especially the mechanisms by which BaP induces MUC5AC gene expression.
The human airway epithelial cell NCI-H292 was used to test the effects of BaP on the expression of MUC5AC in vitro. MUC5AC mRNA and protein expression were assessed with real-time quantitative PCR, immunochemistry, and western blotting. A luciferase assay was conducted to detect the activity of the promoter. The total cellular ROS and mitochondrial ROS were measured by corresponding probes. Small-interfering RNAs were used for gene silencing. AhR-overexpressing cell lines were constructed by transfection with AhR overexpression lentivirus.
We found that BaP stimulation upregulated the MUC5AC mRNA and protein levels and activated the ERK pathway. Suppressing ERK with U0126 (an ERK inhibitor) or knocking down ERK with siRNA decreased BaP-induced MUC5AC expression. The luciferase activity transfected with the MUC5AC promoter and cAMP-response element (CRE) was increased after BaP treatment, whereas CREB siRNA suppressed the BaP-induced overexpression of MUC5AC. In addition, BaP increased mitochondrial ROS production, and Mito-TEMP, a mitochondrial ROS inhibitor, inhibited BaP-induced MUC5AC expression and ERK activation. BaP increased the mRNA levels of CYP1A1 and CYP1B1, while Alizarin, a CYP1s inhibitor, suppressed the effects of BaP, including the MUC5AC overexpression, ERK activation and mitochondrial ROS generation. BaP induced the translocation of aryl hydrocarbon receptor (AhR) from the cytoplasm to the nucleus. SiRNA-mediated knockdown or chemical inhibition of AhR decreased the BaP-induced expression of MUC5AC, while the overexpression of AhR significantly enhanced the BaP-induced expression of MUC5AC. ITE, an endogenous AhR ligand, also upregulated the mRNA and protein expression of MUC5AC. Furthermore, resveratrol treatment inhibited the BaP-induced MUC5AC overexpression, AhR translocation, mitochondrial ROS production and ERK pathway activation.
Here, we highlighted the crucial role of AhR/mitochondrial ROS/ERK pathway activation in BaP-induced MUC5AC overexpression and identified resveratrol as a promising drug to reduce BaP-induced MUC5AC overexpression.
Chloroquine and hydroxychloroquine for combating COVID-19: Investigating efficacy and hypothesizing new formulations using Bio/chemoinformatics tools
2020, Informatics in Medicine Unlocked
Citation Excerpt :
On the delivery level, the docking results of the two drugs on mucin as an indicator of the ability of the drug for better mucoadhesion was also in favor of HCQ. Mucin is an abundant micromolecule that is present in the airways [47]. Furthermore, higher affinity of HCQ to HSPGs, ACE -2 and PICALM was observed as revealed by the lower binding energy scores.
Chloroquine (CQ) and hydroxychloroquine (HCQ) are undergoing several clinical trials for evaluating their efficacy and safety as antiviral drugs. Yet, there is still a great debate about their efficacy in combating COVID-19. This study aimed to evaluate the feasibility of intranasal and/or pulmonary administration of CQ/HCQ for COVID-19 using Bio/chemoinformatics tools. We, hereby, hypothesize the success of the intranasal and the pulmonary routes through a gelatin matrix to overcome several challenges related to CQ and HCQ pharmacodynamics and pharmacokinetics properties and to increase their local concentrations at the sites of initial viral entry while minimizing the potential side effects. Molecular docking on the gelatin-simulated matrix demonstrated high loading values and a sustained release profile. Moreover, the docking on mucin as well as various receptors including Angiotensin-converting enzyme 2 (ACE-2), heparin sulphate proteoglycan and Phosphatidylinositol binding clathrin assembly protein (PICALM), which are expressed in the lung and intranasal tissues and represent initial sites of attachment of the viral particles to the surface of respiratory cells, has shown good binding of CQ and HCQ to these receptors. The presented data provide an insight into the use of a novel drug formulation that needs to be tested in adequately powered randomized controlled clinical trials; aiming for a sustained prophylaxis effect and/or a treatment strategy against this pandemic viral infection.
Pathobiological implications of MUC4 in non-small-cell lung cancer
2013, Journal of Thoracic Oncology
Altered expression of MUC4 plays an oncogenic role in various cancers, including pancreatic, ovarian, and breast. This study evaluates the expression and role of MUC4 in non–small-cell lung cancer (NSCLC).
We used a paired system of MUC4-expressing (H292) and MUC4-nonexpressing (A549) NSCLC cell lines to analyze MUC4-dependent changes in growth rate, migration, and invasion using these sublines. We also evaluated the alterations of several tumor suppressor, proliferation, and metastasis markers with altered MUC4 expression. Furthermore, the association of MUC4 expression (by immunohistochemistry) in lung cancer samples with patient survival was evaluated.
MUC4-expressing lung cancer cells demonstrated a less proliferative and metastatic phenotype. Up-regulation of p53 in MUC4-expressing lung cancer cells led to the accumulation of cells at the G2/M phase of cell cycle progression. MUC4 expression attenuated Akt activation and decreased the expression of Cyclins D1 and E, but increased the expression of p21 and p27. MUC4 expression abrogated cancer cell migration and invasion by altering N- & E-cadherin expression and FAK phosphorylation. A decrease in MUC4 expression was observed with increasing tumor stage (mean composite score: stage I, 2.4; stage II, 1.8; stage III, 1.4; and metastatic, 1.2; p = 0.0093). Maximal MUC4 expression was associated with a better overall survival (p = 0.042).
MUC4 plays a tumor-suppressor role in NSCLC by altering p53 expression in NSCLC. Decrease in MUC4 expression in advanced tumor stages also seems to confirm the novel protective function of MUC4 in NSCLC.
The extracellular signal-regulated kinase mitogen-activated protein kinase/ribosomal S6 protein kinase 1 cascade phosphorylates cAMP response element-binding protein to induce MUC5B gene expression via D-prostanoid receptor signaling
2011, Journal of Biological Chemistry
Citation Excerpt :
We also showed that ERK MAPK/RSK1/CREB activation was required for PGD2-induced MUC5B gene expression. Several studies have demonstrated that multiple MAP kinases are involved in signal transduction pathways downstream of a variety of inflammatory mediators (47). Transcription of specific genes is induced by the phosphorylation and activation of various transcription factors (48); however, little is known about the specific effect of PGD2 on human airway epithelial cells.
Mucus hypersecretion is a prominent feature of respiratory diseases, and MUC5B is a major airway mucin. Mucin gene expression can be affected by inflammatory mediators, including prostaglandin (PG) D_2, an inflammatory mediator synthesized by hematopoietic PGD synthase (H-PGDS). PGD₂ binds to either d-prostanoid receptor (DP1) or chemoattractant receptor homologous molecule expressed on T-helper type 2 cells (CRTH2). We investigated the mechanisms by which PGD₂ induces MUC5B gene expression in airway epithelial cells. Western blot analysis showed that H-PGDS was highly expressed in nasal polyps. Similar results were obtained for PGD₂ expression. In addition, we could clearly detect the expressions of both H-PGDS and DP1 in nasal epithelial cells but not CRTH2. We demonstrated that PGD₂ increased MUC5B gene expression in normal human nasal epithelial cells as well as in NCI-H292 cells in vitro. S5751, a DP1 antagonist, inhibited PGD₂-induced MUC5B expression, whereas a CRTH2 antagonist (OC0459) did not. These data suggest that PGD₂ induced MUC5B expression via DP1. Pretreatment with extracellular signal-regulated kinase (ERK) inhibitor (PD98059) blocked both PGD₂-induced ERK mitogen-activated protein kinase (MAPK) activation and MUC5B expression. Proximity ligation assays showed direct interaction between RSK1 and cAMP response element-binding protein (CREB). Stimulation with PGD₂ caused an increase in intracellular cAMP levels, whereas intracellular Ca²⁺ did not have such an effect. PGD₂-induced MUC5B mRNA levels were regulated by CREB via direct interaction with two cAMP-response element sites (−921/−914 and −900/−893). Finally, we demonstrated that PGD₂ can induce MUC5B overproduction via ERK MAPK/RSK1/CREB signaling and that DP1 receptor may have suppressive effects in controlling MUC5B overproduction in the airway.

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MINI-SYMPOSIUM: MUCUSWhat does mucin have to do with lung disease?

Abstract

Section snippets

INTRODUCTION

MUCIN GLYCOPROTEINS (MUCINS)

RESPIRATORY TRACT MUCINS

MUCIN EXPRESSION IN AIRWAY DISEASES

IN VIVO MODELS OF AIRWAY DISEASES

MUCIN GENE REGULATION BY INFLAMMATORY MEDIATORS

CONCLUSION

PRACTICE POINTS

RESEARCH DIRECTIONS

J. Allergy Clin. Immunol.

Am. J. Med.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

TIBS

J. Biol. Chem.

J. Biol. Chem.

Chest

Chest

Biochemistry of airway mucus secretions

Federation Proc.

Inhibition of neutrophil elastase by mucus glycoprotein

Am. J. Respir. Cell. Mol. Biol.

Antioxidant properties of guinea pig tracheal epithelial cells in vitro

Am. J. Physiol.

Mucins: structure, function, and role in pulmonary diseases

Am. J. Physiol.

Human respiratory mucins

Eur. Respir. J.

The structure and assembly of secreted mucins

J. Biol. Chem.

Complete sequence of the human mucin MUC4: a putative cell membrane-associated mucin

Biochem. J.

The breast cancer-associated MUC1 gene generates both a receptor and its cognate binding protein

Cancer Res.

Alternative splicing generates a family of putative secreted and membrane-associated MUC4 mucins

Eur. J. Biochem.

Involvement of the MAP kinase ERK2 in MUC1 mucin signaling

Am. J. Physiol. Lung Cell. Mol. Physiol.

Muc1 mucins on the cell surface are adhesion sites for Pseudomonas aeruginosa

Am. J. Physiol. Lung Cell. Mol. Physiol.

Multiple facets of sialomucin complex/MUC4, a membrane mucin and ERBB2 ligand, in tumors and tissues (Y2K update)

Front Biosci.

Airway mucus obstruction: mucin glycoproteins, MUC gene regulation and goblet cell hyperplasia

Am. J. Respir. Cell. Mol. Biol.

MINI-SYMPOSIUM: MUCUS
What does mucin have to do with lung disease?