Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease

Livraghi‐Butrico, Alessandra; Grubb, Barbara R.; Wilkinson, Kristen J.; Volmer, Allison S.; Burns, Kimberly; Evans, Christopher M.; O’Neal, Wanda K.; Boucher, Richard C.

doi:10.1038/mi.2016.63

Cited by 98 publications

(93 citation statements)

References 43 publications

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“…It was demonstrated that MUC5B, but not MUC5AC, is required for airway defense, playing an important role in controlling infections in the airways, as well as maintaining lungs immune response and mucociliary clearance in mice (Roy et al, 2014). Moreover, these findings were confirmed recently, and it has been suggested that mucus hyperconcentration controls mucociliary clearance deficit in the production of bronchitic airway pathology (Livraghi-Butrico et al, 2016). Thus, although therapies that reduce mucus production and secretion might decrease obstruction, careful design of therapeutic strategies to promote adequate mucociliary clearance should be taken, considering a complete MUC5B removal from the airways may be undesirable and result in adverse events, such as chronic bacterial infections, macrophages with impaired phagocytic functions, and increased airway inflammation (Livraghi-Butrico et al, 2016; Roy et al, 2014).…”

Section: Mucus Compositionmentioning

confidence: 55%

“…Moreover, these findings were confirmed recently, and it has been suggested that mucus hyperconcentration controls mucociliary clearance deficit in the production of bronchitic airway pathology (Livraghi-Butrico et al, 2016). Thus, although therapies that reduce mucus production and secretion might decrease obstruction, careful design of therapeutic strategies to promote adequate mucociliary clearance should be taken, considering a complete MUC5B removal from the airways may be undesirable and result in adverse events, such as chronic bacterial infections, macrophages with impaired phagocytic functions, and increased airway inflammation (Livraghi-Butrico et al, 2016; Roy et al, 2014). Investigating the role of mucins both in health and disease has been of great interest, and from substantial progress in the past two decades.…”

Section: Mucus Compositionmentioning

confidence: 55%

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Physicochemical properties of mucus and their impact on transmucosal drug delivery

Ghosh

2017

International Journal of Pharmaceutics

381

273

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Mucus is a selective barrier to particles and molecules, preventing penetration to the epithelial surface of mucosal tissues. Significant advances in transmucosal drug delivery have recently been made and have emphasized that an understanding of the basic structure, viscoelastic properties, and interactions of mucus is of great value in the design of efficient drug delivery systems. Mucins, the primary non-aqueous component of mucus, are polymers carrying a complex and heterogeneous structure with domains that undergo a variety of molecular interactions, such as hydrophilic/hydrophobic, hydrogen bonds and electrostatic interactions. These properties are directly relevant to the numerous mucin-associated diseases, as well as delivering drugs across the mucus barrier. Therefore, in this review we discuss regional differences in mucus composition, mucus physicochemical properties, such as pore size, viscoelasticity, pH, and ionic strength. These factors are also discussed with respect to changes in mucus properties as a function of disease state. Collectively, the review seeks to provide a state of the art roadmap for researchers who must contend with this critical barrier to drug delivery.

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Section: Mucus Compositionmentioning

confidence: 55%

Section: Mucus Compositionmentioning

confidence: 55%

Physicochemical properties of mucus and their impact on transmucosal drug delivery

Ghosh

2017

International Journal of Pharmaceutics

381

273

View full text Add to dashboard Cite

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“…11,21,22 When mucus layer concentrations and osmotic pressures exceed those of the periciliary layer (i.e., the threshold value), the mucus layer compresses the periciliary layer and produces mucus stasis and adhesion. 10 Hence, we predicted that mucin concentration is the variable underlying the formation of the intraluminal mucus plaques that are expectorated with cough.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulated mucus that cannot be expectorated serves as the nidus for airflow obstruction, inflammation, and intermittent infection. 6,10,11 Thus, this model predicts that an increased mucin concentration will be associated with sputum production and disease severity in chronic bronchitis.…”

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confidence: 96%

Airway Mucin Concentration as a Marker of Chronic Bronchitis

et al. 2017

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BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitic and emphysematous components. In one biophysical model, the concentration of mucin on the airway surfaces is hypothesized to be a key variable that controls mucus transport in healthy persons versus cessation of transport in persons with muco-obstructive lung diseases. Under this model, it is postulated that a high mucin concentration produces the sputum and disease progression that are characteristic of chronic bronchitis. METHODS We characterized the COPD status of 917 participants from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) using questionnaires administered to participants, chest tomography, spirometry, and examination of induced sputum. Total mucin concentrations in sputum were measured with the use of size-exclusion chromatography and refractometry. In 148 of these participants, the respiratory secreted mucins MUC5AC and MUC5B were quantitated by means of mass spectrometry. Data from chronicbronchitis questionnaires and data on total mucin concentrations in sputum were also analyzed in an independent 94-participant cohort. RESULTS Mean (±SE) total mucin concentrations were higher in current or former smokers with severe COPD than in controls who had never smoked (3166±402 vs. 1515±152 μg per milliliter) and were higher in participants with two or more respiratory exacerbations per year than in those with zero exacerbations (4194±878 vs. 2458±113 μg per milliliter). The absolute concentrations of MUC5B and MUC5AC in current or former smokers with severe COPD were approximately 3 times as high and 10 times as high, respectively, as in controls who had never smoked. Receiver-operating-characteristic curve analysis of the association between total mucin concentration and a diagnosis of chronic bronchitis yielded areas under the curve of 0.72 (95% confidence interval [CI], 0.65 to 0.79) for the SPIROMICS cohort and 0.82 (95% CI, 0.73 to 0.92) for the independent cohort. CONCLUSIONS Airway mucin concentrations may quantitate a key component of the chronic bronchitis pathophysiologic cascade that produces sputum and mediates disease severity. Studies designed to explore total mucin concentrations in sputum as a diagnostic biomarker and therapeutic target for chronic bronchitis appear to be warranted. (Funded by the National Heart, Lung, and Blood Institute and others.)

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“…Mouse Muc5b KO models show a 90% decrease in mucociliary clearance as well as increased airway inflammation and eventually death by spontaneous infection [78,154,155]. Although different exposures such as NRG1beta1 [156], fibronectin and laminin [157] have been shown to change the expression of MUC5B the regulatory mechanisms are still poorly understood.…”

Section: Muc5b's Role In the Lungmentioning

confidence: 99%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis (IPF) is the most common and the most aggressive fibrosing interstitial lung disease (ILD). Despite recent promising clinical trials, IPF remains incurable and largely untreatable. Genetic studies have identified several risk loci for both sporadic and familial forms of IPF. A single variant upstream of MUC5B is predicted to account for more than 30% of all IPF risk. This variant, rs35705950, is associated with expression of MUC5B in healthy lung tissue. However, the mechanism underlying the relationship between rs35705950 and MUC5B expression remains unclear.The first goal of my thesis research was to determine whether rs35705950 is also a risk factor for other forms of ILD. Genomic DNA from individuals with IPF, HP, COPD, iNSIP, and RB-ILD was obtained and genotyped for the common MUC5B promoter variant. In these populations the risk allele was associated with IPF and iNSIP which suggested a potential shared disease mechanism. Additionally, I showed that in the IPF and control populations rs35705950 is associated with lung MUC5B expression.The second goal of my thesis research was to investigate MUC5B promoter DNA methylation which has previously been shown to play a role in MUC5B expression.Methylation analysis of the 4KB region upstream of MUC5B identified two differentially methylated regions (DMRs) associated with IPF, one DMR associated with MUC5B iv expression, and one DMR associated with rs35705950. The IPF, MUC5B expression, and rs35705950 associated DMRs are all differentially methylated at a cluster of 11 CpG motifs. overlapping DMR, including the motif disrupted by rs35705950. These findings suggest that DNA methylation may play a role in MUC5B gene regulation and IPF risk.Next, I used cross species analysis to identify highly conserved domains within the overlapping DMR. Evolutionary conservation indicated selective pressures to maintain sequences overtime and suggests biological importance. The overlapping DMR contains a highly conserved binding motif for FOXA2, a transcription factor. Further analysis using ChIP-qPCR, reporter constructs, and siRNA, established a role for FOXA2 in regulation of MUC5B expression in lung tissue. Additionally, siRNA knock down identified 3 other transcription factors which are associated with MUC5B expression; STAT3, HOXA9 and ZBTB7A. These transcriptional regulators provide insight into possible therapeutic intervention for MUC5B dysregulation and IPF.The form and content of this abstract are approved. I recommend its publication.

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Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease

Cited by 98 publications

References 43 publications

Physicochemical properties of mucus and their impact on transmucosal drug delivery

Physicochemical properties of mucus and their impact on transmucosal drug delivery

Airway Mucin Concentration as a Marker of Chronic Bronchitis

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

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