Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice

Hancock, Laura A.; Hennessy, Corinne E.; Solomon, George M.; Dobrinskikh, Evgenia; Estrella, A.M.; Hara, Naoko; Hill, David B.; Kissner, William J.; Markovetz, Matthew R.; Villalon, Diane E. Grove; Voss, Matthew E.; Tearney, Guillermo J.; Carroll, Kate S.; Shi, Yulong; Schwarz, Marvin I.; Thelin, William R.; Rowe, Steven M.; Yang, Ivana V.; Evans, Christopher M.; Schwartz, David A.

doi:10.1038/s41467-018-07768-9

Cited by 174 publications

(152 citation statements)

References 54 publications

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“…Some investigators have hypothesised that abnormal accumulation of the protein may overwhelm the mucociliary clearance allowing toxic particles and pathogens to accumulate and be localised next to lung AECs where they may be a source of recurrent injury. In support of this, a mouse genetically engineered to overexpress the mucin, MUC5B, was found to have enhanced bleomycin-induced lung fibrosis 32 and these mice display defective mucociliary clearance. Such targeted injury to the AECs may promote fibroproliferation in an attempt at repair.…”

Section: Other Immune-related Genes and Fibrosismentioning

confidence: 86%

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

2019

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Lung fibrosis is characterised by the accumulation of extracellular matrix within the lung and is secondary to both known and unknown aetiologies. This accumulation of scar tissue limits gas exchange causing respiratory insufficiency. The pathogenesis of lung fibrosis is poorly understood, but immunologic‐based treatments have been largely ineffective. Despite this, accumulating evidence suggests that innate immune cells and receptors play important modulatory roles in the initiation and propagation of the disease. Paradoxically, while innate immune signalling may be important for the pathogenesis of fibrosis, there is also evidence to suggest that innate immune function against pathogens may be impaired, leading to dysregulated and/or impaired host defence. This review summarises the evidence for this pathologic two‐way street, highlights new concepts of pathogenesis and recommends future directions for research emphasis.

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Section: Other Immune-related Genes and Fibrosismentioning

confidence: 86%

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

2019

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“…Recent data suggest that in IPF, MUC5B is not restricted to the conducting airways but co-expressed with surfactant protein C in type 2 alveolar (AT2) cells and epithelial cells lining the HC. 54,55 Despite the propensity to develop IPF or RA-ILD with this SNP, it appears to be somewhat protective with life expectancy extending beyond the usual 3-5 years, although a recent paper has challenged this association, suggesting that MUC5B actually decreases survival. 56 The mechanism by which excess MUC5B results in IPF is unknown but current speculation involves impairment of the physical barrier resulting in adherent mucus that is difficult to expectorate and susceptible to colonisation by virulent bacterial strains.…”

Section: Mucins In Pulmonary Fibrosismentioning

confidence: 99%

Mucins and their receptors in chronic lung disease

et al. 2020

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There is growing recognition that mucus and mucin biology have a considerable impact on respiratory health, and subsequent global morbidity and mortality. Mucins play a critical role in chronic lung disease, not only by providing a physical barrier and clearing pathogens, but also in immune homeostasis. The aim of this review is to familiarise the reader with the role of mucins in both lung health and disease, with particular focus on function in immunity, infection and inflammation. We will also discuss their receptors, termed glycan‐binding proteins, and how they provide an attractive prospect for therapeutic intervention.

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“…Acute endogenous clearance was performed as described 18 . In the present studies, AOE challenged mice were exposed to TCEP (500 mM) or saline aerosol for 40 min, at the end of which they were immediately used in lung lavage studies.…”

Section: Acute Endogenous Clearance and Mucolytic Testingmentioning

confidence: 99%

“…2b). Immediately after mucolytic treatment, lungs were lavaged, and the disruption of mucin polymers and elimination of inflammatory cells from airspaces were assessed 18 . In TCEP-treated mice, mucins demonstrated faster electrophoretic migration relative to controls thereby validating effective depolymerization ( Fig.…”

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Disulfide disruption reverses mucus dysfunction in allergic airway disease

Morgan

Shenoy

Raclawska

et al. 2019

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Airway mucus is essential for healthy lung defense 1 , but excessive mucus in asthma obstructs airflow, leading to severe and potentially fatal outcomes 2-5 . Current asthma therapies reduce allergic inflammation and relax airway smooth muscle, but treatments are often inadequate due to their minimal effects on mucus obstruction 6,7 . The lack of efficacious mucus-targeted treatments stems from a poor understanding of healthy mucus function and pathological mucus dysfunction at a molecular level. The chief macromolecules in mucus, polymeric mucins, are massive glycoproteins whose sizes and biophysical properties are dictated in part by covalent disulfide bonds that link mucin molecules into assemblies of 10 or more subunits 8 . Once secreted, mucin glycopolymers can aggregate to form plugs that block airflow. Here we show that reducing mucin disulfide bonds depolymerizes mucus in human asthma and reverses pathological effects of mucus hypersecretion in a mouse allergic asthma model. In mice challenged with a fungal allergen, inhaled mucolytic treatment acutely loosened mucus mesh, enhanced mucociliary clearance (MCC), and abolished airway hyperreactivity (AHR) to the bronchoprovocative agent methacholine. AHR reversal was directly related to reduced mucus plugging. Furthermore, protection in mucolytic treated mice was identical to prevention observed in mice lacking Muc5ac, the polymeric mucin required for allergic AHR in murine models 9 . These findings establish grounds for developing novel fast-acting agents to treat mucus hypersecretion in asthma 10,11 . Efficacious mucolytic therapies could be used to directly improve airflow, help resolve inflammation, and enhance the effects of inhaled treatments for asthma and other respiratory conditions 11,12 .With daily exposures to >8,000 liters of air containing billions of particles and potential pathogens, respiratory tissues embody the need for robust host defense. Airway mucus is critical for protection, but poor control of mucus function is central to numerous lung diseases. In patients who die during asthma exacerbations, mucus obstruction is a feature long-recognized by pathologists 13 , with plugging observed in >90% of cases and thus considered a major cause of fatal obstruction 5 . Mucus obstruction is also prominent in non-fatal cases of severe asthma 2 , but effective mucolytic therapies are lacking.

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Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice

Cited by 174 publications

References 54 publications

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

Mucins and their receptors in chronic lung disease

Disulfide disruption reverses mucus dysfunction in allergic airway disease

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