Airway Mucus Obstruction: Mucin Glycoproteins, <i>MUC</i> Gene Regulation  and Goblet Cell Hyperplasia

Rose, Mary C.; Nickola, Tracey J.; Voynow, Judith A.

doi:10.1165/ajrcmb.25.5.f218

Cited by 148 publications

(126 citation statements)

References 53 publications

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“…Normally, a thin mucus layer on airway surfaces is efficiently transported by coordinated beating of cilia. Mucin hypersecretion has been speculated to compromise mucociliary clearance (MCC) and, therefore, a role for increased mucin secretion has been proposed in the pathogenesis of airway diseases (9,10). Indeed, postmortem and airway biopsy studies support a significant pathophysiologic role for mucus hypersecretion in airways obstruction and inflammation observed in severe forms of asthma and chronic obstructive pulmonary disease (COPD) (11,12).…”

mentioning

confidence: 99%

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

Ehré

Worthington

Liesman

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

172

182

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MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates in response to infectious agents, implying that mucins exert a protective role against inhaled pathogens. However, epidemiological and pathological studies suggest that excessive mucin secretion causes airways obstruction and inflammation. To determine whether increased MUC5AC secretion alone produces airway obstruction and/or inflammation, we generated a mouse model overexpressing Muc5ac mRNA ∼20-fold in the lungs, using the rCCSP promoter. The Muc5ac cDNA was cloned from mouse lungs and tagged internally with GFP. Bronchoalveolar lavage fluid (BALF) analysis demonstrated an approximate 18-fold increase in Muc5ac protein, which formed high-molecular-weight polymers. Histopathological studies and cell counts revealed no airway mucus obstruction or inflammation in the lungs of Muc5ac-transgenic (Muc5ac-Tg) mice. Mucus clearance was preserved, implying that the excess Muc5ac secretion produced an “expanded” rather than more concentrated mucus layer, a prediction confirmed by electron microscopy. To test whether the larger mucus barrier conferred increased protection against pathogens, Muc5ac-Tg animals were challenged with PR8/H1N1 influenza viruses and showed significant decreases in infection and neutrophilic responses. Plaque assay experiments demonstrated that Muc5ac-Tg BALF and purified Muc5ac reduced infection, likely via binding to α2,3-linked sialic acids, consistent with influenza protection in vivo. In conclusion, the normal mucus transport and absence of a pulmonary phenotype in Muc5ac-Tg mice suggests that mucin hypersecretion alone is not sufficient to trigger luminal mucus plugging or airways inflammation/goblet cell hyperplasia. In contrast, increased Muc5ac secretion appears to exhibit a protective role against influenza infection.

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mentioning

confidence: 99%

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

Ehré

Worthington

Liesman

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

172

182

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“…4). In particular, the mucin glycoform MUC5B has been identified as the major secreted form of mucin in the mucosal layers protecting the CV tract (45,46), lungs (46,47), nose (48), and eye (49). The mucin content, Ϸ1-3% by weight, is also similar among cervical, nasal, and lung mucus (50)(51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus

Lai¹,

O’Hanlon

Harrold

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

895

1,012

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Nanoparticles larger than the reported mesh-pore size range (10 -200 nm) in mucus have been thought to be much too large to undergo rapid diffusional transport through mucus barriers. However, large nanoparticles are preferred for higher drug encapsulation efficiency and the ability to provide sustained delivery of a wider array of drugs. We used high-speed multiple-particle tracking to quantify transport rates of individual polymeric particles of various sizes and surface chemistries in samples of fresh human cervicovaginal mucus. Both the mucin concentration and viscoelastic properties of these cervicovaginal samples are similar to those in many other human mucus secretions. Unexpectedly, we found that large nanoparticles, 500 and 200 nm in diameter, if coated with polyethylene glycol, diffused through mucus with an effective diffusion coefficient (D eff) only 4-and 6-fold lower than that for the same particles in water (at time scale ‫؍‬ 1 s). In contrast, for smaller but otherwise identical 100-nm coated particles, D eff was 200-fold lower in mucus than in water. For uncoated particles 100 -500 nm in diameter, D eff was 2,400-to 40,000-fold lower in mucus than in water. Much larger fractions of the 100-nm particles were immobilized or otherwise hindered by mucus than the large 200-to 500-nm particles. Thus, in contrast to the prevailing belief, these results demonstrate that large nanoparticles, if properly coated, can rapidly penetrate physiological human mucus, and they offer the prospect that large nanoparticles can be used for mucosal drug delivery. drug delivery ͉ mucosal tissues ͉ particle tracking ͉ PEG

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“…In these mice GCM was associated with a positive immunostaining for MUC5AC. This is a secreted mucin, expressed in goblet cells and at least in man, may potentially contribute to mucus obstruction [19]. Recently, GCM has been found associated with the expression of MUC5AC mRNA and mucin in murine models of allergic asthma [19].…”

Section: Discussionmentioning

confidence: 99%

Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants

Bartalesi¹

2005

European Respiratory Journal

152

113

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The development of cigarette smoke-induced pulmonary changes in C57 Bl/6J and DBA/2 mice was investigated. Both strains are sensitive to oxidants and C57Bl/6J mice are moderately deficient in serum alpha1-proteinase inhibitor.Following chronic exposure to cigarette smoke, patchy emphysema was present in mice of both strains, but developed faster in DBA/2 mice. A positive reaction for mouse neutrophil elastase was seen on the septa of both strains. Additionally, the DBA/2 mice developed a uniform parenchymal dilation that was preceded by the appearance of apoptotic cells in areas with a low signal for vascular endothelial growth factor-receptor 2. Fibrotic areas scattered throughout the parenchyma, coupled with a positive immunohistochemical reaction for transforming growth factor-b was seen only in DBA/2 mice.Both DBA/2 and C57Bl/6J strains showed epithelial cell injury and areas of deciliation in their airways. However, the appearance of goblet cell metaplasia was common in C57Bl/6J mice but rare in DBA/2 mice. A positive immunohistochemical reaction for interleukin (IL)-4, IL-13 and MUC5AC was seen only in the airways of C57Bl/6J mice.Strain characteristics (alpha1-proteinase inhibitor levels, sensitivity to oxidants, and constitutive levels of vascular endothelial growth factor-receptor 2) and phenotypical responses (apoptosis and cytokine distribution) may condition parenchymal and airway changes to cigarette smoke.

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Airway Mucus Obstruction: Mucin Glycoproteins, MUC Gene Regulation and Goblet Cell Hyperplasia

Cited by 148 publications

References 53 publications

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus

Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants

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