Expression of MUC5AC and MUC5B mucins in normal and cystic fibrosis lung

Groneberg, David A.; Eynott, Paul R.; Oates, Thomas; Lim, Shuang Fang; Wu, Reen; Carlstedt, Ingemar; Nicholson, A.G.; Chung, Kian Fan

doi:10.1053/rmed.2001.1221

Cited by 158 publications

(120 citation statements)

References 28 publications

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“…MUC5B is primarily secreted by submucosal glands, but also by airway goblet cells (2,3), and is thought to play mostly a protective role. In contrast, MUC5AC, which is exclusively produced by goblet cells (4), has been thought to play more of a pathologic role because of greatly increased MUC5AC expression with disease states (5)(6)(7)(8).…”

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

178

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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

178

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“…Apart from demonstrating the significance of IL-1 for inflammatory changes in allergic conjunctivitis by treatment with an IL-1receptor antagonist (106), this model was also used to enlarge the panel of functional parameters to characterize allergic conjunctivitis on a molecular level. As it was known that mucin proteins do not only play a role in the pathophysiology of airway and gastrointestinal diseases (108,109) but also in ocular allergy, an assay was developed to investigate MUC4 and MUC5AC mRNA levels in experimental allergic conjunctivitis. Next to ragweed or cat dander antigens, also the conventional ovalbumin was used as antigen to induce murine allergic conjunctivitis (110).…”

Section: Micementioning

confidence: 99%

Animal models of allergic and inflammatory conjunctivitis

Groneberg

Bielory

Fischer

et al. 2003

Allergy

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Numerous recent reports have demonstrated an increase in the prevalence and incidence of allergic conditions during the past years which affect approximately 25% of the general population (1) and about US$ 6 billion alone are estimated as direct costs of allergic rhinoconjunctivitis (2). Whereas a large amount of studies have focused on the pathophysiology of allergic rhinitis and asthma over the past years, ocular allergies are less well studied. However, allergic diseases affecting the eye are very common (3) and pediatric studies have shown that within distinct cohorts, up to 32% of allergic children have an ocular allergy as the primary manifestation of allergy (4). Allergic eye diseases such as allergic conjunctivitis commonly present with the symptoms of itchy, watery, red, sore and swollen eyes, but not pain (5).In contrast to the large amount of experimental studies on allergic asthma and the detailed knowledge that exists on mediators of allergic airway inflammation (6-8), there are few experimental studies using models of allergic eye diseases. Detailed reviews to assess the pathophysiology and immunology of ocular allergies have been limited. This review hopefully fills this void to provide the clinical and translational researcher in the area of ocular allergy. Pathophysiology of ocular allergiesBefore characterizing the different animal models of ocular allergy which have been established so far, it is crucial to reflect that within the area of ocular allergies, different disease entities exist and that only some of them may be mimicked by animal models. Formally, conjunctivitis may be divided into allergic and nonallergic conjunctivitis and the allergic form may also be subdivided into IgE-mediated and non-IgE-mediated allergic conjunctivitis ( Fig. 1) (9). Clinically, the spectrum of conjunctivitis types can be subdivided into allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis and giant papillary conjunctivitis.In contrast to the other forms of conjunctivitis, allergic conjunctivitis is commonly based on an IgEmediated hypersensitivity reaction. Furthermore, allergic Allergic eye diseases are complex inflammatory conditions of the conjunctiva with an increasing prevalence and incidence. The diseases are often concomitant with other allergic diseases such as allergic rhinitis, atopic dermatitis and allergic asthma. Despite the disabling and prominent symptoms of ocular allergies, they are less well studied and further insights into the molecular basics are still required. To establish new therapeutic approaches and assess immunological mechanisms, animal models of ocular allergies have been developed in the past years. The major forms of allergic ocular diseases, seasonal and perennial allergic conjunctivitis, vernal and atopic keratoconjunctivitis and giant papillary conjunctivitis, each have different pathophysiological and immunological components. In contrast to these distinct entities, the current animal models are based on the sensitization against a small numbe...

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“…Airway mucins are produced by two different cell types: goblet cells of surface epithelium and mucous cells of the submucosal gland (7). Airway goblet cells produce mainly MUC5AC, whereas submucosal gland cells produce MUC5B, although some evidence suggest the presence of MUC5B also in goblet cells (5), especially in those of diseased airways (8,9). In addition to these two major MUC gene products, it has been shown that bacterial infection, more specifically endotoxin released from Gram (-) bacteria such as Pseudomonas aeruginosa, can stimulate MUC2 gene expression which is normally undetectable in airway goblet cells (10).…”

Section: Sources and Structure Of Airway Mucinsmentioning

confidence: 99%

Pharmacology of Airway Goblet Cell Mucin Release

et al. 2003

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Abstract. Airway mucus hypersecretion is one of the major clinical manifestations of patients suffering from various pulmonary diseases. However, no drugs are yet available to control airway mucus hypersecretion. For the past 15 years, a plethora of information has amassed with regard to the pharmacology of airway goblet cell mucin secretion using various primary cell culture systems. The recent discovery of various MUC genes has also greatly stimulated research in this field. Nevertheless, the heterogeneity of the oligosaccharide structure of mucin molecules makes it extremely difficult to assess the significance of the information derived from the pharmacological studies. Therefore, it seems crucially important to understand the roles of individual mucins in conjunction with normal airway physiology and pathology, which should be the future research directions necessary for studying airway goblet cell mucin pharmacology.

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Expression of MUC5AC and MUC5B mucins in normal and cystic fibrosis lung

Cited by 158 publications

References 28 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

Animal models of allergic and inflammatory conjunctivitis

Pharmacology of Airway Goblet Cell Mucin Release

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