Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-α-converting enzyme in human airway epithelial (NCI-H292) cells

Shao, Matt X. G.; Nakanaga, Takashi; Nadel, Jay A.

doi:10.1152/ajplung.00019.2004

Cited by 214 publications

(183 citation statements)

References 38 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Cigarette smoke is also an important environmental stimulus for generating ROS (87). One group has shown that ROS generation from NE and cigarette smoke leads to EGFR activation, through the activation of TNF-α-converting enzyme (TACE), to cleave pro-TGF-α from the membrane into the active soluble form of TGF-α (74,88). Because dual oxidases are expressed in airway epithelial cell surface, dual oxidase-1 (Duox-1) may be involved in TACE activation (78).…”

Section: Transcriptional Activation Of Muc5ac Through Epidermal Growtmentioning

confidence: 99%

Regulation of Airway Mucin Gene Expression

Thai

Loukoianov

Wachi

et al. 2008

Annu. Rev. Physiol.

192

223

View full text Add to dashboard Cite

Mucins are important components that exert a variety of functions in cell-cell interaction, epidermal growth factor receptor signaling, and airways protection. In the conducting airways of the lungs, mucins are the major contributor to the viscoelastic property of mucous secretion, which is the major barrier to trapping inhaled microbial organism, particulates, and oxidative pollutants. The homeostasis of mucin production is an important feature in conducting airways for the maintenance of mucociliary function. Aberrant mucin secretion and accumulation in airway lumen are clinical hallmarks associated with various lung diseases, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, and lung cancer. Among 20 known mucin genes identified, 11 of them have been verified at either the mRNA and/or protein level in airways. The regulation of mucin genes is complicated, as are the mediators and signaling pathways. This review summarizes the current view on the mediators, the signaling pathways, and the transcriptional units that are involved in the regulation of airway mucin gene expression. In addition, we also point out essential features of epigenetic mechanisms for the regulation of these genes.

show abstract

“…Thus, activation of TACE may trigger a number of reactions participating in the promotion of neutrophil inflammation in the airways. In addition, TACE/ TGF-a/EGFR signalling also regulates mucin production, which contributes to exacerbation of asthma, COPD and CF along with neutrophilia [3,24,[59][60][61].…”

Section: Discussionmentioning

confidence: 99%

TACE/TGF- /EGFR regulates CXCL8 in bronchial epithelial cells exposed to particulate matter components

Øvrevik

Refsnes

Totlandsdal

et al. 2011

European Respiratory Journal

View full text Add to dashboard Cite

Airborne particulate matter (PM) may induce or exacerbate neutrophilic airway disease by triggering the release of inflammatory mediators, such as CXC chemokine ligand (CXCL)8, from the airway epithelium. It is still unclear which PM components are driving CXCL8 responses, as most candidates occur at low concentrations in the dusts. We therefore hypothesised that different PM constituents may contribute through common mechanisms to induce CXCL8.Human bronchial epithelial cells (BEAS-2B) were exposed to different PM components (Zn 2+ / Fe 2+ salts, 1-nitropyrene, lipopolysaccharide and diesel exhaust/mineral particles). Gene expression patterns were detected by real-time PCR array. CXCL8 responses were measured by real-time PCR and ELISA. CXCL8 regulation was assessed with a broad inhibitor panel and neutralising antibodies. Epidermal growth factor receptor (EGFR) phosphorylation was examined by immunoprecipitation and Western blotting. Component-induced gene expression was mainly linked to nuclear factor-kB, Ca 2+ /protein kinase C, phospholipase C, low-density lipoprotein and mitogenic signalling. Many inhibitors attenuated CXCL8 release induced by all PM components, but to varying extents. However, EGFR inhibition strongly reduced CXCL8 release induced by all test compounds and selected compounds increased EGFR phosphorylation. Interference with transforming growth factor (TGF)-a or tumour necrosis factor-a-converting enzyme (TACE), which mediates TGF-a ectodomain shedding, also attenuated CXCL8 release. Different PM constituents induced CXCL8 partly through similar signalling pathways but the relative importance of the different pathways varied. However, TACE/TGF-a/EGFR signalling appears to be a convergent pathway regulating innate immune responses of airway epithelial cells upon exposure to multiple airborne pollutants.

show abstract

Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-α-converting enzyme in human airway epithelial (NCI-H292) cells

Cited by 214 publications

References 38 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

Regulation of Airway Mucin Gene Expression

TACE/TGF- /EGFR regulates CXCL8 in bronchial epithelial cells exposed to particulate matter components

Contact Info

Product

Resources

About