Neutrophil elastase increases MUC4 expression in normal human bronchial epithelial cells

Fischer, Bernard M.; Cuellar, Jacob G.; Diehl, Meredith L.; deFreytas, Akira M.; Zhang, Jin; Carraway, Kermit L.; Voynow, Judith A.

doi:10.1152/ajplung.00220.2002

Cited by 68 publications

(59 citation statements)

References 47 publications

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“…We have recently reported that NE upregulates a cytoplasmic oxidoreductase, NADPH quinone oxidoreductase 1 that is required for NE-induced lipid peroxidation and for NE-regulated MUC5AC mRNA expression . NE also upregulates two membrane-associated mucins, MUC4 (Fischer, 2003) and MUC1 (Kuwahara et al, 2005), in airway epithelial cells. MUC1 and MUC4 regulate intracellular signaling via the ErbB family of receptor tyrosine kinases in cancer cells (Hollingsworth and Swanson, 2004) and may have similar functions in the lung.…”

Section: Neutrophil Elastase and Mucins Mucus Secretion And Mucocilmentioning

confidence: 98%

Proteases and cystic fibrosis

Voynow

Fischer

Zheng

2008

The International Journal of Biochemistry & Cell Biology

175

159

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Cystic fibrosis is the most common, inherited fatal disease in Caucasians. The major cause of morbidity and mortality is chronic lung disease due to infection and inflammation in the airways leading to bronchiectasis and respiratory failure. The signature pathologic features of CF lung disease including abnormal mucus obstructing airways, chronic infection with S. aureus, P. aeruginosa and other gram negative bacteria, and a robust neutrophil-dominant airway inflammation, are exacerbated by unopposed proteases present at high concentrations in the ASL. There is strong evidence that proteases, particularly neutrophil elastase, contribute to the pathology of CF by impairing mucociliary clearance, interfering with innate immune functions, and perpetuating neutrophilic inflammation. The mechanisms employed by proteases to impact airway function in CF will be reviewed.

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Section: Neutrophil Elastase and Mucins Mucus Secretion And Mucocilmentioning

confidence: 98%

Proteases and cystic fibrosis

Voynow

Fischer

Zheng

2008

The International Journal of Biochemistry & Cell Biology

175

159

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“…Neutrophilic products such as proteases and oxidants have been evaluated for their role in regulating MUC gene expression. Neutrophil elastase, a serine protease, increases expression of at least two major respiratory tract mucin genes, MUC5AC (135,291) and MUC4 (77). Neutrophil elastase can regulate MUC5AC by at least two different mechanisms: 1) NE induces oxidant stress in A549 and NHBE cells (79) and regulates MUC5AC, as well as MUC4 by a posttranscriptional mechanism, e.g., by prolonging mRNA half-life, as briefly discussed in section IIID; and 2) NE releases TGF-␣ resulting in EGFR activation and transcriptional regulation of MUC5AC in H292 cells (135).…”

Section: Transcriptional Regulation By Inflammatory/ Immune Responmentioning

confidence: 99%

Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

Rose

Voynow²

2006

Physiological Reviews

Self Cite

956

892

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This review focuses on the role and regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (≥50% carbohydrate, wt/wt). MUC protein backbones are characterized by numerous tandem repeats that contain proline and are high in serine and/or threonine residues, the sites of O-glycosylation. Secretory and membrane-tethered mucins contribute to mucociliary defense, an innate immune defense system that protects the airways against pathogens and environmental toxins. Inflammatory/immune response mediators and the overproduction of mucus characterize chronic airway diseases: asthma, chronic obstructive pulmonary diseases (COPD), or cystic fibrosis (CF). Specific inflammatory/immune response mediators can activate mucin gene regulation and airway remodeling, including goblet cell hyperplasia (GCH). These processes sustain airway mucin overproduction and contribute to airway obstruction by mucus and therefore to the high morbidity and mortality associated with these diseases. Importantly, mucin overproduction and GCH, although linked, are not synonymous and may follow from different signaling and gene regulatory pathways. In section i, structure, expression, and localization of the 18 human MUC genes and MUC gene products having tandem repeat domains and the specificity and application of MUC-specific antibodies that identify mucin gene products in airway tissues, cells, and secretions are overviewed. Mucin overproduction in chronic airway diseases and secretory cell metaplasia in animal model systems are reviewed in section ii and addressed in disease-specific subsections on asthma, COPD, and CF. Information on regulation of mucin genes by inflammatory/immune response mediators is summarized in section iii. In section iv, deficiencies in understanding the functional roles of mucins at the molecular level are identified as areas for further investigations that will impact on airway health and disease. The underlying premise is that understanding the pathways and processes that lead to mucus overproduction in specific airway diseases will allow circumvention or amelioration of these processes.

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“…IL-4, IL-9, and NE have also been reported to increase expression of MUC4 in airway epithelial cells. In the case of the IL-4 and IL-9, transcriptional activation was believed to be the mechanism (131,132), whereas for NE increase in mRNA stability occurred (133).…”

Section: Regulation Of Other Mucin Genes In the Lungsmentioning

confidence: 99%

Regulation of Airway Mucin Gene Expression

Thai

Loukoianov

Wachi

et al. 2008

Annu. Rev. Physiol.

193

223

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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.

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Neutrophil elastase increases MUC4 expression in normal human bronchial epithelial cells

Cited by 68 publications

References 47 publications

Proteases and cystic fibrosis

Proteases and cystic fibrosis

Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

Regulation of Airway Mucin Gene Expression

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