Metalloproteinases Mediate Mucin 5AC Expression by Epidermal Growth Factor Receptor Activation

Deshmukh, Hitesh; Case, Lisa M.; Wesselkamper, Scott C.; Borchers, Michael T.; Martin, Linda D.; Shertzer, Howard G.; Nadel, Jay A.; Leikauf, George D.

doi:10.1164/rccm.200408-1003oc

Cited by 135 publications

(113 citation statements)

References 61 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…Because dual oxidases are expressed in airway epithelial cell surface, dual oxidase-1 (Duox-1) may be involved in TACE activation (78). Other enzymes besides TACE that can also cleave pro-EGFR ligands to activate MUC5AC include MMPs, dis-integrin and metalloproteinase domain proteins (ADAMs), and tissue kallikrein (TK) (89,90). Downstream of EGFR, the mechanism that leads to MUC5AC expression can involve ERK activation with subsequent binding of transcription factors Sp1 (18) and Fra-2 to the MUC5AC promoter (91).…”

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.

193

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

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.

193

223

View full text Add to dashboard Cite

show abstract

“…Mucous metaplasia has been found in the small airways of patients with COPD, and significantly contributes to airflow obstruction (20,23,24). This may develop from cigarette smoke exposure by itself (25,26), acute and/or chronic viral infection (27), or inflammatory cell activation of mucin gene transcription (28).…”

Section: Epithelial Abnormalitiesmentioning

confidence: 99%

New Concepts in the Pathobiology of Chronic Obstructive Pulmonary Disease

Kim¹,

Rogers²,

Criner³

2008

Proceedings of the American Thoracic Society

174

120

View full text Add to dashboard Cite

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal persistent inflammatory response to cigarette smoke. This noxious insult leads to emphysema and airway remodeling, manifested by squamous and mucous metaplasia of the epithelium, smooth muscle hypertrophy, and airway wall fibrosis. These pathologic abnormalities interact synergistically to cause progressive airflow obstruction. Although it has been accepted that the spectrum of COPD is vast, the reasons for the development of different phenotypes from the same exposure to cigarette smoke have not been determined. Furthermore, it is becoming increasingly clear that airways disease and emphysema often coexist in many patients, even with a clear clinical phenotype of either emphysema or chronic bronchitis. Recent studies have focused on the nature of the inflammatory response to cigarette smoke, the inflammatory cell lines responsible for COPD pathogenesis, and new biomarkers for disease activity and progression. New cytokines are being discovered, and the complex interactions among them are being unraveled. The inflammatory biomarker that has received the most attention is Creactive protein, but new ones that have caught our attention are interleukin (IL)-6, tumor necrosis factor-a, IL-8, and IL-10. Further research should focus on how these new concepts in lung inflammation interact to cause the various aspects of COPD pathology.

show abstract

“…It induces airway goblet cell hyperplasia and enhances the expression of mucin genes, such as MUC5AC. When EGFR is activated, its ligands induce MUC5AC proPotential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation duction through the signaling tyrosine kinase cascade in the airway (Deshmukh et al, 2005). Therefore, inhibitors of tyrosine kinase have been widely studied as a novel therapeutic strategy for the treatment of asthma (Vargaftig and Singer, 2003).…”

Section: Introductionmentioning

confidence: 99%

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

Hur

Lee²,

Lee³

et al. 2007

Exp Mol Med

View full text Add to dashboard Cite

The EGFR plays an essential role in goblet cell hyperplasia and mucus hypersecretion. EGFR has an intrinsic tyrosine kinase activity that, when activated, induces the production of MUC5AC through the signaling kinase cascade in the airway epithelium. We have investigated the effects of an EGFR tyrosine kinase inhibitor, gefitinib, on ovalbumin (OVA)-induced, allergic inflammation in airway epithelia of mice. OVA-sensitized mice were pretreated with gefitinib at two different doses (12.5 and 50 mg/kg) and then challenged with OVA. The OVA challenge increased the total cell count and eosinophil count in bronchoalveolar lavage fluid (BALF), as well as the concentrations of T-helper2 (Th2) cytokines, such as IL-4 and IL-13, overall eosinophil recruitment in the lung tissue and airway hyperresponsiveness (AHR). Pretreatment with gefitinib reduced the inflammatory cell counts and released cytokine concentrations (IL-4 and IL-13) in BALF, as well as eosinophil recruitment in the lungs and AHR, in a dose-dependent manner. This was associated with decreased EGFR and Akt phosphorylation. We showed that gefitnib inhibits EGFR and phosphoinositol 3'-kinase (PI3K)/Akt activation which were activated in OVA sensitized mice. These findings suggest that inhibitors of the EGFR cascade may have a role in the treatment of asthma.

show abstract

Metalloproteinases Mediate Mucin 5AC Expression by Epidermal Growth Factor Receptor Activation

Cited by 135 publications

References 61 publications

Regulation of Airway Mucin Gene Expression

Regulation of Airway Mucin Gene Expression

New Concepts in the Pathobiology of Chronic Obstructive Pulmonary Disease

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

Contact Info

Product

Resources

About