Expression of ErbB receptors and mucins in the airways of long term current smokers

O’Donnell, Rory

doi:10.1136/thx.2004.028043

Cited by 126 publications

(103 citation statements)

References 47 publications

(40 reference statements)

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“…Goblet cells are located on the bronchial surface epithelium and MUC5AC is the best characterised mucin in this cell type, and its expression is directly correlated with airway obstruction [18][19][20]. Therefore, MUC5AC was selected for this study.…”

Section: Discussionmentioning

confidence: 99%

Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways

Cortijo¹,

Mata²,

Milara³

et al. 2010

European Respiratory Journal

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Mucus hypersecretion and mucin MUC5AC overexpression are pathological features of chronic obstructive pulmonary disease (COPD). This study examines the inhibitory effect of aclidinium, a new long-acting muscarinic antagonist, on MUC5AC expression in human airway epithelial cells.MUC5AC mRNA (RT-PCR) and protein expression (ELISA and immunohistochemistry) were studied in human bronchial tissue and differentiated human airway epithelial cells activated with carbachol (100 mM) or cigarette smoke extract in the absence or presence of aclidinium.Carbachol increased MUC5AC mRNA and protein expression in human bronchus and cultured epithelial cells. Aclidinium inhibited the carbachol-induced MUC5AC mRNA and protein expression with potency (half maximal inhibitory concentration) ,1 nM in human bronchus and cultured airway epithelial cells. AG1478, a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, inhibited carbachol-induced MUC5AC responses, indicating EGFR transactivation. Aclidinium inhibited carbachol-induced phospho-EGFR and phospho-p44/42 MAPK expression. In cultured airway epithelial cells transfected with small interfering (si)RNA against muscarinic receptor subtypes, siRNA-M3 but not siRNA-M2 blocked carbachol-induced MUC5AC expression. Cigarette smoke-induced MUC5AC upregulation in cultured airway epithelial cells was suppressed by aclidinium.In conclusion, aclidinium decreases carbachol and tobacco smoke-induced MUC5AC overexpression in human airway epithelial cells. This effect may contribute to the clinical efficacy of aclidinium in mucus hypersecretory diseases including COPD.

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Section: Discussionmentioning

confidence: 99%

Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways

Cortijo¹,

Mata²,

Milara³

et al. 2010

European Respiratory Journal

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“…365 Smoking was associated with significant increases in EGFR and especially in ERBB3 in bronchial epithelial cells compared to nonsmokers. 366 In intact polarized human airway epithelium, NRG1 and ERBB3 were segregated, the former on the apical membrane, and the latter on the basolateral surface. 367 When the epithelium was disrupted, as in lung injury, NRG1 contacts and activates ERBB3 (and ERBB2).…”

Section: Respiratory Tissuesmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…Lung Epithelial Cells-MUC5AC mRNA levels are known to be significantly elevated in the lungs of human smokers (9,21). However, the mechanisms by which this occurs are unknown.…”

Section: Cigarette Smoke Stimulates Muc5ac Synthesis In Humanmentioning

confidence: 99%

Cigarette Smoke Induces MUC5AC Protein Expression through the Activation of Sp1

Zhao

Harper

2012

Journal of Biological Chemistry

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Background: Cigarette smokers have increased mucus secretion and MUC5AC gene expression. Results: Cigarette smoke increases Sp1 protein expression and activates Sp1 binding to a smoke-responsive promoter region of the MUC5AC. Conclusion: Sp1 is the key regulator of cigarette smoke-induced MUC5AC mRNA transcription in lung epithelial cells. Significance: Sp1 may be a putative target to treat mucus hypersecretion in COPD patients.

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Expression of ErbB receptors and mucins in the airways of long term current smokers

Cited by 126 publications

References 47 publications

Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways

Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways

The ERBB3 receptor in cancer and cancer gene therapy

Cigarette Smoke Induces MUC5AC Protein Expression through the Activation of Sp1

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