Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke.
Mucus hypersecretion from hyperplastic airway goblet cells is a hallmark of chronic obstructive pulmonary disease (COPD). Although cigarette smoking is thought to be involved in mucus hypersecretion in COPD, the mechanism by which cigarette smoke induces mucus overproduction is unknown. Here we show that activation of epidermal growth factor receptors (EGFR) is responsible for mucin production after inhalation of cigarette smoke in airways in vitro and in vivo. In the airway epithelial cell line NCI-H292, exposure to cigarette smoke upregulated the EGFR mRNA expression and induced activation of EGFR-specific tyrosine phosphorylation, resulting in upregulation of MUC5AC mRNA and protein production, effects that were inhibited completely by selective EGFR tyrosine kinase inhibitors (BIBX1522, AG-1478) and that were decreased by antioxidants. In vivo, cigarette smoke inhalation increased MUC5AC mRNA and goblet cell production in rat airways, effects that were prevented by pretreatment with BIBX1522. These effects may explain the goblet cell hyperplasia that occurs in COPD and may provide a novel strategy for therapy in airway hypersecretory diseases.
Takeyama
K
K
Cardiovascular Research Institute, University of California, San Francisco, California 94143-0130, USA.
Jung
B
B
Shim
J J
JJ
Burgel
P R
PR
Dao-Pick
T
T
Ueki
I F
IF
Protin
U
U
Kroschel
P
P
Nadel
J A
JA
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008173:Lung Diseases, Obstructive / Q000209:etiology / Q000378:metabolism; D055271:Mucin 5AC; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D014443:Tyrosine / Q000378:metabolism
D004791:Enzyme Inhibitors; C524678:MUC5AC protein, human; C524680:Muc5ac protein, rat; D055271:Mucin 5AC; D009077:Mucins; D012333:RNA, Messenger; D014443:Tyrosine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases