title: Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation.
abstract: Chronic obstructive pulmonary disease is marked by alveolar enlargement and excess production of airway mucus. Acrolein, a component of cigarette smoke, increases mucin 5AC (MUC5AC), a prevalent airway mucin in NCI-H292 cells by transcriptional activation, but the signal transduction pathways involved in acrolein-induced MUC5AC expression are unknown. Acrolein depleted cellular glutathione at doses of 10 muM or greater, higher than those sufficient (0.03 muM) to increase MUC5AC mRNA, suggesting that MUC5AC expression was independent of oxidative stress. In contrast, acrolein increased MUC5AC mRNA levels by phosphorylating epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase 3/2, or MAPK 3/2(ERK1/2). Pretreating the cells with an EGFR-neutralizing antibody, or a metalloproteinase inhibitor, decreased the acrolein-induced MUC5AC mRNA increase. Small, interfering RNA directed against ADAM17 or MMP9 inhibited the acrolein-induced MUC5AC mRNA increase. Acrolein increased the release and subsequent activation of pro-MMP9. Acrolein increased MMP9 and decreased tissue inhibitor of metalloproteinase 3 (TIMP3), an endogenous inhibitor of ADAM17, transcripts. Together, these data suggest that acrolein induces MUC5AC expression via an initial ligand-dependent activation of EGFR mediated by ADAM17 and MMP9. In addition, a prolonged effect of acrolein may be mediated by altering MMP9 and TIMP3 transcription.
authors.affiliation: University of Cincinnati, P.O. Box 670056, Cincinnati, OH 45267-0056, USA.
authors.forename: Hitesh S
authors.initials: HS
authors.lastname: Deshmukh
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Case
authors.forename: Scott C
authors.initials: SC
authors.lastname: Wesselkamper
authors.forename: Michael T
authors.initials: MT
authors.lastname: Borchers
authors.forename: Linda D
authors.initials: LD
authors.lastname: Martin
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nadel
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
mesh_terms: D000171:Acrolein / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D045726:Metalloproteases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D055271:Mucin 5AC; D009077:Mucins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D012333:RNA, Messenger; D000171:Acrolein; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D045726:Metalloproteases; D005978:Glutathione