title: Histamine may induce airway remodeling through release of epidermal growth factor receptor ligands from bronchial epithelial cells.
abstract: Asthma is a chronic inflammatory disease that is associated with airway remodeling, including hyperplasia of airway epithelial cells and airway smooth muscle cells, and goblet cell differentiation. We wished to address the potential role of histamine, a key biogenic amine involved in allergic reactions, in airway remodeling through the epidermal growth factor receptor (EGFR) pathway. Here, we demonstrate that histamine releases 2 EGFR ligands, amphiregulin and heparin-binding epidermal growth factor-like growth factor (HB-EGF), from airway epithelial cells. Amphiregulin and HB-EGF were expressed in airway epithelium of patients with asthma. Histamine up-regulated their mRNA expression (amphiregulin 3.2-fold, P<0.001; HB-EGF 2.3-fold, P<0.05) and triggered their release (amphiregulin EC(50) 0.50 μM, 31.2 ± 2.7 pg/ml with 10 μM histamine, P<0.01; HB-EGF EC(50) 0.54 μM, 78.5 ± 1.8 pg/ml with 10 μM histamine, P<0.001) compared to vehicle control (amphiregulin 19.3 ± 0.9 pg/ml; HB-EGF 60.2 ± 1.0 pg/ml), in airway epithelial cells. Histamine increased EGFR phosphorylation (2.1-fold by Western blot analysis) and induced goblet cell differentiation (CLCA1 up-regulation by real-time qPCR) in normal human bronchial epithelial (NHBE) cells. Moreover, amphiregulin and HB-EGF caused proliferation and migration of both NHBE cells and human airway smooth muscle cells. These results suggest that histamine may induce airway remodeling via the epithelial-derived EGFR ligands amphiregulin and HB-EGF.
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, 3626 St-Urbain, Montréal, QC, H2X 2P2 Canada.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Hirota
authors.forename: Paul-Andre
authors.initials: PA
authors.lastname: Risse
authors.forename: Mauro
authors.initials: M
authors.lastname: Novali
authors.forename: Toby
authors.initials: T
authors.lastname: McGovern
authors.forename: Laila
authors.initials: L
authors.lastname: Al-Alwan
authors.forename: Sarah
authors.initials: S
authors.lastname: McCuaig
authors.forename: David
authors.initials: D
authors.lastname: Proud
authors.forename: Patrick
authors.initials: P
authors.lastname: Hayden
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
authors.forename: James G
authors.initials: JG
authors.lastname: Martin
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000187:drug effects*; D066258:Amphiregulin; D001249:Asthma / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000166:cytology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D066255:EGF Family of Proteins; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008875:Middle Aged; D011969:Receptors, Histamine H1 / Q000378:metabolism; D055815:Young Adult
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D011969:Receptors, Histamine H1; D006632:Histamine; D066246:ErbB Receptors