title: The modulation of large airway smooth muscle phenotype and effects of epidermal growth factor receptor inhibition in the repeatedly allergen-challenged rat.
abstract: Allergen challenges induce airway hyperresponsiveness (AHR) and increased airway smooth muscle (ASM) mass in the sensitized rat. Whether the remodeled ASM changes its phenotype is uncertain. We examined, in sensitized Brown Norway rats, the effects of multiple ovalbumin (Ova) challenges on ASM remodeling and phenotype and the role of the epidermal growth factor receptor (EGFR) in these processes. Rats were sensitized with Ova and challenged three times at 5-day intervals with phosphate-buffered saline or Ova and pretreated with the EGFR inhibitor AG-1478 (5 mg/kg) or its vehicle dimethyl sulfoxide. Ova challenges increased ASM mass in all-sized airways and in large airway mRNA expression of smooth muscle myosin heavy chain (sm-MHC), assessed by laser capture. Myosin light chain kinase and the fast myosin isoform SM-B mRNA expressions were not affected. Ova induced AHR to methacholine, and, based on the constant-phase model, this was largely attributable to the small airways and lung derecruitment at 48 h that recovered by 1 wk. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor (HB-EGF) were increased in bronchoalveolar lavage fluid at 48 h after Ova exposure. AG-1478 inhibited AHR and prevented ASM growth. Epithelial gene expression of EGFR, HB-EGF, matrix metalloproteinase (MMP)-9, Gro-α, and transforming growth factor-β was unaffected by Ova challenges. We conclude that EGFR drives remodeling of ASM, which results from repeated Ova challenge. Furthermore, the latter results in excessive small airway and, to a lesser degree, large airway narrowing to methacholine, and large airway gene expression of contractile protein is conserved.
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Siddiqui
authors.forename: M
authors.initials: M
authors.lastname: Novali
authors.forename: K
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: N
authors.initials: N
authors.lastname: Hirota
authors.forename: B J
authors.initials: BJ
authors.lastname: Geller
authors.forename: T K
authors.initials: TK
authors.lastname: McGovern
authors.forename: P A
authors.initials: PA
authors.lastname: Risse
authors.forename: T
authors.initials: T
authors.lastname: Jo
authors.forename: M A
authors.initials: MA
authors.lastname: Zeroual
authors.forename: J G
authors.initials: JG
authors.lastname: Martin
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000276:immunology; D000485:Allergens / Q000276:immunology / Q000494:pharmacology; D066258:Amphiregulin; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D024745:Smooth Muscle Myosins / Q000235:genetics / Q000276:immunology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000485:Allergens; D066258:Amphiregulin; C587850:Areg protein, rat; D066255:EGF Family of Proteins; D006023:Glycoproteins; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011799:Quinazolines; D020032:Tyrphostins; D016210:Methacholine Chloride; C101044:RTKI cpd; D010047:Ovalbumin; C483803:Egfr protein, rat; D066246:ErbB Receptors; D024745:Smooth Muscle Myosins; D018995:Myosin Heavy Chains
keywords: Brown Norway rat; airway hyperresponsiveness; amphiregulin; asthma; heparin-binding epidermal growth factor; laser capture; remodeling; smooth muscle myosin heavy chain