title: Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma.
abstract: BACKGROUND
  The origin of the excess airway smooth muscle in asthma and when in the course of the disease it is acquired are uncertain.
  
  
  OBJECTIVE
  We examined the relative sensitivities of 2 markers of proliferation, proliferating cell nuclear antigen (PCNA) and Ki 67, in airway smooth muscle in vivo and in vitro. We then studied whether muscle remodeling is a dynamic process in asthma by quantifying proliferation rate and area. Finally we examined heparin-binding epidermal growth factor as a biomarker of remodeling.
  
  
  METHODS
  We obtained bronchoscopic biopsies from subjects with moderate or severe asthma and healthy controls (n = 9/group). For in vitro studies, airway smooth muscle cells were cultured from tracheas of transplant donors. The proliferation rate was quantified from PCNA and Ki 67, co-localized to smooth muscle-specific alpha-actin cells in vivo. Muscle area was assessed morphometrically. We examined the expression of heparin-binding epidermal growth factor on tissues by in situ hybridization and by immunohistochemistry and in cells in culture by RT-PCR.
  
  
  RESULTS
  Proliferating cell nuclear antigen and Ki 67 were highly correlated, but PCNA was a significantly more sensitive marker both in vivo and in vitro. Muscle area was 3.4-fold greater and the fraction of PCNA(+) nuclei in muscle was 5-fold greater in severe asthma than in healthy subjects. Heparin-binding epidermal growth factor was upregulated in proliferating muscle cells in culture and in airway smooth muscle in severe asthmatic tissues.
  
  
  CONCLUSIONS
  Proliferating cell nuclear antigen is a highly sensitive marker of proliferation and heparin-binding epidermal growth factor is a potential biomarker during active remodeling of ASM in severe asthma.
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada.
authors.forename: Muhannad
authors.initials: M
authors.lastname: Hassan
authors.forename: Taisuke
authors.initials: T
authors.lastname: Jo
authors.forename: Paul-André
authors.initials: PA
authors.lastname: Risse
authors.forename: Barbara
authors.initials: B
authors.lastname: Tolloczko
authors.forename: Catherine
authors.initials: C
authors.lastname: Lemière
authors.forename: Ronald
authors.initials: R
authors.lastname: Olivenstein
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 / Q000502:physiology*; D001249:Asthma / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen