Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma

J Allergy Clin Immunol. 2010 May;125(5):1037-1045.e3. doi: 10.1016/j.jaci.2010.02.031.


Background: The origin of the excess airway smooth muscle in asthma and when in the course of the disease it is acquired are uncertain.

Objectives: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Airway Remodeling / physiology*
  • Asthma / pathology
  • Asthma / physiopathology*
  • Cell Proliferation
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Ki-67 Antigen / metabolism
  • Male
  • Middle Aged
  • Muscle, Smooth* / cytology
  • Muscle, Smooth* / metabolism
  • Muscle, Smooth* / pathology
  • Muscle, Smooth* / physiopathology
  • Polymerase Chain Reaction
  • Proliferating Cell Nuclear Antigen / metabolism
  • Severity of Illness Index*


  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Ki-67 Antigen
  • Proliferating Cell Nuclear Antigen