The Journal of Allergy and Clinical Immunology
Volume 125, Issue 2 , Pages 349-356.e13 , February 2010

Effects of budesonide and formoterol on allergen-induced airway responses, inflammation, and airway remodeling in asthma

  • Margaret M. Kelly, MB, PhD, FRCPC

      Affiliations

    • Firestone Institute for Respiratory Health, Department of Medicine, St Joseph's Healthcare and McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada
    • Firestone Institute for Respiratory Health, Department of Pathology and Molecular Medicine, St Joseph's Healthcare and McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada
    • Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada
    • These authors contributed equally to this work.
  • ,
  • Terence M. O'Connor, MB, FRCPI

      Affiliations

    • Firestone Institute for Respiratory Health, Department of Medicine, St Joseph's Healthcare and McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada
    • These authors contributed equally to this work.
  • ,
  • Richard Leigh, MB, PhD, FRCPC

      Affiliations

    • Firestone Institute for Respiratory Health, Department of Medicine, St Joseph's Healthcare and McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada
    • Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada
  • ,
  • Joceline Otis, MLT

      Affiliations

    • Firestone Institute for Respiratory Health, Department of Medicine, St Joseph's Healthcare and McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada
  • ,
  • Carol Gwozd, MLT

      Affiliations

    • Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada
  • ,
  • Gail M. Gauvreau, PhD

      Affiliations

    • Firestone Institute for Respiratory Health, Department of Medicine, St Joseph's Healthcare and McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada
  • ,
  • Jack Gauldie, PhD

      Affiliations

    • Firestone Institute for Respiratory Health, Department of Pathology and Molecular Medicine, St Joseph's Healthcare and McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada
  • ,
  • Paul M. O'Byrne, MB, FRCPC, FRCPI

      Affiliations

    • Firestone Institute for Respiratory Health, Department of Medicine, St Joseph's Healthcare and McMaster University Medical Center, McMaster University, Hamilton, Ontario, Canada
    • Corresponding Author InformationAddress for reprints: Paul M. O'Byrne, MB, FRCPC, HSC 3 W10, McMaster University, 1200 Main St West, Hamilton, Ontario L8N 3Z5, Canada.

Received 8 February 2009 ,Revised 2 September 2009 ,Accepted 8 September 2009.

  • Image Result

    Effect of study treatment on allergen-induced early (EAR) and late (LAR) asthmatic responses.

    Effect of study treatment on allergen-induced early (EAR) and late (LAR) asthmatic responses.

  • Image Result

    Effect of study treatment on AHR (MCh PC20) before (day 8) and after (day 11) allergen challenge.

    Effect of study treatment on AHR (MCh PC20) before (day 8) and after (day 11) allergen challenge.

  • Image Result

    Effect of study treatment on sputum eosinophil numbers before (day 8) and 7 hours (day 9) and 48 hours (day 11) after allergen challenge.

    Effect of study treatment on sputum eosinophil numbers before (day 8) and 7 hours (day 9) and 48 hours (day 11) after allergen challenge.

  • Image Result

    Smooth muscle (percentage of area) and numbers of myofibroblasts in the subepithelial compartment in bronchial biopsy specimens. Box plots represent the medians and IQRs.

    Smooth muscle (percentage of area) and numbers of myofibroblasts in the subepithelial compartment in bronchial biopsy specimens. Box plots represent the medians and IQRs.

  • Image Result

    Study protocol. CBC, Complete blood count; INR, international normalized ratio.

    Study protocol. CBC, Complete blood count; INR, international normalized ratio.

  • Image Result

    Numbers of intraepithelial (A) and subepithelial (B) eosinophils in bronchial biopsy samples. Box plots represent medians and IQRs.

    Numbers of intraepithelial (A) and subepithelial (B) eosinophils in bronchial biopsy samples. Box plots represent medians and IQRs.

  • Image Result

    Immunohistochemistry to detect α-SMA in myofibroblasts (A and B, brown stain). Transmission electron microscopy of area rich in myofibroblasts (C and D). The similar morphology of myofibroblasts when

    Immunohistochemistry to detect α-SMA in myofibroblasts (A and B, brown stain). Transmission electron microscopy of area rich in myofibroblasts (C and D). The similar morphology of myofibroblasts when viewed under light microscopy and low-power transmission electron microscopy can be appreciated by comparing Fig E3, B, and Fig E3, C. Fig E3, D and E, represent high-power photomicrographs of the area seen in Fig E3, C, which confirms the ultrastructural features of myofibroblasts. White arrows indicate microfilament bundles within myofibroblast cytoplasm. Original magnification: Fig E3, A, ×200; Fig E3, B, ×400. The bar in Fig E3, C, represents 20 μm, and the bar in Fig E3, D and E, represents 1 μm. EP, Epithelium.

  • Image Result
    Immunohistochemistry directed against α-SMA in myofibroblasts and smooth muscle (brown stain). A and B, Areas of possible transition between smooth muscle (sm) cells and myofibroblasts (mf; ∗). The ep

    Immunohistochemistry directed against α-SMA in myofibroblasts and smooth muscle (brown stain). A and B, Areas of possible transition between smooth muscle (sm) cells and myofibroblasts (mf; ). The epithelial surface (ep) has been mostly stripped away, with only the basal layer intact. C, Myofibroblasts within the submucosa that have a similar orientation and appear to form a syncytium. Original magnification: ×200 for left-sided panels and ×400 for right-sided panels.

  • Image Result
    Immunohistochemistry to detect α-SMA in smooth muscle (A and B, brown stain). Transmission electron microscopy of smooth muscle (C and D). The similar morphology of smooth muscle bundles when viewed u

    Immunohistochemistry to detect α-SMA in smooth muscle (A and B, brown stain). Transmission electron microscopy of smooth muscle (C and D). The similar morphology of smooth muscle bundles when viewed under light microscopy and low-power transmission electron microscopy can be appreciated by comparing Fig E5, B, and Fig E5, C. Fig E5, D, represents a high-power photomicrograph of Fig E5, C, which confirms the ultrastructural features of smooth muscle. Original magnification: Fig E5, A, ×60; Fig E5, B, ×400. The bar in Fig E5, C, represents 20 μm, and the bar in Fig E5, D, represents 1 μm. SM, Smooth muscle; BV, blood vessel.

  • Image Result
    Special stains for eosinophils (A; Congo Red, red stain), CD3+ lymphocytes (B; anti-CD3, brown stain), plasma cells (C; anti-CD138, brown stain), and neutrophils (D; anti-neutrophil elastase, brown st

    Special stains for eosinophils (A; Congo Red, red stain), CD3+ lymphocytes (B; anti-CD3, brown stain), plasma cells (C; anti-CD138, brown stain), and neutrophils (D; anti-neutrophil elastase, brown stain). Original magnification: Fig E6, A, ×400; Fig E6, B, ×400; Fig E6, C, ×400; and Fig E6, D, ×60. Anti-CD138 stains the basal bronchial epithelial cells, as well as the plasma cells. Arrows indicate cells of interest. SM, Smooth muscle; EP, bronchial epithelium.

  • Image Result
    Special stains for mast cells (anti-tryptase, brown stain). Original magnification: A, ×60; B, ×400. Arrows indicate cells of interest. SM, Smooth muscle; EP, bronchial epithelium.

    Special stains for mast cells (anti-tryptase, brown stain). Original magnification: A, ×60; B, ×400. Arrows indicate cells of interest. SM, Smooth muscle; EP, bronchial epithelium.

 Supported by an unrestricted grant from AstraZeneca, Lund, Sweden.

 Disclosure of potential conflict of interest: T. M. O'Connor receives research support from AstraZeneca Ireland. R. Leigh is a consultant for AstraZeneca Canada, GlaxoSmithKline, Novartis Pharmaceuticals Canada, and Boehringer-Ingelheim Canada; is on the speakers' bureau for AstraZeneca Canada, GlaxoSmithKline, and Novartis Pharmaceuticals Canada; and receives research support from Novartis Pharmaceuticals Canada, MedImmune, Ception, Merck-Frosst Canada, Schering-Plough, and Bayer. G. M. Gauvreau receives grant support from Schering-Plough and MedImmune. P. M. O'Byrne is on the Advisory Board for AstraZeneca, GlaxoSmithKline, Topigen, Wyeth, and Schering-Plough; is on the speakers' bureau for AstraZeneca and GlaxoSmithKline; and receives research support from AstraZeneca, GlaxoSmithKline, Merck, Wyeth, Schering-Plough, and Alexion. The rest of the authors have declared that they have no conflict of interest.

PII: S0091-6749(09)01340-2

doi: 10.1016/j.jaci.2009.09.011

The Journal of Allergy and Clinical Immunology
Volume 125, Issue 2 , Pages 349-356.e13 , February 2010