How Airway Remodeling and Hyperresponsiveness Contribute to Airflow Obstruction in Asthma

Airway hyperresponsiveness is a characteristic feature of the asthma. It is known that there is an association between airway hyperresponsiveness and eosinophilic airway inflammation. However, even though inflammation can be reduced with appropriate asthma therapy, it is typical that airway hyperresponsiveness improves only modestly with treatment. The determinants of airway hyperresponsiveness are unclear.

It is also not clear as to the site of airway narrowing in asthma. It is hypothesized that airways beyond the 4th order have the greatest resistance.

We hope to determine the relationships between the airway inflammation, remodeling of the airway and airway hyperresponsiveness. Through local instillation of methacholine at bronchoscopy we will be able to study proximal and distal airways and the extent to which they constrict in vivo

Study Overview

• Status: Withdrawn
• Conditions: Asthma

Detailed Description

Airway hyperresponsiveness (AHR) is a characteristic feature of the asthmatic condition in humans. There is an association between AHR and eosinophilic airway inflammation. However, even though eosinophilic inflammation can be abolished with appropriate therapy, it is typical that AHR improves only modestly with treatment. The determinants of AHR are poorly understood. Recent data implicate mediators such as the cytokine Interleukin-13 (IL-13), structural changes to the airway wall (remodeling), increased contractility of airway smooth muscle cells (ASMC) and loss of mechanical connections or tethering, as potential factors contributing to AHR.

There is also uncertainty around the site of airway narrowing in asthma. In normal airways, bronchii around the 4th order have the greatest contribution to total resistance. It is hypothesized that the site of greatest resistance is moved distally in asthma and might even involve quite small airways close to the level of terminal bronchioles. Non-invasive methods to assess airway caliber in vivo are still unproven. One untested concern is that the airways of subjects with severe AHR have the potential to close completely putting them at risk of severe and even fatal airflow obstruction.

We propose to study AHR in humans with asthma: we will determine the relationships between AHR and (i) eosinophilic inflammation in the airway (sputum cellularity) via sputum induction, (ii) soluble mediators of inflammation (IL-13, IL-4, IL-5), (iii) remodeling of the airway wall (sub-epithelial fibrosis, ASMC accumulation)via biopsy. In addition we will compare measurements of AHR assessed by inhalation challenge with the results of direct, local installation of methacholine. At bronchoscopy, methacholine is delivered to the airway and bronchoconstriction is assessed directly. This method will allow study of proximal and distal airways, identification of heterogeneity of responses among airways and the extent to which human airways can constrict in vivo.

• Study Type: Observational
• Enrollment (Anticipated): 12

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • St Joseph's Healthcare

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

adults with asthma

Description

Inclusion/ Exclusion Criteria:

• adults age 18 - 65 years
• stable asthma, defined as no need for new medical intervention in previous 4 weeks
• pre FEV1 > or = to 70% and able to have a methacholine challenge
• hyper-responsiveness as measured by methacholine challenge PC20 < or = 16 mg/ml
• steroid naive or stable inhaled corticosteroid medication in previous 8 weeks
• symptomatic treatment with bronchodilators permitted
• able to give written informed consent
• no other active/unstable medical conditions as judged by investigator
• subjects must be suitable for bronchoscopy in opinion of the investigator
• female subjects must no be pregnant, nursing or unwilling to use appropriate contraception

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Collaborators and Investigators

• Sponsor: St. Joseph's Healthcare Hamilton
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Gerard Cox, MB FRCPC FRCPI, McMaster University

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Study Completion (Anticipated): June 1, 2009

Study Registration Dates

• First Submitted: September 10, 2005
• First Submitted That Met QC Criteria: September 10, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Estimate): July 26, 2011
• Last Update Submitted That Met QC Criteria: July 25, 2011
• Last Verified: July 1, 2006

More Information

Terms related to this study

• Keywords: Asthma; Airway remodeling; Hyper-responsiveness
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Pathological Conditions, Anatomical; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Airway Remodeling
• Other Study ID Numbers: 05-2453