How Airway Remodeling and Hyperresponsiveness Contribute to Airflow Obstruction in Asthma

NCT ID: NCT00186693

Last Updated: 2011-07-26

Basic Information

• Recruitment Status: WITHDRAWN
• Total Enrollment: 12 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2006-09-30
• Study Completion Date: 2009-06-30

Brief Summary

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

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.

Conditions

Asthma

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

St. Joseph's Healthcare Hamilton

OTHER

Sponsor Role: lead

Principal Investigators

Gerard Cox, MB FRCPC FRCPI

Role: PRINCIPAL_INVESTIGATOR

McMaster University

Locations

St Joseph's Healthcare

Hamilton, Ontario, Canada

Countries

Canada

Other Identifiers

05-2453

Identifier Type: -

Identifier Source: org_study_id