Towards Restoring the Physiological Inhibition of Airway Narrowing in Asthma

Asthma and COPD are characterized by airway narrowing. The most potent, physiological mechanism leading to bronchodilation is taking a deep inspiration. This protects healthy subjects against bronchoconstrictive stimuli, and reverses pre-existing bronchoconstriction. However, the deep breath-induced bronchoprotection and -bronchodilation is impaired in asthma. We questioned whether this is specific for asthma (in comparison to COPD), and whether this is associated with bronchial inflammation and -remodelling. The study is a two-groups comparison, of physiological and pathological disease markers, obtained by methacholine challenges, monitoring airways resistance, and by taking bronchial biopsies.

Study Overview

• Status: Unknown
• Conditions: Chronic Obstructive Pulmonary Disease; Asthma

Detailed Description

Rationale. Asthma is associated with variable airways obstruction and airways inflammation. It is generally assumed that inflammatory mechanisms are promoting airway narrowing, by stimulating airway smooth muscle and by geometrical changes of the airway wall. Healthy subjects are very effectively protected against stimuli of airway narrowing, by mechanisms that are apparently failing in asthma. The most potent inhibitor of airway narrowing in healthy subjects is taking a deep inspiration. This prevents and reverses bronchoconstriction (DI-induced bronchoprotection and -bronchodilation, respectively), which is less effective or absent in asthma. The DI-induced inhibition of airway narrowing in normal subjects is presumably due to relaxation of smooth muscle after mechanical stretch or to the release of relaxant mediators (such as endogenous NO). Such mechanisms might have become impaired in asthma, secondary to e.g. mechanical uncoupling of smooth muscle from the surrounding parenchyma (e.g. by congestion or edema), by altered structure and function of airway smooth muscle, and/or by reduced inhibitory mediator release.

It can be postulated that the impaired response to deep inspiration is a central pathophysiological feature of asthma at all ages. Therefore, we believe that it is imperative to address this, by identifying and restoring these inhibitory pathways in patients with asthma.

Hypotheses.

We hypothesize that DI-induced bronchoprotection and -broncho¬dilation:

1. are associated with cellular and morphological features of airways inflammation,
2. can be restored by deep insufflation rather than deep inspiration, and by pharmacological interventions aimed to reduce microvascular congestion or to increase endogenous nitric oxide synthesis..

Design and methods. To examine to what extent DI-responses differ between asthma and COPD in adulthood, and whether this is associated with features of airways inflammation and changes in smooth muscle function. 12 Adult patients with asthma and 12 with COPD will undergo single-dose methacholine challenge, with prohibition of DI's or 5 DI's prior to challenge in a cross-over design, measuring airways resistance. On a separate day bronchial biopsies will obtained with immunohistochemistry for inflammatory cell markers, vascularity, microvascular leakage, myosin light chain kinase, NO-synthases, and arginase.

• Study Type: Observational
• Enrollment: 36

Contacts and Locations

• Study Contact: Name: Peter J. Sterk, MD, PhD; Phone Number: +31 71 526 3578; Email: p.j.sterk@lumc.nl
• Study Contact Backup: Name: Annelies M. Slats, MD; Phone Number: +31 71 526 3734; Email: a.m.slatts@lumc.nl

Study Locations

• Netherlands
  • Leiden, Netherlands, NL-2300 RC
    • Recruiting
    • Leiden University Medical Center
    • Contact: Peter J. Sterk, MD, PhD; Phone Number: +31 71 526 3578; Email: p.j.sterk@lumc.nl
    • Contact: Annelies M. Slats, MD; Phone Number: +31 71 526 3734; Email: a.m.slats@lumc.nl
    • Principal Investigator: Peter J. Sterk, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Asthma according to GINA criteria (www.ginasthma.org)
• COPD according to GOLD criteria (www.goldcopd.org)

Exclusion Criteria:

• nonsmoking
• inhaled or oral steroid therapy

Study Plan

How is the study designed?

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: The Netherlands Asthma Foundation
• Investigators: Study Chair: Peter J. Sterk, MD, PhD, Leiden University Medical Center

Publications and helpful links

General Publications

• Slats AM, Janssen K, van Schadewijk A, van der Plas DT, Schot R, van den Aardweg JG, de Jongste JC, Hiemstra PS, Mauad T, Rabe KF, Sterk PJ. Bronchial inflammation and airway responses to deep inspiration in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007 Jul 15;176(2):121-8. doi: 10.1164/rccm.200612-1814OC. Epub 2007 Mar 22.

Helpful Links

• Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start: September 1, 2004
• Study Completion: March 1, 2006

Study Registration Dates

• First Submitted: January 17, 2006
• First Submitted That Met QC Criteria: January 17, 2006
• First Posted (Estimate): January 19, 2006

Study Record Updates

• Last Update Posted (Estimate): January 19, 2006
• Last Update Submitted That Met QC Criteria: January 17, 2006
• Last Verified: September 1, 2005

More Information

Terms related to this study

• Keywords: bronchial biopsies; airway smooth muscle; lung function,; Bronchial hyperresponsiveness,; airway inflammation,; deep inspiration,
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Respiratory Hypersensitivity; Hypersensitivity; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Asthma
• Other Study ID Numbers: AF 3.2.02.34, DIACON; Grant AF 3.2.02.34