Towards Restoring the Physiological Inhibition of Airway Narrowing in Asthma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00279136
Recruitment Status : Unknown
Verified September 2005 by Leiden University Medical Center.
Recruitment status was:  Recruiting
First Posted : January 19, 2006
Last Update Posted : January 19, 2006
The Netherlands Asthma Foundation
Information provided by:
Leiden University Medical Center

Brief Summary:
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.

Condition or disease
Asthma Chronic Obstructive Pulmonary Disease

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.


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 participants
Observational Model: Defined Population
Observational Model: Natural History
Time Perspective: Cross-Sectional
Time Perspective: Prospective
Official Title: Towards Restoring the Physiological Inhibition of Airway Narrowing in Asthma
Study Start Date : September 2004
Study Completion Date : March 2006

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma
U.S. FDA Resources

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Asthma according to GINA criteria (
  • COPD according to GOLD criteria (

Exclusion Criteria:

  • nonsmoking
  • inhaled or oral steroid therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00279136

Contact: Peter J. Sterk, MD, PhD +31 71 526 3578
Contact: Annelies M. Slats, MD +31 71 526 3734

Leiden University Medical Center Recruiting
Leiden, Netherlands, NL-2300 RC
Contact: Peter J. Sterk, MD, PhD    +31 71 526 3578   
Contact: Annelies M. Slats, MD    +31 71 526 3734   
Principal Investigator: Peter J. Sterk, MD, PhD         
Sponsors and Collaborators
Leiden University Medical Center
The Netherlands Asthma Foundation
Study Chair: Peter J. Sterk, MD, PhD Leiden University Medical Center

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number): Identifier: NCT00279136     History of Changes
Other Study ID Numbers: AF, DIACON
Grant AF
First Posted: January 19, 2006    Key Record Dates
Last Update Posted: January 19, 2006
Last Verified: September 2005

Keywords provided by Leiden University Medical Center:
Bronchial hyperresponsiveness,
lung function,
airway inflammation,
deep inspiration,
bronchial biopsies
airway smooth muscle

Additional relevant MeSH terms:
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Bronchial Diseases
Respiratory Tract Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Immune System Diseases