Role of A Disintegrin and Metalloproteinase (ADAM) in Epithelial Dysfunction

The recruitment status of this study is unknown because the information has not been verified recently.
Verified May 2009 by University Medical Centre Groningen.
Recruitment status was  Not yet recruiting
Sponsor:
Information provided by:
University Medical Centre Groningen
ClinicalTrials.gov Identifier:
NCT00898859
First received: May 11, 2009
Last updated: NA
Last verified: May 2009
History: No changes posted
  Purpose

Despite emerging implications for ADAMs (and matrix metalloproteinases (MMPs)) in disease progression, the mechanisms that lead to activation of specific ADAMs (and MMPs) and their actions in chronic obstructive pulmonary disease (COPD) are still incompletely understood. In the current study, the researchers aim to investigate the effects of cigarette smoke on cellular parameters that are relevant for development of COPD and the involvement of ADAM activity in these effects. By studying the effects of ADAM inhibition, the researchers aim to provide novel insights in the role of ADAMs in the development of COPD, which may offer new therapeutic targets for the treatment of COPD.


Condition
Chronic Obstructive Pulmonary Disease

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Role of ADAMs in Epithelial Dysregulation in COPD. Differences Between From Non-Smokers, Healthy Smokers and Patients With COPD.

Resource links provided by NLM:


Further study details as provided by University Medical Centre Groningen:

Primary Outcome Measures:
  • IL8-production [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples Without DNA

Bronchial brushes


Estimated Enrollment: 50
Study Start Date: May 2009
Estimated Study Completion Date: May 2010
Estimated Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Groups/Cohorts
1
Healthy, non-smoking
2
healthy, ex-smoking
3
healthy, current-smokers
4
COPD, ex-smokers
5
COPD, smokers

Detailed Description:

Smoking is the largest risk factor for the development of COPD. It has been shown in patients with COPD that smoking induces airway inflammation characterized by bronchial infiltration of neutrophils, macrophages, lymphocytes and mast cells. In addition, smoking accelerates lung function loss and increases bronchial hyperresponsiveness, symptoms, and even mortality in COPD. When inhaled, tobacco smoke first encounters the airway epithelium, which forms a barrier to environmental substances and limits their access to the subepithelial layer. There is suggestive evidence that impaired repair responses and loss of epithelial integrity in the airways play a crucial role in the pathogenesis and contribute to tissue remodeling in COPD. Remodeling of the airway epithelium, e.g., squamous metaplasia and mucous hyperplasia, is often observed in COPD.

Metalloproteases (MMPs) and A Disintegrin and Metalloproteinase (ADAM)s may play an important role in respiratory diseases. MMPs and ADAMs, a class of membrane-bound MMPs, form a family of enzymes involved in degrading extracellular matrix (ECM) components. Their proteolytic activity is involved in remodeling of the ECM, which is required for migration and repair processes and regulated tissue turn-over. However, aberrant activity can lead to tissue destruction and irreversible damage. Thus MMPs, and ADAMs may play an important role in respiratory diseases and a protease-antiprotease imbalance may contribute to airway remodeling and impaired epithelial repair in COPD. In addition, MMPs/ADAMs act in regulatory events in inflammation and airway remodeling by liberating adhesion molecules and shedding of growth factors and cytokines from the cell surface. Furthermore, ADAMs play a role in cell-cell and cell-matrix interactions by their so-called disintegrin domain. In epithelial cells, both MMPs and ADAMs are known to regulate intercellular contacts, cell-matrix contacts, migratory responses, shedding of cytokines/growth factors, and intracellular signaling pathways. Since increased MMP levels (e.g., MMP-9, 12) have been observed during COPD exacerbations and polymorphisms in specific ADAM genes (i.e., ADAM33) have been associated with COPD susceptibility, the activation of MMPs and ADAMs on the airway epithelium may play an important role in the pathogenesis of COPD. Reactive oxygen species present in cigarette smoke may activate Duox, leading to activation of ADAM17 in airway epithelial cells. ADAM17 has been described to be involved in the release of growth factors (TGF-α), leading to the release of proinflammatory cytokines (IL-8) and production of MUC5AC 10-13. TGF-α acts on the EGF receptor (EGFR), which is involved in the production of MUC5AC and goblet cell hyperplasia. IL-8 is a well-known chemo-attractant for neutrophils, and thus may play a central role in neutrophilic inflammation in COPD, leading to ROS production, the release of neutrophil elastase and emphysema.

Despite emerging implications for ADAMs (and MMPs) in disease progression, the mechanisms that lead to activation of specific ADAMs (and MMPs) and their actions in COPD are still incompletely understood. In the current study, we aim to investigate the effects of cigarette smoke on cellular parameters that are relevant for development of COPD and the involvement of ADAM activity in these effects. By studying the effects of ADAM inhibition, we aim to provide novel insights in the role of ADAMs in the development of COPD, which may offer new therapeutic targets for the treatment of COPD.

  Eligibility

Ages Eligible for Study:   40 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

Healthy subjects and subjects with COPD

Criteria

Inclusion Criteria:

  • Age between 40 and 75 years.
  • Individuals who currently smoke ≥ 10 cigarettes/day and > 10 pack years.
  • Documented FEV1 > 80% predicted, FEV1/FVC > 70%.
  • Referred by own physician for a bronchoscopy.

Exclusion Criteria:

  • Any disease that, as judged by the Investigator, could affect the outcome of this study.
  • A respiratory tract infection within 4 weeks of the start of the study.
  • History of myocardial infarction or documented myocardial ischemia or the presence of an artificial heart valve.
  • Use of anticoagulants.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00898859

Contacts
Contact: Maarten van den Berge, PhD 0031-50-3615162 m.van.den.berge@int.umcg.nl

Sponsors and Collaborators
University Medical Centre Groningen
Investigators
Study Chair: Maarten van den Berge, PhD University Medical Centre Groningen
Study Director: maarrten van den Berge, PhD University Medical Centre Groningen
Principal Investigator: Irene Heijink, PhD University Medical Centre Groningen
  More Information

No publications provided

Responsible Party: Dr. H.I. Heijink, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT00898859     History of Changes
Other Study ID Numbers: METc2009086
Study First Received: May 11, 2009
Last Updated: May 11, 2009
Health Authority: Netherlands: Dutch Health Care Inspectorate

Keywords provided by University Medical Centre Groningen:
ADAM
epithelial
COPD

Additional relevant MeSH terms:
Lung Diseases
Respiration Disorders
Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on April 15, 2014