Role of A Disintegrin and Metalloproteinase (ADAM) in Epithelial Dysfunction
|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.|
|ClinicalTrials.gov Identifier: NCT00898859|
Recruitment Status : Completed
First Posted : May 12, 2009
Last Update Posted : January 16, 2015
|Condition or disease|
|Chronic Obstructive Pulmonary Disease|
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.
|Study Type :||Observational|
|Actual Enrollment :||50 participants|
|Official Title:||Role of ADAMs in Epithelial Dysregulation in COPD. Differences Between From Non-smokers, Healthy Smokers and Patients With COPD.|
|Study Start Date :||May 2009|
|Actual Primary Completion Date :||May 2012|
|Actual Study Completion Date :||December 2012|
- IL8-production [ Time Frame: 12 months ]
Biospecimen Retention: Samples Without DNA
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 ClinicalTrials.gov identifier (NCT number): NCT00898859
|Study Chair:||Maarten van den Berge, PhD||University Medical Center Groningen|
|Study Director:||maarrten van den Berge, PhD||University Medical Center Groningen|
|Principal Investigator:||Irene Heijink, PhD||University Medical Center Groningen|