Role of A Disintegrin and Metalloproteinase (ADAM) in Epithelial Dysfunction
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Observational

Summary: 
      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.
    

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.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Healthy subjects and subjects with COPD
      
Biospecimen description: 
      Bronchial brushes
    
Keywords: ADAM; epithelial; COPD