Abstract
Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) share molecular mechanisms that cause the pathological symptoms they have in common. Here, we review evidence suggesting that hyperactivity of the EGFR/ADAM17 axis plays a role in the development of chronic lung disease in both CF and COPD. The ubiquitous transmembrane protease A disintegrin and metalloprotease 17 (ADAM17) forms a functional unit with the EGF receptor (EGFR), in a feedback loop interaction labeled the ADAM17/EGFR axis. In airway epithelial cells, ADAM17 sheds multiple soluble signaling proteins by proteolysis, including EGFR ligands such as amphiregulin (AREG), and proinflammatory mediators such as the interleukin 6 coreceptor (IL-6R). This activity can be enhanced by injury, toxins, and receptor-mediated external triggers. In addition to intracellular kinases, the extracellular glutathione-dependent redox potential controls ADAM17 shedding. Thus, the epithelial ADAM17/EGFR axis serves as a receptor of incoming luminal stress signals, relaying these to neighboring and underlying cells, which plays an important role in the resolution of lung injury and inflammation. We review evidence that congenital CFTR deficiency in CF and reduced CFTR activity in chronic COPD may cause enhanced ADAM17/EGFR signaling through a defect in glutathione secretion. In future studies, these complex interactions and the options for pharmaceutical interventions will be further investigated.
Highlights
Airway epithelium, apart from providing a structural barrier against microbes and inhaled particles, plays an active role in the first line of inflammatory responses [1], and emerged as a therapeutic target in chronic lung disease [2]
We recently found that cigarette smoke induced shedding of the A disintegrin and metalloprotease 17 (ADAM17) substrate amphiregulin (AREG), and interleukin 6 coreceptor (IL-6R) was enhanced in differentiated bronchial cells in culture obtained from Chronic obstructive pulmonary disease (COPD) patients compared to non-COPD, suggesting that epigenetic factors controlling the activity of the ADAM17/EGF receptor (EGFR) axis are affected in COPD [87]
Several lines of evidence, discussed above, suggest that the ADAM17/EGFR axis and downstream regulatory pathways are hyperactive in cystic fibrosis (CF) and COPD chronic lung disease, promoting inflammation and tissue remodeling by shedding EGFR binding growth factors and proinflammatory agonists from airway epithelial cells
Summary
Apart from providing a structural barrier against microbes and inhaled particles, plays an active role in the first line of inflammatory responses [1], and emerged as a therapeutic target in chronic lung disease [2]. Common features (i) Progress over time, irreversible (ii) Chronic bronchitis (iii) Bronchiectasis (iv) Reduced mucociliaryclearance (v) Mucus plugging (vi) Depletion of the ASL (vii) Bacterial colonization (viii) Recurrent infections (ix) Chronic inflammation (x) Tissue remodeling This leads to the question whether these diseases, while quite different in many aspects, share common molecular mechanisms and therapeutic targets (Figure 1) [15,16,17]. This system is highly sensitive to various extracellular triggers, including cigarette smoke and bacterial toxins, resulting in the enhanced shedding of a large repertoire of growth factors, cytokines, and cytokine receptors that are substrates of ADAM17 This in turn leads to paracrine and autocrine receptor activation, which plays an important role in the resolution of airway inflammation and tissue damage.
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