The EGFR-ADAM17 Axis in Chronic Obstructive Pulmonary Disease and Cystic Fibrosis Lung Pathology

Figure 7

ADAM17/EGFR signaling an important player in CF and COPD lung disease. In airway epithelial cells in culture, both CFTR deficiency [61] and cigarette smoke exposure [87] cause enhanced activity of the EGFR/ADAM17 signaling cascade, and thus enhanced release of proinflammatory cytokines and growth factors that are ADAM17 substrates and signaling molecules that are downstream of the EGFR/MAPK pathway (Figure 1) including the proinflammatory CXCL8 (IL-8). In chronic lung disease, this could contribute to mucous metaplasia, inflammation, and tissue remodeling. A potential link between CFTR deficiency, COPD, and EGFR/ADAM17 activity (dashed arrows) is the extracellular redox potential, which is in part dependent on CFTR-related glutathione transport [30, 165, 166], and which in turn regulates ADAM17 activity (Figure 5). In COPD, CS induced long-term downregulation of CFTR expression [16, 47, 80] can have the same long-term effect, in addition to the acute oxidative stress caused by cigarette smoke. In this figure, we focus on two canonical ADAM17 substrates: proinflammatory IL-6 receptor (IL-6R) and growth factor amphiregulin (AREG). AREG is proteolytically cleaved by ADAM17 from airway epithelial cells and activates EGFR in the airway epithelial cells and on the underlying fibroblasts. IL-6R trans-signaling requires ADAM17-mediated shedding of the extracellular domain or alternative mRNA splicing. The soluble sIL-6R binds to IL-6 creating IL-6/sIL-6R complexes that trans-activate gp130 on the underlying myofibroblasts and myeloid cells. Signals transduced by AREG and IL-6R shed from airway epithelial cells converge in combined activation of the transcription factor STAT3 in myofibroblasts and smooth muscle cells. STAT3 is involved in fibrotic responses and inflammatory lung disease, and a modifier of CF lung disease [221]. Based on available literature cited in text, enhanced EGFR/ADAM17 signaling may contribute to hyperinflammation and epithelial metaplasia, fibroblast and smooth muscle cell activation, angiogenesis, and net deposition of extracellular matrix (tissue remodeling) observed in COPD and CF lung disease.