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

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.

Mechanisms of Virus-Induced Airway Immunity Dysfunction in the Pathogenesis of COPD Disease, Progression, and Exacerbation

“…Viral infection per se also activates EGFR and EGFR signaling to ERK1/2, while STATs control the severity of HRV mediated airway inflammation. In vitro, HRV induced goblet cell hyperplasia was demonstrated to function through NF-κB-dependent MMP-mediated TGF-α release, leading to EGFR activation and mucus secretion (97). Interestingly, virusinduced EGFR activation suppressed interferon regulatory factor 1 (IRF1)-dependent IFN-λ airway epithelial antiviral signaling (98, 99).…”

Antiviral properties of placental growth factors: A novel therapeutic approach for COVID-19 treatment

“…Basic fibroblast growth factor (bFGF or FGF2) is a potent mitogen for many cell types, including airway smooth muscle cells, fibroblasts, and endothelial cells [ 107 ]. FGF2 can be released from inflammatory cells including T lymphocytes, eosinophil, mast cells, macrophages, and myeloid dendritic cells [ [108] , [109] , [110] ]. FGF carry out multiple biological processes by signalling through FGF receptors, including tumor angiogenesis, embryonic development, differentiation, proliferation, migration, and injury repair [ [111] , [112] , [113] ].FGF2 generate innate immune response by stabilizing retinoic acid-inducible gene-I (RIG-I) and preventing proteasome-mediated RIG-I degradation( 114 ).…”

Viral replication of SARS-CoV-2 could be self-limitative – The role of the renin-angiotensin system on COVID-19 pathophysiology

“…Studies show that diabetes, cardiovascular diseases, obesity, and other comorbidities are risk factors for COVID-19 [48] , [49] . When what these comorbidities have in common is analyzed, it is observed that individuals affected by these comorbidities have a higher expression of ADAM17 [50] , [51] , [52] , [53] . ADAM17 is a protease with a single transmembrane domain and a cytoplasmic portion.…”