Correlation of Apical Fluid-Regulating Channel Proteins with Lung Function in Human COPD Lungs

Abstract

Links between epithelial ion channels and chronic obstructive pulmonary diseases (COPD) are emerging through animal model and in vitro studies. However, clinical correlations between fluid-regulating channel proteins and lung function in COPD remain to be elucidated. To quantitatively measure epithelial sodium channels (ENaC), cystic fibrosis transmembrane conductance regulator (CFTR), and aquaporin 5 (AQP5) proteins in human COPD lungs and to analyze the correlation with declining lung function, quantitative western blots were used. Spearman tests were performed to identify correlations between channel proteins and lung function. The expression of α and β ENaC subunits was augmented and inversely associated with lung function. In contrast, both total and alveolar type I (ATI) and II (ATII)-specific CFTR proteins were reduced. The expression level of CFTR proteins was associated with FEV1 positively. Abundance of AQP5 proteins and extracellular superoxide dismutase (SOD3) was decreased and correlated with spirometry test results and gas exchange positively. Furthermore, these channel proteins were significantly associated with severity of disease. Our study demonstrates that expression of ENaC, AQP5, and CFTR proteins in human COPD lungs is quantitatively associated with lung function and severity of COPD. These apically located fluid-regulating channels may thereby serve as biomarkers and potent druggable targets of COPD.

The therapeutic potential of CFTR modulators for COPD and other airway diseases

“…This was also confirmed in the lower airways [7]. In these studies, CFTR dysfunction was tightly associated with symptoms of chronic bronchitis [5,7], and was positively correlated with reduced forced expiratory volume (FEV 1 ) in the lungs of patients with COPD [8]. …”

Effect of lentivirus-mediated CFTR overexpression on oxidative stress injury and inflammatory response in the lung tissue of COPD mouse model

“…In recent years, cystic fibrosis transmembrane conductance regulator (CFTR) as a drug target in some major diseases has been gaining increasing attention. The latest clinical research has found that the expression of the ion channel protein CFTR can decrease significantly in patients with COPD [6]. This finding indicates that CFTR may be related to the pathogenesis of COPD.…”

Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases

“…Over-activation of ENaC by airway-targeted βENaC overexpression leads to the generation of concentration gradient of sodium ions (e.g., sodium ions going from outside to inside of the cell) followed by over-absorption of water into the cells, which results in dysregulated airway mucus production and airway clearance59. Based on the lines of evidence showing that the expression and function of ENaC were inversely associated with lung function in CF patients910 and could be augmented in COPD patients1112, βENaC-Tg mice could be valuable tools for exploring mucus obstructive phenotypes of COPD and CF in vivo . However, the mortality of βENaC-Tg mice with a mixed C3H/HeN:C57/BL6N background was extremely high5, which limits usage of the original βENaC-Tg line as an animal model of acute and fulminant airway diseases.…”