Abstract
Emphysema is characterized by irreversibly enlarged airspaces and destruction of alveolar walls. One of the factors contributing to this disease pathogenesis is an elevation in extracellular matrix (ECM) degradation in the lung. Alveolar type II (ATII) cells produce and secrete pulmonary surfactants and proliferate to restore the epithelium after damage. We isolated ATII cells from control non-smokers, smokers and patients with emphysema to determine the role of NFE2 (nuclear factor, erythroid-derived 2). NFE2 is a heterodimer composed of two subunits, a 45 kDa (p45 NFE2) and 18 kDa (p18 NFE2) polypeptides. Low expression of p45 NFE2 in patients with emphysema correlated with a high ECM degradation. Moreover, we found that NFE2 knockdown increased cell death induced by cigarette smoke extract. We also studied the cross talk between p45 NFE2 and DJ-1. DJ-1 protein is a redox-sensitive chaperone that protects cells from oxidative stress. We detected that cigarette smoke significantly increased p45 NFE2 levels in DJ-1 KO mice compared to wild-type mice. Our results indicate that p45 NFE2 expression is induced by exposure to cigarette smoke, has a cytoprotective activity against cell injury, and its downregulation in human primary ATII cells may contribute to emphysema pathogenesis.
Highlights
Chronic obstructive pulmonary disease (COPD) is the fourth cause of death in the world and it is currently presenting a major global public health challenge[1]
Here we focused on the mechanism of dysregulated antioxidant defense system in human primary Alveolar type II (ATII) cells, which may contribute to an impaired proteinase-antiproteinase balance and emphysema development
We concentrated on the cytoprotective role of p45 NFE2 against ATII cell injury induced by Cigarette smoke (CS)
Summary
Chronic obstructive pulmonary disease (COPD) is the fourth cause of death in the world and it is currently presenting a major global public health challenge[1]. Intratracheal instillation of cathepsin B induced emphysema in hamsters[14] It can increase the activity of MMPs by destroying their inhibitors[15] and contribute to alveolar wall destruction[3,16]. We wanted to analyze the cross talk between p45 NFE2 and DJ-1 to determine their functional relationship in ATII cells under oxidative stress induced by CS and in emphysema. To our knowledge, this is the first study on the role of p45 NFE2 and DJ-1 in human ATII cells in this disease
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