How GP96 upregulation shields against COPD: mitigating endoplasmic reticulum stress-induced cellular damage via p38/ERK pathway activation.

Abstract

Chronic obstructive pulmonary disease (COPD) is closely associated with endoplasmic reticulum stress (ERS). We explored the potential role of Glycoprotein 96 (GP96) in mitigating ERS-induced cellular damage in an in vitro COPD model. Human bronchial epithelial 16HBE cells were exposed to nicotine to establish a COPD model in vitro. The expression of GP96 was manipulated, and the involvement of the extracellular signal-regulated kinase (ERK) signaling pathway was assessed by treatment with the ERK inhibitor PD98059. The effects of GP96 and the p38/ERK pathway on ERS-related markers, apoptosis and its associated proteins, reactive oxygen species (ROS) levels, proinflammatory cytokines, and the activation levels of ERK and p38 were evaluated. Nicotine induced GP96 expression in 16HBE cells. Nicotine also repressed cell viability, and promoted apoptosis, ROS release, expressions of ERS-related markers and pro-inflammatory cytokines levels in 16HBE cells, which were reversed by GP96 overexpression. Besides, nicotine elevated p-ERK/ERK and p-P38/P38 levels in 16HBE cells, which was further enhanced by GP96 overexpression. In contrast, GP96 silencing produced effects opposite to those of GP96 overexpression. The ERK inhibitor PD98059 offset the effects of GP96 overexpression, except for its impact on the p-P38/P38 levels, which remained unaffected. GP96 overexpression inhibits ERS-induced apoptosis, oxidative stress and inflammation in nicotineinduced in vitro COPD model through potentiating ERK activation.