Cigarette Smoke-Induced Oxidant Stress in the Lung, the Unfolded Protein Response, and COPD

Cigarette smoking which exposes the lung to high concentrations of reactive oxidant species (ROS) is the major risk factor for chronic obstructive pulmonary disease (COPD). Recent studies indicate that the defense against oxidant stress is impaired in COPD and oxidant burden is increased in COPD even after smoking has ceased. ROS present in cigarette smoke interfere with protein folding in the endoplasmic reticulum thereby eliciting a compensatory response termed the “unfolded protein response.” The importance of the UPR lies in its ability to alter expression of a large number of gene programs involved in basic cellular processes including anti-oxidant defense. This article will review the several signaling pathways which mediate the unfolded protein response and, in particular, the role of the PERK (protein kinase R-like endoplasmic reticulum kinase) signaling pathway in protecting the lung against oxidant injury. Moreover, the impairment in oxidant defense present in the lung in COPD will be discussed.