Glutathione Peroxidase-1 Suppresses the Unfolded Protein Response upon Cigarette Smoke Exposure

Abstract

Oxidative stress provokes endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) in the lungs of chronic obstructive pulmonary (COPD) subjects. The antioxidant, glutathione peroxidase-1 (GPx-1), counters oxidative stress induced by cigarette smoke exposure. Here, we investigate whether GPx-1 expression deters the UPR following exposure to cigarette smoke. Expression of ER stress markers was investigated in fully differentiated normal human bronchial epithelial (NHBE) cells isolated from nonsmoking, smoking, and COPD donors and redifferentiated at the air liquid interface. NHBE cells from COPD donors expressed heightened ATF4, XBP1, GRP78, GRP94, EDEM1, and CHOP compared to cells from nonsmoking donors. These changes coincided with reduced GPx-1 expression. Reintroduction of GPx-1 into NHBE cells isolated from COPD donors reduced the UPR. To determine whether the loss of GPx-1 expression has a direct impact on these ER stress markers during smoke exposure, Gpx-1 −/− mice were exposed to cigarette smoke for 1 year. Loss of Gpx-1 expression enhanced cigarette smoke-induced ER stress and apoptosis. Equally, induction of ER stress with tunicamycin enhanced antioxidant expression in mouse precision-cut lung slices. Smoke inhalation also exacerbated the UPR response during respiratory syncytial virus infection. Therefore, ER stress may be an antioxidant-related pathophysiological event in COPD.

Oxidative and endoplasmic reticulum stress in respiratory disease

“…There is evidence for ER stress in COPD but it is based on a limited number of validated studies 97, 98, 99. However, there is reasonably clear evidence that exposure of bronchial epithelial cells to cigarette smoke (the environmental driver of COPD) increases ER stress 100, 101…”

Endoplasmic reticulum stress in lung disease

“…One plausible explanation is that recovery of protein synthesis is pro-survival during responses to transient ER stress, but becomes toxic during chronic ER stress, when ongoing protein synthesis overwhelms the adaptive potential of the system. Evidence has implicated these pathways in the responses to oxidative stress imposed by cigarette smoke, but this requires further exploration [25][26][27][28]. Although ATF4 signalling is activated in the airways of many patients with chronic obstructive pulmonary disease [44], a direct mechanistic link with disease pathogenesis remains elusive.…”

Pulmonary endoplasmic reticulum stress—scars, smoke, and suffocation

“…Nevertheless, the lack of viral antigens in many cases of IPF despite evidence of an active UPR suggests other ER stress‐inducing agents may also be involved in the pathogenesis of pulmonary fibrosis. For example, inhaled smoke is a plausible candidate (see later) since smoking cigarettes is a known risk factor for IPF and components of smoke can cause ER stress . Equally, airborne particulate matter can activate the UPR in cultured cells and in the murine lung , while exposure to airborne particulate matter is associated with more rapid progression of IPF .…”

“…This sparked interest in a potential role for smoke‐induced ER stress as a mediator of COPD. Despite apparent discrepancies in some of the effects of cigarette smoke in different disease models, smoke‐induced ER stress appears to be initiated by perturbations in redox that lead, in many instances, to the triggering of cell death pathways .…”

“…In vitro exposure of cells to cigarette smoke and other airborne pollutants can trigger the UPR . When primary bronchial epithelial cells from nonsmoking individuals were exposed for a brief period to whole cigarette smoke, transient PERK‐dependent phosphorylation of eIF2α was observed followed by induction of ATF4 and GADD34 .…”