title: 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 ofGpx-1expression 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.
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA; Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Patrick
authors.identifier: 0000-0003-1647-5505
authors.initials: P
authors.lastname: Geraghty
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Miami, Miami, FL, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Baumlin
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Miami, Miami, FL, USA.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Salathe
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA; Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Robert F
authors.identifier: 0000-0003-3964-5335
authors.initials: RF
authors.lastname: Foronjy
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: D'Armiento
mesh_terms: D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D001980:Bronchi / Q000166:cytology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells; D005260:Female; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008875:Middle Aged; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D015398:Signal Transduction; D012906:Smoke; D012907:Smoking; D062789:Tobacco Products; D014415:Tunicamycin / Q000737:chemistry; D056811:Unfolded Protein Response; D055815:Young Adult; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D012906:Smoke; D014415:Tunicamycin; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1