Glutathione peroxidase-1 protects against cigarette smoke-induced lung inflammation in mice.
Reactive oxygen species (ROS) produced from cigarette smoke cause oxidative lung damage including protein denaturation, lipid peroxidation, and DNA damage. Glutathione peroxidase-1 (gpx-1) is a detoxifying enzyme that may protect lungs from such damage. The aim of this study was to determine whether gpx-1 protects the lung against oxidative stress-induced lung inflammation in vivo. Male wild-type (WT) or gpx-1(-/-) mice were exposed to cigarette smoke generated from nine cigarettes per day for 4 days to induce oxidative stress and lung inflammation. The effect of the gpx mimetic ebselen on cigarette smoke-induced lung inflammation was evaluated when given prophylactically and therapeutically, i.e., during established inflammation. Mice were killed, and the lungs were lavaged with PBS and then harvested for genomic and proteomic analysis. Gpx-1(-/-) mice exposed to cigarette smoke had enhanced BALF neutrophils, macrophages, proteolytic burden, whole lung IL-17A, and MIP1alpha mRNA compared with WT mice. The gpx mimetic ebselen (10 and 100 microM) inhibited cigarette smoke extract-induced oxidation of MH-S cells in vitro and inhibited cigarette smoke-induced increases in BALF macrophages, neutrophils, proteolytic burden, and macrophage and neutrophil chemotactic factor gene expression when administered prophylactically. In addition, ebselen inhibited established BALF inflammation when administered therapeutically. These data show that gpx-1 protects against cigarette smoke-induced lung inflammation, and agents that mimic the actions of gpx-1 may have therapeutic utility in inflammatory lung diseases where cigarette smoke plays a role.
Department of Pharmacology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Chi
C
Duong
Huei Jiunn
HJ
Seow
Steven
S
Bozinovski
Peter J
PJ
Crack
Gary P
GP
Anderson
Ross
R
Vlahos
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D002630:Chemotactic Factors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D054833:Isoindoles; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D016566:Organoselenium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010447:Peptide Hydrolases / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D011506:Proteins / Q000378:metabolism; D012907:Smoking; D000094765:Glutathione Peroxidase GPX1
D000975:Antioxidants; D001393:Azoles; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D054833:Isoindoles; D016566:Organoselenium Compounds; D011506:Proteins; C042986:ebselen; D005979:Glutathione Peroxidase; D010447:Peptide Hydrolases; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse