Endogenous enzymes (NOX and ECSOD) regulate smoke-induced oxidative stress.
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and the incidence is increasing as the population ages. Cigarette smoking is the primary risk factor; however, only a minority of smokers develop the disease. Inhalation of cigarette smoke introduces an abundance of free radicals into the lungs, causing oxidative stress and inflammation. We hypothesized that after the initial burst of oxidative stress associated with cigarette smoke exposure, a sustained source of endogenous free radical production is modulated by the antioxidant enzyme extracellular superoxide dismutase (ECSOD) and the superoxide-generating complex NADPH oxidase (NOX). Primary mouse macrophages exposed to cigarette smoke extract exhibited increased oxidative stress as indicated by fluorogenic dyes and isoprostane concentration, which was suppressed in the presence of both a superoxide dismutase mimetic and a NOX inhibitor. Similarly, primary macrophages isolated from ECSOD-overexpressing mice or NOX-deficient mice showed reduced oxidative stress in response to cigarette smoke treatment. In addition, both reduced glutathione and cytokines (MIP2 and IFNγ) were increased in bronchoalveolar lavage fluid of wild-type mice exposed to cigarette smoke but not in ECSOD-overexpressing or NOX-deficient mice. These data suggest that the mechanisms underlying the host defense against cigarette smoke-induced oxidative damage and subsequent development of COPD may include endogenous oxidases and antioxidant enzymes.
Tollefson
Angela K
AK
Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
Oberley-Deegan
Rebecca E
RE
Butterfield
Kiel T
KT
Nicks
Michael E
ME
Weaver
Michael R
MR
Remigio
Linda K
LK
Decsesznak
Jessica
J
Chu
H W
HW
Bratton
Donna L
DL
Riches
David W
DW
Bowler
Russell P
RP
D000818:Animals; D054426:Chemokine CXCL2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014026:Nicotiana / Q000009:adverse effects*; D015854:Up-Regulation
D054426:Chemokine CXCL2; D004791:Enzyme Inhibitors; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D012906:Smoke; C007517:diphenyleneiodonium; D013482:Superoxide Dismutase; D019255:NADPH Oxidases