Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM.
Extracellular superoxide dismutase (ECSOD or SOD3) is highly expressed in lungs and functions as a scavenger of O(2)(*-). ECM fragmentation, which can be triggered by oxidative stress, participates in the pathogenesis of chronic obstructive pulmonary disease (COPD) through attracting inflammatory cells into the lungs. The level of SOD3 is significantly decreased in lungs of patients with COPD. However, the role of endogenous SOD3 in the development/progression of emphysema is unknown. We hypothesized that SOD3 protects against emphysema by attenuating oxidative fragmentation of ECM in mice. To test this hypothesis, SOD3-deficient, SOD3-transgenic, and WT C57BL/6J mice were exposed to cigarette smoke (CS) for 3 d (300 mg total particulate matter/m(3)) to 6 mo (100 mg/m(3) total particulate matter) or by intratracheal elastase injection. Airspace enlargement, lung inflammation, lung mechanical properties, and exercise tolerance were determined at different time points during CS exposure or after elastase administration. CS exposure and elastase administration caused airspace enlargement as well as impaired lung function and exercise capacity in SOD3-null mice, which were improved in mice overexpressing SOD3 and by pharmacological SOD mimetic. These phenomena were associated with SOD3-mediated protection against oxidative fragmentation of ECM, such as heparin sulfate and elastin, thereby attenuating lung inflammatory response. In conclusion, SOD3 attenuates emphysema and reduces oxidative fragmentation of ECM in mouse lung. Thus, pharmacological augmentation of SOD3 in the lung may have a therapeutic potential in the intervention of COPD/emphysema.
Yao
Hongwei
H
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY 14642, USA.
Arunachalam
Gnanapragasam
G
Hwang
Jae-Woong
JW
Chung
Sangwoon
S
Sundar
Isaac K
IK
Kinnula
Vuokko L
VL
Crapo
James D
JD
Rahman
Irfan
I
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D015151:Immunoblotting; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008170:Lung Compliance / Q000187:drug effects; D008665:Metalloporphyrins / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress; D010196:Pancreatic Elastase / Q000008:administration & dosage; D011656:Pulmonary Emphysema / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D012906:Smoke; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D013997:Time Factors; D014026:Nicotiana / Q000737:chemistry
D004549:Elastin; D006497:Heparan Sulfate; D008665:Metalloporphyrins; D010196:Pancreatic Elastase; D012906:Smoke; D013482:Superoxide Dismutase; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin; C499090:Sod3 protein, mouse