Extracellular Superoxide Dismutase Inhibits Inflammation by Preventing Oxidative Fragmentation of Hyaluronan

Gao, Fei; Koenitzer, Jeffrey R.; Tobolewski, Jacob M.; Jiang, Dianhua; Liang, Jiurong; Noble, Paul W.; Oury, Tim D.

doi:10.1074/jbc.m709273200

Cited by 162 publications

(142 citation statements)

References 72 publications

(49 reference statements)

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…Lung inflammation was significantly decreased by SOD3 overexpression in mice exposed to CS and elastase. This is in agreement with previous studies showing a protective effect of SOD3 on lung inflammatory responses to hyperoxia, bleomycin, and asbestos (4,17,29,30). Furthermore, the SOD mimetic exhibited a protective effect in lung inflammation in SOD3 KO as well as in WT mice.…”

Section: Discussionsupporting

confidence: 82%

“…Con, control; Mimetic, SOD mimetic. flammatory response caused by a variety of stimuli (15)(16)(17)(18)(23)(24)(25). Hence, immunoblotting was performed to determine whether the protective effect of SOD3 on lung inflammation and subsequent emphysema is caused by an increased integrity of ECM in mouse lung exposed to CS.…”

Section: Sod3 Protected Against Cs-induced Heparan Sulfate Shedding Andmentioning

confidence: 99%

“…In addition to being a direct exogenous source of reactive oxygen species (ROS), CS also induces endogenous production of ROS from activated inflammatory cells in the lung. ROS can fragment ECM components, such as elastin, heparan sulfate, and hyaluronan, which is an important factor in triggering lung inflammation and causing subsequent airspace enlargement (15)(16)(17)(18). SOD3 has been shown to bind to ECM through its positively charged C-terminal, thereby preventing oxidative fragmentation of ECM components (15,19).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Yao

Arunachalam

Hwang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

175

166

View full text Add to dashboard Cite

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.antioxidants | cigarette smoke | chronic obstructive pulmonary disease | oxidants | glutathione E xtracellular superoxide dismutase (ECSOD or SOD3) is one of the three SOD antioxidant enzyme isoforms, and is highly expressed in lungs and vessels (1, 2). It is located in the ECM, the junctions of airway epithelial cells, the surface of airway smooth muscle, and the lining of vessels of the lung. SOD3 functions as a superoxide anion scavenger, thereby attenuating oxidative stress, which may play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Acute loss of SOD3 in adult mice causes death, whereas low mortality rates are seen in SOD3-overexpressing animals exposed to hyperoxia, suggesting an essential role of SOD3 for survival (3,4). Accumulating evidence shows that SOD3 polymorphism is associated with a decline in lung function in rodents and humans, and susceptibility to COPD, which may be a result of alteration of its encoding protein structure, function, and level (5-14). However, it is unclear whether endogenous SOD3 participates in the development/ progression of the inflammatory response, leading to COPD/ emphysema.Cigarette smoke (CS) is the major etiological factor in the pathogenesis of COPD, which is characterized by chronic lung inflammation, parenchymal destruction (i.e., emphysema), and accelerated decline in lung function....

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Sod3 Protected Against Cs-induced Heparan Sulfate Shedding Andmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Yao

Arunachalam

Hwang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

175

166

View full text Add to dashboard Cite

show abstract

“…Extracellular superoxide dismutase or superoxide dismutase 3, the last discovered superoxide dismutase isoform that binds lung matrix components, inhibiting their fragmentation in response to oxidative stress, [38][39][40] is the primary extracellular lung antioxidant enzyme. 41,42 It protects the extracellular matrix during lung injury [43][44][45][46] and accounts for the majority of superoxide dismutase activity in airways and vessels.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Utility of Biomarkers in COPD

Ambade¹,

Sontakke

Barthwal³

et al. 2015

Respir Care

View full text Add to dashboard Cite

BACKGROUND: COPD will become the third leading cause of death by 2020. There are many situations in which spirometry, the primary tool for diagnosis of COPD, cannot be performed, and thus, the staging and status of these patients cannot be determined. To date, there is no known biochemical marker used for diagnosing COPD. This study aimed to explore the utility of biomarkers for diagnosis of COPD. METHODS: This was an observational study composed of 96 stable subjects with COPD and 96 subjects with normal lung function. Each group contained an equal number of smokers and nonsmokers. Serum levels of superoxide dismutase 3, glutathione peroxidase, catalase, ceruloplasmin ferroxidase activity, C-reactive protein, and surfactant protein D (SPD) were estimated. Ferroxidase activity was estimated by a kinetic method, whereas the other analytes were measured by enzyme-linked immunosorbent assay. The cutoff value, sensitivity and specificity at the cutoff value, and area under the curve for each analyte were determined from receiver operating characteristic curve. RESULTS: Significantly decreased superoxide dismutase 3 and increased ferroxidase activity, SPD, glutathione peroxidase, and C-reactive protein levels were found in subjects with COPD. For all subjects and nonsmoking subjects with COPD, the area under the curve was highest for ferroxidase activity, followed by glutathione peroxidase, SPD, and C-reactive protein, with a sensitivity and specificity of > 73%. For smoking subjects with COPD, the area under the curve was highest for SPD, followed by glutathione peroxidase, ferroxidase activity, and C-reactive protein, with a sensitivity and specificity > 67%. Some combinations of markers were found to give either a sensitivity or specificity of > 95%, which can be utilized to rule in and rule out COPD. CONCLUSIONS: Biomarkers can be reliably utilized in the diagnosis of COPD. Of all the markers, SPD appears to be the most promising in smokers, whereas ferroxidase activity shows promise in nonsmokers. To rule out COPD, ferroxidase activity or glutathione peroxidase can be potentially useful, whereas to rule in COPD, ferroxidase activity and glutathione peroxidase appear to be the most promising combination in both nonsmoking and smoking subjects.

show abstract

“…19,20 One mechanism by which EC-SOD inhibits inflammation is directly binding to and inhibiting oxidative fragmentation of several components in the extracellular matrix including collagen, heparan sulfate, and hyaluronan after interstitial lung injury. 11,[21][22][23][24] The importance of endogenous pulmonary EC-SOD was recently highlighted in a study that demonstrated that acute loss of EC-SOD resulted in 85% mortality secondary to the spontaneous development of acute respiratory distress syndrome. 25 This indicates that EC-SOD is essential for protecting the lungs against inflammation and injury even in ambient air.…”

mentioning

confidence: 99%

Extracellular Superoxide Dismutase in Macrophages Augments Bacterial Killing by Promoting Phagocytosis

Manni

Tomai

Norris

et al. 2011

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Extracellular superoxide dismutase (EC-SOD) is abundant in the lung and limits inflammation and injury in response to many pulmonary insults. To test the hypothesis that EC-SOD has an important role in bacterial infections, wild-type and EC-SOD knockout (KO) mice were infected with Escherichia coli to induce pneumonia. Although mice in the EC-SOD KO group demonstrated greater pulmonary inflammation than did wild-type mice, there was less clearance of bacteria from their lungs after infection. Macrophages and neutrophils express EC-SOD; however, its function and subcellular localization in these inflammatory cells is unclear. In the present study, immunogold electron microscopy revealed EC-SOD in membrane-bound vesicles of phagocytes. These findings suggest that inflammatory cell EC-SOD may have a role in antibacterial defense. To test this hypothesis, phagocytes from wild-type and EC-SOD KO mice were evaluated. Although macrophages lacking EC-SOD produced more reactive oxygen species than did cells expressing EC-SOD after stimulation, they demonstrated significantly impaired phagocytosis and killing of bacteria. Overall, this suggests that EC-SOD facilitates clearance of bacteria and limits inflammation in response to infection by promoting bacterial phagocytosis.

show abstract

Extracellular Superoxide Dismutase Inhibits Inflammation by Preventing Oxidative Fragmentation of Hyaluronan

Cited by 162 publications

References 72 publications

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Diagnostic Utility of Biomarkers in COPD

Extracellular Superoxide Dismutase in Macrophages Augments Bacterial Killing by Promoting Phagocytosis

Contact Info

Product

Resources

About