Increased sensitivity to asbestos-induced lung injury in mice lacking extracellular superoxide dismutase

Fattman, Cheryl L.; Tan, Roderick J.; Tobolewski, Jacob M.; Oury, Tim D.

doi:10.1016/j.freeradbiomed.2005.09.030

Cited by 86 publications

(76 citation statements)

References 43 publications

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“…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: 92%

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

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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....

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Section: Discussionsupporting

confidence: 92%

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

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“…These results are consistent with those of previous studies that demonstrated that EC-SOD expression in the lung inhibits inflammation in response to a wide variety of pulmonary injuries. [11][12][13]19 …”

Section: Ec-sod Limits Inflammation After E Coli Inoculationmentioning

confidence: 99%

“…7 This isozyme of the superoxide dismutase family is highly expressed in the lung and arteries and is bound to the extracellular matrix via its positively charged heparin/matrix-binding domain. [7][8][9][10] EC-SOD acts as both an anti-inflammatory and antifibrotic agent in a number of pulmonary diseases including bleomycin-and asbestos-induced pulmonary fibrosis, [11][12][13][14] hyperoxia, [15][16][17] lipopolysaccharide-induced inflammation, 18 and pulmonary infection. 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.…”

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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Extracellular Superoxide Dismutase in Macrophages Augments Bacterial Killing by Promoting Phagocytosis

Manni

Tomai

Norris

et al. 2011

The American Journal of Pathology

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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.

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“…Because apoptosis alone does not elicit autoimmunity, a second pro-inflammatory signal such as an adjuvant must be provided in order to generate an immune response (Bondanza et al 2004;Mevorach et al 1998;Tzeng et al 2006). Asbestos induces a highly inflammatory state in the lung (Fattman et al 2006;Kamp and Weitzman 1999;Tan et al 2004). Moreover, exposure to amphibole asbestos in alveolar macrophages has been previously shown to increase the release of proinflammatory cytokines such as TNF-α and IL-1 (Driscoll et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Autoantibodies from mice exposed to Libby amphibole asbestos bind SSA/Ro52-enriched apoptotic blebs of murine macrophages

2008

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Asbestos exposure is associated with increased autoimmune responses in humans. For example, in Libby, MT where significant asbestos exposure has occurred due to an asbestos contaminated vermiculite mine near the community, residents have developed increased autoimmune responses compared to an unexposed population. However, the exact mechanism by which Libby amphibole asbestos generates autoimmune responses is unclear. A murine model of amphibole asbestos-induced autoimmunity was recently established, and one of the targets of the autoantibodies was the SSA/ Ro52 autoantigen. The purpose of this study was to determine whether the SSA/Ro52 autoantigen is exposed at the surface of cells as a result of asbestos exposure as a possible mechanism leading to antigenicity. Our results indicate that Libby asbestos induces apoptosis in murine macrophages as determined by phosphatidylserine exposure, cleavage of poly (ADP-ribose) polymerase and morphological changes such as nuclear condensation. Moreover, asbestos induced apoptosis results in the formation of apoptotic cell surface blebs enriched in SSA/Ro52 as determined by confocal microscopy. Most importantly, apoptotic cell surface blebs are recognized by autoantibodies from mice exposed to amphibole asbestos suggesting that these cell surface structures may be antigenic when presented in a pro-inflammatory context. This study supports the hypothesis that the induction of apoptosis plays a key role in environmentally-induced autoimmunity through cell surface exposure of a known autoantigen.

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Increased sensitivity to asbestos-induced lung injury in mice lacking extracellular superoxide dismutase

Cited by 86 publications

References 43 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

Extracellular Superoxide Dismutase in Macrophages Augments Bacterial Killing by Promoting Phagocytosis

Autoantibodies from mice exposed to Libby amphibole asbestos bind SSA/Ro52-enriched apoptotic blebs of murine macrophages

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