Extracellular Superoxide Dismutase Attenuates Lipopolysaccharide-Induced Neutrophilic Inflammation

Abstract

Extracellular superoxide dismutase (EC-SOD) is an abundant antioxidant in the lung and vascular walls. Previous studies have shown that EC-SOD attenuates lung injury in a diverse variety of lung injury models. In this study, we examined the role of EC-SOD in mediating lipopolysaccharide (LPS)-induced lung inflammation. We found that LPS-induced neutrophilic lung inflammation was exaggerated in EC-SOD-deficient mice and diminished in mice that overexpressed EC-SOD specifically in the lung. Similar patterns were seen for bronchoalveolar lavage cytokines, such as tumor necrosis factor-alpha, keratinocyte-derived chemokines, and macrophage inflammatory protein-2 as well as expression of lung intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial cell selectin, and platelet selectin. In a macrophage cell line, EC-SOD inhibited LPS-induced macrophage cytokine release, but did not alter expression of intercellular adhesion molecules in endothelial cells. These results suggest that EC-SOD plays an important role in attenuating the inflammatory response in the lung most likely by decreasing release of proinflammatory cytokines from phagocytes.

Extracellular Superoxide Dismutase in Macrophages Augments Bacterial Killing by Promoting Phagocytosis

“…Specifically, EC-SOD attenuates lipopolysaccharide-induced inflammation in the lung by decreasing proinflammatory cytokine release from phagocytes. 18 Similarly, the antioxidant N-acetylcysteine modulates the macrophage phagocytic response to endotoxin by decreasing the production of ROS and the release of the proinflammatory cytokine tumor necrosis factor-␣. 38,39 This effect was found to be potentially due to its ability to undergo cellular uptake and, therefore, to influence the oxidant-induced intracellular signal transduction activity in the phagocyte.…”

“…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.…”

Atividade antioxidante de macrófagos alveolares em ratos endotoxêmicos

“…Uma vez que os macrófagos estão normalmente presentes nos tecidos, a maioria dos neutrófilos em resposta à endotoxina migra do sangue para o pulmão (Sunil et al 2002). Os resultados do presente estudo estão de acordo com Bowler et al (2004), que demonstraram aumento de neutrófilos em LBA tanto em valores absolutos quanto relativos. Estudo realizado por Sunil et al (2002) demonstrou que o número de neutrófilos aderentes à vasculatura pulmonar aumentou na endotoxemia aguda em ratos da linhagem Wistar.…”

“…Contudo, houve uma tendência a valores mais elevados após administração de LPS. Tal fato é relevante uma vez que estudos prévios sugerem que a SOD atenua a injúria pulmonar em vários modelos experimentais (Bowler et al 2004). De acordo com alguns autores (Cox et al 1995, Bowler et al 2004), a SOD pode modular a inflamação atenuando a liberação de citocinas pró-inflamatórias por MA, que recrutam os neutrófilos para o pulmão.…”

“…Apesar da indução de resposta inflamatória pulmonar, o presente trabalho, diferentemente de outros (Bowler et al 2003, Bowler et al 2004, não demonstrou deficiência na atividade da SOD relacionada a este processo inflamatório. Esses resultados sugerem que neste sítio inflamatório/infeccioso, o pulmão, a SOD não modula a inflamação mesmo sem apresentar atividade reduzida.…”