Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: A potential mechanism underlying adult respiratory distress syndrome

Maria Carolina Gongora, Heinrich E. Lob, Ulf Landmesser, Tomasz J. Guzik, W. David Martin, Kiyoski Ozumi, Susan M. Wall, David Scott Wilson, Niren Murthy, Michael Gravanis, Tohru Fukai, David G. Harrison

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

The extracellular superoxide dismutase 3 (SOD3) is highly expressed in both blood vessels and lungs. In different models of pulmonary injury, SOD3 is reduced; however, it is unclear whether this contributes to lung injury. To study the role of acute SOD3 reduction in lung injury, the SOD3 gene was deleted in adult mice by using the Cre-Lox technology. Acute reduction of SOD3 led to a fivefold increase in lung superoxide, marked inflammatory cell infiltration, a threefold increase in the arterial-alveolar gradient, respiratory acidosis, histological changes similar to those observed in adult respiratory distress syndrome, and 85% mortality. Treatment with the SOD mimetic MnTBAP and intranasal administration of SOD-containing polyketal microparticles reduced mortality, prevented the histological alterations, and reduced lung superoxide levels. To understand how mice with the SOD3 embryonic deletion survived without lung injury, gene array analysis was performed. These data demonstrated the up-regulation of 37 genes and down-regulation of nine genes, including those involved in cell signaling, inflammation, and gene transcription in SOD3 -/- mice compared with either mice with acute SOD3 reduction or wild-type controls. These studies show that SOD3 is essential for survival in the presence of ambient oxygen and that acute loss of this enzyme can lead to severe lung damage. Strategies either to prevent SOD3 inactivation or to augment its levels might prove useful in the treatment of acute lung injury.

Original languageEnglish (US)
Pages (from-to)915-926
Number of pages12
JournalAmerican Journal of Pathology
Volume173
Issue number4
DOIs
StatePublished - Oct 2008
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Gongora, M. C., Lob, H. E., Landmesser, U., Guzik, T. J., Martin, W. D., Ozumi, K., Wall, S. M., Wilson, D. S., Murthy, N., Gravanis, M., Fukai, T., & Harrison, D. G. (2008). Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: A potential mechanism underlying adult respiratory distress syndrome. American Journal of Pathology, 173(4), 915-926. https://doi.org/10.2353/ajpath.2008.080119