Year : 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

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. Cardiovascular, Pulmonary and Renal Pathology 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,* and David G. Harrison* From the Department of Medicine,* Divisions of Cardiology and Nephrology, and the Department of Pathology, Emory University School of Medicine; and the Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 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 wildtype 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. (Am J Pathol 2008, 173:915–926; DOI: 10.2353/ajpath.2008.080119) The superoxide dismutases (SODs) are major defenses against oxidative damage caused by the superoxide anion (O2 .). 1 There are three isoforms of SOD in mammalian cells. In most tissues, the copper/zinc superoxide dismutase (Cu/ZnSOD or SOD1), a cytoplasmic coppercontaining enzyme, is predominant. Mice lacking SOD1 are predisposed to hepatic fat deposition, hepatic tumor development, motor neuron disease, abnormal vascular function, and vascular hypertrophy. Manganese superoxide dismutase (MnSOD or SOD2) is localized to the mitochondria, where it plays a major role in defending against O2 . generated as a co-product of electron transport. Mice lacking MnSOD die of a cardiomyopathy within the first 10 days of life. The last discovered of the SOD isoforms is extracellular superoxide dismutase, or SOD3. SOD3 is similar to SOD1 in that it is a copper/zinccontaining enzyme; however, it contains a signal seSupported by National Institutes of Health grants HL390006, HL59248, and R21 EB006418; National Institutes of Health Program Project grant HL58000; Nanotechnology Center grant UO1 HL80711-01; a Department of Veterans Affairs merit grant; Georgia Tech/Emory Center for the Engineering of Living Tissues funded by the National Science Foundation grant EEC-9731643; and National Science Foundation Career Award