TY - JOUR
T1 - Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air
T2 - A potential mechanism underlying adult respiratory distress syndrome
AU - Gongora, Maria Carolina
AU - Lob, Heinrich E.
AU - Landmesser, Ulf
AU - Guzik, Tomasz J.
AU - Martin, W. David
AU - Ozumi, Kiyoski
AU - Wall, Susan M.
AU - Wilson, David Scott
AU - Murthy, Niren
AU - Gravanis, Michael
AU - Fukai, Tohru
AU - Harrison, David G.
N1 - Funding Information:
Supported 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 BES-0546962 .
PY - 2008/10
Y1 - 2008/10
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2008.080119
DO - 10.2353/ajpath.2008.080119
M3 - Article
C2 - 18787098
AN - SCOPUS:53149108208
SN - 0002-9440
VL - 173
SP - 915
EP - 926
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -