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.
Gongora
Maria Carolina
MC
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Lob
Heinrich E
HE
Landmesser
Ulf
U
Guzik
Tomasz J
TJ
Martin
W David
WD
Ozumi
Kiyoski
K
Wall
Susan M
SM
Wilson
David Scott
DS
Murthy
Niren
N
Gravanis
Michael
M
Fukai
Tohru
T
Harrison
David G
DG
D000388:Air; D000818:Animals; D001011:Aorta / Q000473:pathology; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology*; D017353:Gene Deletion; D006334:Heart Function Tests; D006801:Humans; D007249:Inflammation; D019426:Integrases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012128:Respiratory Distress Syndrome / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000172:deficiency* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D016019:Survival Analysis; D013629:Tamoxifen / Q000494:pharmacology
D008665:Metalloporphyrins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D013629:Tamoxifen; D013481:Superoxides; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; C045073:Cre recombinase; D019426:Integrases
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