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Am J Physiol Lung Cell Mol Physiol (January 10, 2003). doi:10.1152/ajplung.00374.2002
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Submitted on November 1, 2002
Accepted on December 11, 2002

Synthesis and Anti-inflammatory Activity of a Chimeric Recombinant Superoxide Dismutase: SOD2/3

Bifeng Gao1, Sonia C. Flores1, Jonathan A. Leff2, Swapan K. Bose1, and Joe M. McCord1*

1 Webb-Waring Institute, University of Colorado Health Sciences Center, Denver, CO, USA
2 Webb-Waring Institute, University of Colorado Health Sciences Center, Denver, CO, USA; Amgen, Inc., Thousand Oaks, CA, USA

* To whom correspondence should be addressed. E-mail: joe.mccord{at}uchsc.edu.

External surfaces of cells are normally protected by extracellular superoxide dismutase, SOD3, which binds to polyanions such as heparan sulfate. We constructed a fusion gene encoding a chimeric SOD consisting of the mature human mitochondrial SOD2 plus the carboxyl-terminal 26-amino acid heparin-binding "tail" from SOD3. This "tail" is responsible for the enzyme's affinity for endothelial surfaces. The fusion gene was expressed in Escherichia coli and the fully active enzyme, SOD2/3, was purified. While native SOD2 has no affinity for heparin, SOD2/3 binds to a heparin-agarose column. In a rat model of acute lung injury induced by intratracheal instillation of IL-1, SOD2/3, SOD2 and denatured SOD2/3 showed 92%, 13.8% and 0% reduction of lung leak, respectively. Only SOD2/3 prevented neutrophil accumulation. In the carrageenan-induced foot edema model in the rat, SOD2/3 reduced edema by 62% (p < 0.003) at a dose where native SOD2 produced no significant effect. Thus, SOD2/3 appears to have properties as a therapeutic anti-inflammatory agent that are greatly superior to other available forms of the enzyme.




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