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Chapter category: Ischemia-Reperfusion
The Role of Superoxide in Acute and Chronic Inflammation
Chapter authors:
Salvatore Cuzzocrea, Daniela Salvemini
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A vast number of experimental and clinical studies implicates oxygen-derived free radi
cals (especially, superoxide and hydroxyl radical) and high energy oxidants (such as
peroxynitrite) as mediators of acute and chronic inflammation. Superoxide anion can
modulate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation,
direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde
-3phosphate dehydrogenase, inhibition of membrane sodium/potassium ATP-ase activity, inactivation
of membrane sodium channels, and other oxidative modifications of proteins. All
these toxicities are likely to play a role in the pathophysiology of inflammation. Much of the
knowledge that has been gleaned concerning the roles of superoxide anion in disease has been
gathered using the native superoxide dismutase enzyme and, more recently, by data generated
in transgenic animals that over-express the human enzyme. Although, the native enzyme has
shown promising anti-inflammatory properties in both preclinical and clinical studies, in a
variety of diseases, there were drawbacks and issues associated with the use of the native enzymes
as therapeutic agents and as pharmacological tools. Based on the concept that removal of
superoxide anion modulates the course of inflammation, we have pursued the concept of designing
synthetic, low molecular weight mimetics of the superoxide dismutase enzymes that
could overcome some of the limitations associated with the use of the native enzyme. In this
chapter we will discuss the role of superoxide anion as well as the advances made using selective
superoxide dismutase mimetics that led to the proposal that superoxide anion is a crucial mediator
of inflammation, and to the conclusion that superoxide dismutase mimetics could be
utilized as therapeutic agents in acute and chronic inflammation.
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