The intense systemic inflammatory response characterizing
septic shock is associated with an increased generation of
free radicals by multiple cell types in cardiovascular and non cardiovascular tissues. The
oxygen-centered radical
superoxide anion (O2 .-) rapidly reacts with the
nitrogen-centered radical
nitric oxide (NO.) to form the potent
oxidant species
peroxynitrite.
Peroxynitrite oxidizes multiple targets molecules, either directly or via the secondary generation of highly reactive radicals, resulting in significant alterations in
lipids,
proteins and
nucleic acids, with significant cytotoxic consequences. The formation of
peroxynitrite is a key pathophysiological mechanism contributing to the cardiovascular collapse of
septic shock, promoting vascular contractile failure, endothelial and myocardial dysfunction, and is also implicated in the occurrence of multiple organ dysfunction in this setting. The recent development of various
porphyrin-based pharmacological compounds accelerating the degradation of
peroxynitrite has allowed to specifically address these pathophysiological roles of
peroxynitrite in experimental
septic shock. Such agents, including 5,10,15,20-tetrakis(4- sulfonatophenyl)porphyrinato
iron III
chloride (FeTTPs),
manganese tetrakis(4-N-methylpyridyl)porphyrin (
MnTMPyP), Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl
porphyrin) (FP-15) and WW-85, have been shown to improve the cardiovascular and
multiple organ failure in small and large animal models of
septic shock. Therefore, these findings support the development of
peroxynitrite decomposition catalysts as potentially useful novel therapeutic agents to restore cardiovascular function in
sepsis.