The aim of the current article is to overview the recent developments in the field of
hemorrhagic shock research, as it relates to the roles of
nitric oxide (NO) in the pathogenesis of this condition. The first part of the review focuses on the roles of
peroxynitrite, a reactive
oxidant produced from the reaction of NO and
superoxide. The second part of the review deals with the novel findings related to the recently identified regulatory roles of the inducible
isoform of
nitric oxide synthase (iNOS) in the expression of pro-inflammatory mediators in
hemorrhagic shock. (1) The role of
peroxynitrite: Immunohistochemical and biochemical evidence demonstrate the production of
peroxynitrite in
hemorrhagic shock.
Peroxynitrite can initiate a wide range of toxic oxidative reactions. These include initiation of
tyrosine nitration, lipid peroxidation, direct inhibition of mitochondrial respiratory chain
enzymes, inactivation of
glyceraldehyde-3-phosphate 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
hemorrhagic shock. A combined
anti-inflammatory agent,
mercaptoethylguanidine, which selectively inhibits iNOS and scavenges
peroxynitrite, prevents the delayed vascular decompensation and the cellular energetic failure associated with late
hemorrhagic shock.
Peroxynitrite is a potent trigger of
DNA single strand breakage, with subsequent activation of the nuclear
enzyme poly (ADP ribose)
synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Pharmacological inhibition of PARS, with
3-aminobenzamide or
5-iodo-6-amino-1,2-benzopyrone, improves hemodynamic status and prolongs survival time in rodent and porcine models of severe
hemorrhagic shock. (2) Novel signaling roles of induced NO in
hemorrhagic shock. Although the severity and duration of
shock may dictate the timing and extent of iNOS expression, it is now evident that the up-regulation of iNOS can take place during sustained
shock. Accumulated data indicate that iNOS expressed during
shock contributes to vascular decompensation, as classically described by Wiggers. In addition, the presence of even low levels of iNOS at the time of
resuscitation enhances the inflammatory response that follows the reperfusion state. Pharmacological inhibition of iNOS with N6-(iminoethyl)-L-lysine or genetic inactivation of iNOS (iNOS knockout mice) attenuates the activation of the
transcription factors nuclear factor kappa B (NFkappaB) and
Signal Transducer and Activator of Transcription 3 (STAT3), and ameliorates the increases in
interleukin-6 and
G-CSF messenger RNA levels in the lungs and liver. Inhibition of iNOS results in a marked reduction of lung and liver injury produced by
hemorrhagic shock. Thus, induced
nitric oxide, in addition to being a "final common mediator" of
hemorrhagic shock, is essential for the up-regulation of the inflammatory response in resuscitated
hemorrhagic shock. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of
peroxynitrite, with its associated toxicities, and indirectly through the amplification of the inflammatory response.