Novel roles of nitric oxide in hemorrhagic shock

Csaba Szabo, Timothy R. Billiar

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

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 (NFκB) 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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalShock
Volume12
Issue number1
StatePublished - Jul 1999
Externally publishedYes

Fingerprint

Hemorrhagic Shock
Nitric Oxide Synthase
Peroxynitrous Acid
Nitric Oxide
Protein Isoforms
Poly Adenosine Diphosphate Ribose
Shock
Ligases
Blood Vessels
Up-Regulation
Pharmacology
STAT3 Transcription Factor
Glyceraldehyde-3-Phosphate Dehydrogenases
Enzyme Activation
NF-kappa B
Sodium Channels
Poisons
Liver
Lung Injury
Nitric Oxide Synthase Type II

Keywords

  • Cytokines
  • Endotoxin
  • Gene expression
  • Hemorrhage
  • Inducible nitric oxide synthase
  • Interleukin
  • Nitric oxide
  • Peroxynitrite
  • Poly (ADP-ribose) synthetase
  • Sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Physiology

Cite this

Szabo, C., & Billiar, T. R. (1999). Novel roles of nitric oxide in hemorrhagic shock. Shock, 12(1), 1-9.

Novel roles of nitric oxide in hemorrhagic shock. / Szabo, Csaba; Billiar, Timothy R.

In: Shock, Vol. 12, No. 1, 07.1999, p. 1-9.

Research output: Contribution to journalArticle

Szabo, C & Billiar, TR 1999, 'Novel roles of nitric oxide in hemorrhagic shock', Shock, vol. 12, no. 1, pp. 1-9.
Szabo, Csaba ; Billiar, Timothy R. / Novel roles of nitric oxide in hemorrhagic shock. In: Shock. 1999 ; Vol. 12, No. 1. pp. 1-9.
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KW - Peroxynitrite

KW - Poly (ADP-ribose) synthetase

KW - Sepsis

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