Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase

Lucas Liaudet, Francisco Garcia Soriano, Éva Szabó, László Virág, Jon G. Mabley, Andrew L. Salzman, Csaba Szabo

Research output: Contribution to journalArticle

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Abstract

Hemorrhagic shock (HS) and resuscitation leads to widespread production of oxidant species. Activation of the enzyme poly(ADP-ribose) polymerase (PARP) has been shown to contribute to cell necrosis and organ failure in various disease conditions associated with oxidative stress. We tested the hypothesis whether PARP activation plays a role in the multiple organ dysfunction complicating HS and resuscitation in a murine model of HS and resuscitation by using mice genetically deficient in PARP (PARP(-/-)) and their wild-type littermates (PARP(+/+)). Animals were bled to a mean blood pressure of 45 mmHg (1 mmHg = 133 Pa) and resuscitated after 45 min with isotonic saline (2x volume of shed blood). There was a massive activation of PARP, detected by poly(ADP-ribose) immunohistochemistry, which localized to the areas of the most severe intestinal injury, i.e., the necrotic epithelial cells at the tip of the intestinal villi, and colocalized with tyrosine nitration, an index of peroxynitrite generation. Intestinal PARP activation resulted in gut hyperpermeability, which developed in PARP(+/+) but not PARP(-/-) mice. PARP(-/-) mice were also protected from the rapid decrease in blood pressure after resuscitation and showed an increased survival time, as well as reduced lung neutrophil sequestration. The beneficial effects of PARP suppression were not related to a modulation of the NO pathway nor to a modulation of signaling through IL-6, which similarly increased in both PARP(+/+) and PARP(-/-) mice exposed to HS. We propose that PARP activation and associated cell injury (necrosis) plays a crucial role in the intestinal injury, cardiovascular failure, and multiple organ damage associated with resuscitated HS.

Original languageEnglish (US)
Pages (from-to)10203-10208
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number18
StatePublished - Aug 29 2000
Externally publishedYes

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Poly(ADP-ribose) Polymerases
Hemorrhagic Shock
Resuscitation
Wounds and Injuries
Necrosis
Poly Adenosine Diphosphate Ribose
Blood Pressure
Peroxynitrous Acid
Enzyme Activation
Multiple Organ Failure
Blood Volume
Oxidants
Tyrosine
Interleukin-6
Oxidative Stress
Neutrophils

Keywords

  • Gut
  • Knockout

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Liaudet, L., Soriano, F. G., Szabó, É., Virág, L., Mabley, J. G., Salzman, A. L., & Szabo, C. (2000). Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase. Proceedings of the National Academy of Sciences of the United States of America, 97(18), 10203-10208.

Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase. / Liaudet, Lucas; Soriano, Francisco Garcia; Szabó, Éva; Virág, László; Mabley, Jon G.; Salzman, Andrew L.; Szabo, Csaba.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 18, 29.08.2000, p. 10203-10208.

Research output: Contribution to journalArticle

Liaudet, L, Soriano, FG, Szabó, É, Virág, L, Mabley, JG, Salzman, AL & Szabo, C 2000, 'Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase', Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 18, pp. 10203-10208.
Liaudet, Lucas ; Soriano, Francisco Garcia ; Szabó, Éva ; Virág, László ; Mabley, Jon G. ; Salzman, Andrew L. ; Szabo, Csaba. / Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase. In: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; Vol. 97, No. 18. pp. 10203-10208.
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