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 Szabó

    Research output: Contribution to journalArticle

    173 Scopus citations

    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
    DOIs
    StatePublished - Aug 29 2000

      Fingerprint

    Keywords

    • Gut
    • Knockout

    ASJC Scopus subject areas

    • General

    Cite this