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

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 variou s disease conditions associated with oxidative stress. We tested the hypoth esis whether PARP activation plays a role in the multiple organ dysfunction complicating HS and resuscitation in a murine model of HS and resuscitatio n by using mice genetically deficient in PARP (PARP(-/-)) and their wild-ty pe littermates (PARP(+/+)). Animals were bled to a mean blood pressure of 4 5 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, detecte d 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, a n 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 press ure after resuscitation and showed an increased survival time, as well as r educed lung neutrophil sequestration. The beneficial effects of PARP suppre ssion were not related to a modulation of the NO pathway nor to a modulatio n of signaling through IL-6, which similarly increased in both PARP(+/+) an d PARP(-/-) mice exposed to HS, We propose that PARP activation and associa ted cell injury (necrosis) plays a crucial role in the intestinal injury, c ardiovascular failure, and multiple organ damage associated with resuscitat ed HS.