Activation of poly(ADP-ribose) polymerase in severe hemorrhagic shock and resuscitation

John A. Watts, Robert M. Grattan, Bradley S. Whitlow, Jeffrey A. Kline

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

This study examines activation of poly(ADP-ribose) polymerase (PARP) in the ileum during hemorrhage and resuscitation and determines if inhibition of PARP reduces organ dysfunction and metabolic acidosis. Awake, nonheparinized rats were hemorrhaged (40 mmHg, 60 min). Resuscitation used Ringer's solution (21/3 × shed volume) and packed red blood cells (2/3 shed volume). Ileal PARP activity was elevated at the end of hemorrhage (3.6-fold) and 10 min of resuscitation (5-fold). The subsequent decline in PARP activity observed after 60 min of resuscitation was not due to cleavage by caspase-3. Ileum permeability increased 10-fold and circulating liver enzymes increased 4- to 6-fold following 60 min of resuscitation in animals pretreated with 3-aminobenzoic acid, a structural analog that does not inhibit PARP. Pretreatment with 3-aminobenzamide (3-AB), a PARP inhibitor, reduced these changes, whereas posttreatment with a bolus of 3-AB was ineffective. Metabolic acidosis, accumulation of lactate, and base deficit was reduced by pretreatment with 3-AB. PARP is activated in the ileum by hemorrhage and by resuscitation. Activation of PARP contributes to organ dysfunction in the ileum and liver and appears to be central to the development of metabolic acidosis.

Original languageEnglish (US)
Pages (from-to)G498-G506
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume281
Issue number2 44-2
StatePublished - Aug 27 2001
Externally publishedYes

Keywords

  • 3-Aminobenzamide
  • Caspase
  • Gut permeability
  • Ileum
  • Multiorgan failure

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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