Role of poly(adenosine diphosphate-ribose) polymerase 1 in septic peritonitis.
Peritonitis generally results from gastrointestinal perforation, with systemic sepsis developing over hours or days from an initially localized nidus of infection. The consecutive inflammatory response induces the widespread generation of oxidants and free radicals, which are potent inducers of breaks and nicks in double-stranded DNA. This genetic damage triggers the activation of the nuclear enzyme poly(ADP-ribose) polymerase 1, which, in turn, cleaves the respiratory coenzyme nicotinamide adenine dinucleotide into nicotinamide and ADP ribose. The consecutive decrease in cellular nicotinamide adenine dinucleotide inhibits glycolysis and mitochondrial respiration, leading to cellular energy collapse and necrotic cell death. In parallel, poly(ADP-ribose) polymerase 1 positively regulates inflammatory signal transduction pathways through a functional association with the transcription factor nuclear factor kappaB, resulting in a progressive amplification of local inflammation. Recent data indicate that these molecular mechanisms are instrumental in the development of cardiovascular collapse and multiple organ dysfunction in sepsis, supporting the view that pharmacologic inhibitors of poly(ADP-ribose) polymerase 1 may represent useful tools for the treatment of this condition.
Liaudet
Lucas
L
Critical Care Division, Department of Internal Medicine, University Hospital, Lausanne, Switzerland. Lucas.Liaudet@chuv.hospvd.ch
Oddo
Mauro
M
D000818:Animals; D004249:DNA Damage; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D009102:Multiple Organ Failure / Q000378:metabolism; D010538:Peritonitis / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism*
D011065:Poly(ADP-ribose) Polymerases