Poly (ADP-Ribose) Polymerase Activation and Circulatory Shock

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Sepsis is associated with increased production of reactive oxidant species. Oxidative and nitrosative stress can lead to activation of the nuclear enzyme poly (ADPribose) polymerase (PARP), with subsequent loss of cellular functions. Activation of PARP may dramatically lower the intracellular concentration of its substrate, NAD thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. This process can result in cell dysfunction and cell death. In addition, PARP enhances the expression of various pro-inflammatory mediators, via activation of NF-κB, MAP kinase and AP-1 and other signal transduction pathways. Preclinical studies in various rodent and large animal models demonstrate that PARP inhibition or PAR deficiency exerts beneficial effects on the haemodynamic and metabolic alterations associated with septic and haemorrhagic shock. Recent human data also support the role of PARP in septic shock: In a retrospective study in 25 septic patients, an increase in plasma troponin level was related to increased mortality risk. In patients who died, significant myocardial damage was detected, and histological analysis of heart showed inflammatory infiltration, increased collagen deposition, and derangement of mitochondrial criptae. Immunohistochemical staining for poly(ADP-ribose) (PAR), the product of activated PARP was demonstrated in septic hearts. There was a positive correlation between PAR staining and troponin I; and a correlation of PAR staining and LVSSW. Thus, there is significant PARP activation in animal models subjected to circulatory shock, as well as in the hearts of septic patients. Based on the interventional studies in animals and the correlations observed in patients we propose that PARP activation may be, in part responsible for the cardiac depression and haemodynamic failure seen in humans with severe sepsis. Interestingly, recent studies reveal that the protective effects of PARP inhibitors are predominant in male animals, and are not apparent in female animals. Oestrogen, by providing a baseline inhibitory effect on PARP activation, may be partially responsible for this gender difference.

Original languageEnglish (US)
Title of host publicationSepsis
Subtitle of host publicationNew Insights, New Therapies
Publisherwiley
Pages92-103
Number of pages12
Volume280
ISBN (Electronic)9780470059593
ISBN (Print)0470027983, 9780470027981
DOIs
StatePublished - Oct 7 2008
Externally publishedYes

Fingerprint

Poly(ADP-ribose) Polymerases
Shock
Staining and Labeling
Septic Shock
Sepsis
Animal Models
Hemodynamics
Poly Adenosine Diphosphate Ribose
Troponin
Enzyme Activation
Troponin I
Hemorrhagic Shock
Transcription Factor AP-1
Glycolysis
Electron Transport
Oxidants
NAD
Rodentia
Signal Transduction
Estrogens

Keywords

  • Nitric oxide
  • Peroxynitrite
  • Sepsis
  • Superoxide

ASJC Scopus subject areas

  • Medicine(all)
  • Immunology and Microbiology(all)

Cite this

Szabo, C. (2008). Poly (ADP-Ribose) Polymerase Activation and Circulatory Shock. In Sepsis: New Insights, New Therapies (Vol. 280, pp. 92-103). wiley. https://doi.org/10.1002/9780470059593.ch7

Poly (ADP-Ribose) Polymerase Activation and Circulatory Shock. / Szabo, Csaba.

Sepsis: New Insights, New Therapies. Vol. 280 wiley, 2008. p. 92-103.

Research output: Chapter in Book/Report/Conference proceedingChapter

Szabo, C 2008, Poly (ADP-Ribose) Polymerase Activation and Circulatory Shock. in Sepsis: New Insights, New Therapies. vol. 280, wiley, pp. 92-103. https://doi.org/10.1002/9780470059593.ch7
Szabo C. Poly (ADP-Ribose) Polymerase Activation and Circulatory Shock. In Sepsis: New Insights, New Therapies. Vol. 280. wiley. 2008. p. 92-103 https://doi.org/10.1002/9780470059593.ch7
Szabo, Csaba. / Poly (ADP-Ribose) Polymerase Activation and Circulatory Shock. Sepsis: New Insights, New Therapies. Vol. 280 wiley, 2008. pp. 92-103
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