Chapter 7. Poly (ADP-Ribose) Polymerase Activation and Circulatory Shock

  1. Derek J. Chadwick Organizer and
  2. Jamie Goode
  1. Csaba Szabó

Published Online: 7 OCT 2008

DOI: 10.1002/9780470059593.ch7

Sepsis: New Insights, New Therapies: Novartis Foundation Symposium 280

Sepsis: New Insights, New Therapies: Novartis Foundation Symposium 280

How to Cite

Szabó, C. (2006) Poly (ADP-Ribose) Polymerase Activation and Circulatory Shock, in Sepsis: New Insights, New Therapies: Novartis Foundation Symposium 280 (eds D. J. Chadwick and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470059593.ch7

Author Information

  1. Department of Surgery, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, University Heights, Newark, NJ 07103-2714, USA

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 26 JAN 2006

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470027981

Online ISBN: 9780470059593

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Keywords:

  • sepsis;
  • nitric oxide;
  • superoxide;
  • peroxynitrite

Summary

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.