Abstract
Sepsis is the leading cause of death in critically ill patients. The pathophysiological mechanisms implicated in the development of sepsis and organ failure are complex and involve activation of systemic inflammatory response and coagulation together with endothelial dysfunction. Oxidative stress is a major promoter and mediator of the systemic inflammatory response. Serum PON1 has been demonstrated in multiple clinical and animal studies to protect against oxidative stress, but also to undergo inactivation upon that condition. We found decreased plasma PON1 activity in patients with sepsis compared to healthy controls or critically ill patients without sepsis; furthermore, in sepsis patients PON1 activity was lower and remained lower in the course of sepsis in the non-survivors compared to the survivors. Plasma PON1 activity was positively correlated with high-density lipoprotein cholesterol and negatively correlated with markers of lipid peroxidation. In an experimental animal model of sepsis, murine cecal ligation and puncture, the time course of plasma PON1 activity was very similar to that found in sepsis patients. Persistently low PON1 activity in plasma was associated with lethal outcome in human and murine sepsis.
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Abbreviations
- ArE:
-
arylesterase activity
- G:
-
(needle size) gauge
- HDL:
-
high-density lipoprotein
- ICU:
-
Intensive Care Unit
- IL-6:
-
interleukin-6
- LPO:
-
lipid peroxides
- RNS:
-
reactive nitrogen species
- ROS:
-
reactive oxygen species
- SIRS:
-
systemic inflammatory response
- TAA:
-
total antioxidant activity
- TBARS:
-
thiobarbituric acid reacting substances
References
Abraham E, Singer M (2007) Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 35:2408–2416
Aviram M, Rosenblat M. (2004) Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. Free Radic Biol Med 37:1304–1316
Aviram M, Rosenblat M. (2005) Paraoxonases and cardiovascular diseases: pharmacological and nutritional influences. Curr Opin Lipidol 16:393–399
Berger M, Chiolero RL (2007) Antioxidant supplementation in sepsis and systemic inflammatory response syndrome. Crit Care Med 35(Suppl):584–590
Chien J-Y, Jerng J-S, Yu C-J et al. (2005) Low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis. Crit Care Med 33:1688–1693
Costa LG, Vitalone A, Cole TB et al. (2005) Modulation of paraoxonase (PON1) activity. Biochem Pharmacol 69:541–550
De Backer D (2007) Benefit-risk assessment of drotrecogin alfa (activated) in the treatment of sepsis. Drug Saf 30:995–1010
Draganov DI, Teiber JF, Billecke SS et al. (2008) Serum paraoxonase (PON1) and apolipoprotein A-I (apoA-I) are reduced in critically ill patients with sepsis. Manuscript in preparation.
Goode HF, Cowley HC, Walker BE et al. (1995) Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med 23:646–651
Gordon BR, Parker TS, Levine DM et al. (1996) Low lipid concentrations in critically illness: implications for preventing and treating endotoximia. Crit Care Med 24:584–589
Gordon BR, Parker TS, Levine DM et al. (2001) Relationship of hypolipidemia in cytokine concentrations and outcome in critically ill surgical patients. Crit Care Med 29:1563–1568
Martin GS, Mannino DM, Eaton S et al. (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546–1554
James RW, Deakin SP (2004) The importance of high-density lipoproteins for paraoxonase-1 secretion, stability, and activity. Free Radic Biol Med 15:1986–1994
Navab M, Yu R, Gharavi N, Huang W et al. (2007) High-density lipoprotein: antioxidant and anti-inflammatory properties. Curr Atheroscler Rep 9:244–248
Ng CJ, Shih DM, Hama SY et al. (2005) The paraoxonase gene family and atherosclerosis. Free Radic Biol Med 38:153–163
Remick DG, Newcomb DE, Bolgos GL et al. (2000) Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysacharide vs. cecal ligation and puncture. Shock 13:110–116
Remick DG, Bolgos GR, Siddiqui J et al. (2002) Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock 17:463–467
Van Leeuwen HJ, Heezius EC, Dallinga GM et al. (2003) Lipoprotein metabolism in patients with severe sepsis. Crit Care Med 31:1359–1366
Wu A, Hinds CJ, Thiemermann C (2004) High-density lipoproteins in sepsis and septic shock: metabolism, actions, and therapeutic applications. Shock 21:210–221
Acknowledgments
The contribution of Scott Billecke, Audrey Speelman, Gerry Bolgos, Dennis Cooperson, Michael Newsteadt (University of Michigan), Kristin Sass and Sandra Drake (Esperion Therapeutics) is gratefully acknowledged. This work was supported by Michigan Life Sciences Corridor Fund No. 001796.
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Draganov, D. et al. (2010). PON1 and Oxidative Stress in Human Sepsis and an Animal Model of Sepsis. In: Reddy, S. (eds) Paraoxonases in Inflammation, Infection, and Toxicology. Advances in Experimental Medicine and Biology, vol 660. Humana Press. https://doi.org/10.1007/978-1-60761-350-3_9
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DOI: https://doi.org/10.1007/978-1-60761-350-3_9
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