PON1 and oxidative stress in human sepsis and an animal model of sepsis.
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.
Draganov
Dragomir
D
Head of Toxicokinetics, Metabolism Department, WIL Research Laboratories, LLC, Ashland, OH 44805, USA. ddraganov@wilresearch.com
Teiber
John
J
Watson
Catherine
C
Bisgaier
Charles
C
Nemzek
Jean
J
Remick
Daniel
D
Standiford
Theodore
T
La Du
Bert
B
D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D043303:Aryldialkylphosphatase / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D008054:Lipid Peroxides / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D018805:Sepsis / Q000097:blood* / Q000235:genetics*; D017392:Thiobarbituric Acid Reactive Substances; D013997:Time Factors
D000975:Antioxidants; D008054:Lipid Peroxides; D008075:Lipoproteins, HDL; D017392:Thiobarbituric Acid Reactive Substances; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C560867:PON1 protein, mouse