Membrane-permeable radical scavenger, tempol, reduces multiple organ injury in a rodent model of gram-positive shock.
OBJECTIVE
An enhanced formation of reactive oxygen species contributes to the multiple organ dysfunction syndrome (MODS) caused by endotoxin. We have recently discovered that two cell wall components, namely lipoteichoic acid (LTA) and peptidoglycan (PepG) of the gram-positive bacterium, Staphylococcus aureus, synergize to cause shock and MODS in the rat. Here, we investigate the effects of a membrane-permeable radical scavenger (tempol) on the circulatory failure and MODS (kidney, liver, lung) caused by coadministration of LTA (3 mg/kg i.v.) and PepG (10 mg/kg i.v.) in the anesthetized rat.


METHODS
Prospective, randomized study.


METHODS
University-based research laboratory.


METHODS
Thirty-four anesthetized, male Wistar rats.


METHODS
After surgical preparation, anesthetized rats were observed for 6 hrs. Control rats were given vehicle (control plus saline, 2 mL/kg bolus injection, followed by an infusion of 1.5 mL/kg i.v., n = 6) or tempol (control plus tempol, 100 mg/kg i.v. bolus injection, followed by an infusion of 30 mg/kg i.v., n = 6). Gram-positive septic shock was induced by coadministration of LTA (3 mg/kg i.v.) and PepG (10 mg/kg i.v.) (LTA/PepG plus saline, n = 12). Another group of rats was pretreated with tempol before shock was induced (LTA/PepG plus tempol, 100 mg/kg i.v. bolus injection, 15 mins before LTA/PepG administration, followed by an infusion of 30 mg/kg i.v., n = 10).


RESULTS
Within 6 hrs, administration of LTA/PepG resulted in hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury, and increased plasma concentrations of nitrite/nitrate. Pretreatment of rats with tempol augmented the hypotension but attenuated the renal dysfunction and the hepatocellular injury/dysfunction caused by LTA/PepG. Tempol did not affect the increase in nitrite/nitrate caused by LTA/PepG.


CONCLUSIONS
These results imply that an enhanced formation of reactive oxygen species (including superoxide anions) contributes to the kidney and liver injury and dysfunction caused by LTA/PepG in the anesthetized rat.
Zacharowski
K
K
William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, UK.
Olbrich
A
A
Cuzzocrea
S
S
Foster
S J
SJ
Thiemermann
C
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology; D009104:Multiple Trauma / Q000150:complications*; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D010457:Peptidoglycan / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D013113:Spin Labels; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D013682:Teichoic Acids / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D010457:Peptidoglycan; D013113:Spin Labels; D013682:Teichoic Acids; C002744:3-nitrotyrosine; D014443:Tyrosine; C009900:lipoteichoic acid; C001803:tempol