title: Excessive liver oxidant stress causes mortality in response to burn injury combined with endotoxin and is prevented with antioxidants.
abstract: We studied the effect of the oral administration of a water-soluble antioxidant solution containing ascorbic acid, glutathione, and a precursor for glutathione synthesis, N-Acetyl-L-cysteine, on liver antioxidant activity, liver cell energetics, and mortality in rats in response to a 20% third-degree burn injury challenged 5 days later with an intraperitoneal injection of 30 mg/kg endotoxin. Rats with burns were fluid-resuscitated with subcutaneous Ringer's lactate solution according to the Parkland formula (4 cc/kg/%burn). Rats challenged with endotoxin 5 days after burn were given an additional 100 ml/kg of subcutaneous Ringer's lactate solution immediately after the injection of endotoxin. A group of rats with burns challenged with endotoxin 5 days after burn were given an oral antioxidant solution beginning after burn injury. Liver cell energetics were measured as tissue energy charge potential (ECP), adenosine triphosphate (ATP) content, and total adenine nucleotides. The levels of endogenous liver glutathione, catalase, vitamin C, and vitamin E were measured to monitor antioxidant status. We found that burn injury alone did not produce any mortality over the 6-day period despite a 35% decrease in liver energy charge potential resulting from a decrease in ATP, a 34% decrease in liver catalase activity, and a 20% decrease in liver vitamin C. It was interesting that glutathione increased and vitamin E remained unchanged. We found that endotoxin injury combined with burn injury produced a 61% mortality rate with a 63% decrease in liver energy charge potential, again resulting from a decrease in ATP, a 74% decrease in liver catalase activity, a 16% decrease in vitamin C, and a 29% decrease in vitamin E. Glutathione was significantly decreased compared with burn alone. We compared the liver antioxidant status of survivors with that of nonsurvivors who were killed when appearing moribund and found that glutathione was decreased by 51% and vitamin C by 73% in nonsurvivors over that in survivors, whereas catalase and vitamin E levels were comparable between the two groups. The oral administration of the antioxidants prevented mortality and the decrease in antioxidant activity and attenuated the decrease in energy charge potential. We conclude that a 20% burn produces a modest decrease in liver energy charge potential and antioxidant defenses without producing mortality. The addition of endotoxin further decreases liver antioxidant defenses, liver energy charge potential, and markedly increases mortality. Antioxidants, given post-burn, restored antioxidant defenses, attenuated the altered cell energetics, and prevented mortality, indicating oxidants to be the cause of mortality. This data also suggests that a critical value of decreases in antioxidant defenses and ATP exists, resulting in mortality.
authors.affiliation: Brigham & Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: C
authors.initials: C
authors.lastname: LaLonde
authors.forename: U
authors.initials: U
authors.lastname: Nayak
authors.forename: J
authors.initials: J
authors.lastname: Hennigan
authors.forename: R H
authors.initials: RH
authors.lastname: Demling
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D000227:Adenine Nucleotides / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000378:metabolism / Q000627:therapeutic use; D002056:Burns / Q000150:complications* / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D019446:Endotoxemia / Q000150:complications* / Q000378:metabolism*; D004734:Energy Metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000378:metabolism
chemical_list: D000227:Adenine Nucleotides; D000975:Antioxidants; D014810:Vitamin E; D000255:Adenosine Triphosphate; D002374:Catalase; D005978:Glutathione; D001205:Ascorbic Acid; D000111:Acetylcysteine