Causal role of oxidative stress in liver preconditioning by thyroid hormone in rats.
Hepatic ischemia-reperfusion (IR) injury, a major clinical drawback during surgery, is abolished by L-3,3',5-triiodothyronine (T(3)) administration. Considering that the triggering mechanisms are unknown, the aim of this study is to assess the role of oxidative stress in T(3) preconditioning using N-acetylcysteine (NAC) before T(3) administration. Male Sprague-Dawley rats given a single dose of 0.1 mg of T(3)/kg were subjected to 1 h ischemia followed by 20 h reperfusion, in groups of animals pretreated with 0.5 g of NAC/kg 0.5 h before T(3) or with the respective control vehicles. At the end of the reperfusion period, blood and liver samples were taken for analysis of serum aspartate aminotransferase (AST) and hepatic histology, glutathione (GSH) and protein carbonyl contents, and nuclear factor-kappaB (NF-kappaB) and activating protein 1 (AP-1) DNA binding. The IR protocol used led to a 4.5-fold increase in serum AST levels and drastic changes in liver histology, with significant GSH depletion and enhancement of protein carbonyl levels and of the protein carbonyl/GSH content ratio, whereas NF-kappaB and AP-1 DNA binding was decreased and enhanced, respectively. In a time window of 48 h, T(3) exerted protection against hepatic IR injury, with 88% reduction in the protein carbonyl/GSH ratio and normalization of NF-kappaB and AP-1 DNA binding, changes that were suppressed by NAC administration before T(3). Data presented suggest that a transient increase in the oxidative stress status of the liver is an important trigger for T(3) preconditioning, evidenced in a warm IR injury model through antioxidant intervention.
Fernández
Virginia
V
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 70000, Chile.
Tapia
Gladys
G
Varela
Patricia
P
Gaete
Leonardo
L
Vera
Gemma
G
Mora
Catalina
C
Vial
María T
MT
Videla
Luis A
LA
D000111:Acetylcysteine / Q000097:blood / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019194:Ischemic Preconditioning; D008099:Liver / Q000473:pathology*; D008297:Male; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury; D013963:Thyroid Hormones / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism
D016328:NF-kappa B; D013963:Thyroid Hormones; D014284:Triiodothyronine; D001219:Aspartate Aminotransferases; D005978:Glutathione; D000111:Acetylcysteine