Thyroid hormone preconditioning: protection against ischemia-reperfusion liver injury in the rat.
Recently, we reported that oxidative stress due to 3,3',5-triiodothyronine (T(3))-induced calorigenesis up-regulates the hepatic expression of mediators promoting cell protection. In this study, T(3) administration in rats (single dose of 0.1 mg/kg intraperitoneally) induced significant depletion of reduced liver glutathione (GSH), with higher protein oxidation, O(2) consumption, and Kupffer cell function (carbon phagocytosis and carbon-induced O(2) uptake). These changes occurred within a period of 36 hours of T(3) treatment in animals showing normal liver histology and lack of alteration in serum AST and ALT levels. Partial hepatic ischemia-reperfusion (IR) (1 h of ischemia via vascular clamping and 20 h reperfusion) led to 11-fold and 42-fold increases in serum AST and ALT levels, respectively, and significant changes in liver histology, with a 36% decrease in liver GSH content and a 133% increase in that of protein carbonyls. T(3) administration in a time window of 48 hours was substantially protective against hepatic IR injury, with a net 60% and 90% reduction in liver GSH depletion and protein oxidation induced by IR, respectively. Liver IR led to decreased DNA binding of nuclear factor-kappaB (NF-kappaB) (54%) and signal transducer and activator of transcription 3 (STAT3) (53%) (electromobility shift assay), with 50% diminution in the protein expression of haptoglobin (Western blot), changes that were normalized by T(3) preconditioning.


CONCLUSIONS
T(3) administration involving transient oxidative stress in the liver exerts significant protection against IR injury, a novel preconditioning maneuver that is associated with NF-kappaB and STAT3 activation and acute-phase response.
Fernández
Virginia
V
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Castillo
Iván
I
Tapia
Gladys
G
Romanque
Pamela
P
Uribe-Echevarría
Sebastián
S
Uribe
Mario
M
Cartier-Ugarte
Denise
D
Santander
Gonzalo
G
Vial
María T
MT
Videla
Luis A
LA
D000210:Acute-Phase Reaction / Q000503:physiopathology; D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000235:genetics / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013961:Thyroid Gland / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D014284:Triiodothyronine / Q000494:pharmacology*
D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D014284:Triiodothyronine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione