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-B (NF-B) (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. Conclusion: 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-B and STAT3 activation and acute-phase response. (HEPATOLOGY 2007;45:170-177.)

Recently, we demonstrated that 3,3, ,5-triiodothyronine (T3) induces oxidative stress in rat liver, with enhancement in the DNA binding of nuclear factor-B (NF-B) and the NF-B-dependent expression of tumor necrosis factor-(TNF-). In this study, we show that T3 administration (daily doses of 0·1 mg/kg i.p. for three consecutive days) elicited a calorigenic response and higher liver O 2 consumption rates, with increased serum levels of TNF-(ELISA), liver inhibitor of B (I B-) phosphorylation (Western blot analysis), and hepatic NF-B DNA binding (EMSA) at 56-72 h after treatment. Within this time interval, liver manganese superoxide dismutase (MnSOD) activity and the protein expression of MnSOD and Bcl-2 are enhanced. These changes are abrogated by the administration of -tocopherol (100 mg/kg i.p.) prior to T3. It is concluded that T3 treatment leads to the redox upregulation of MnSOD and Bcl-2 in rat liver, in association with TNF-release and activation of the I Bkinase/NF-B cascade, which may constitute a protective mechanism against free radical toxicity involving cell death signaling.

Maresin-1 (MaR1) is a specialized pro-resolving mediator, derived from omega-3 fatty acids, whose functions are to decrease the pro-inflammatory and oxidative mediators, and also to stimulate cell division. We investigated the hepatoprotective actions of MaR1 in a rat model of liver ischemia-reperfusion (IR) injury. MaR1 (4 ng/gr body weight) was administered prior to ischemia (1 h) and reperfusion (3 h), and controls received isovolumetric vehicle solution. To analyze liver function, transaminases levels and tissue architecture were assayed, and serum cytokines TNF-α, IL-6, and IL-10, mitotic activity index, and differential levels of NF-κB and Nrf-2 transcription factors, were analyzed. Transaminase, TNF-α levels, and cytoarchitecture were normalized with the administration of MaR1 and associated with changes in NF-κB. IL-6, mitotic activity index, and nuclear translocation of Nrf-2 increased in the MaR1-IR group, which would be associated with hepatoprotection and cell proliferation. Taken together, these results suggest that MaR1 alleviated IR liver injury, facilitated by the activation of hepatocyte cell division, increased IL-6 cytokine levels, and the nuclear localization of Nrf-2, with a decrease of NF-κB activity. All of them were related to an improvement of liver injury parameters. These results open the possibility of MaR1 as a potential therapeutic tool in IR and other hepatic pathologies.

Thyroid hormone-induced calorigenesis triggers liver oxidative stress with concomitant TNF-alpha production by Kupffer cells and up-regulation of gene expression. Considering that cyclin-dependent kinase-2 (CDK-2) performs essential functions for cellular proliferation, our aim was to test the hypothesis that l-3,3',5-triiodothyronine (T(3)) stimulates liver cell proliferation by upstream mechanisms involving CDK-2 expression dependent on Kupffer cell signaling. T(3) administration induced a calorigenic response at 60-70 h after treatment, with increased TNF-alpha generation and hepatic oxidative stress status, as shown by enhanced protein carbonyls and decreased glutathione content compared to controls. In this time interval, liver c-jun N-terminal kinase (JNK) phosphorylation, activator protein-1 (AP-1) DNA binding, and CDK-2 expression were enhanced, with concomitantly higher levels of the proliferation markers Ki-67 and proliferating cell nuclear antigen. These changes are abolished by administration of the Kupffer cell inactivator gadolinium chloride prior to T(3) treatment. We conclude that T(3) administration triggers liver CDK-2 expression and cellular proliferation through a cascade associated with Kupffer cell-dependent TNF-alpha generation, JNK phosphorylation, and AP-1 activation. Since CDK-2 promotes phase S progression within the cell cycle, this response may constitute a major mechanism involved in T(3)-induced liver preconditioning to ischemia/reperfusion injury.