Involvement of Kupffer cell-dependent signaling in T3-induced hepatocyte proliferation in vivo

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.     

Ischaemic preconditioning modulates the activity of Kupffer cells during in vivo reperfusion injury of rat liver

This work was performed to elucidate further the main cellular events underlying the protective effect of ischaemic preconditioning in an in vivo rat liver model of 90 min ischaemia followed by 30 min reperfusion. A significant attenuation of the various aspects of post-ischaemic injury, namely necrosis and the levels of hydrogen peroxide and 5- and 15-hydroperoxyeicosatetraenoic acids, was afforded by the prior application of a short cycle of ischaemia/reperfusion (10 + 10 min) or when rats were previously treated with gadolinium chloride. However, when preconditioning was applied on Kupffer cell-depleted livers, no additional level of ischaemic tolerance was obtained. In terms of cellular pathology, this result could be suggestive of Kupffer cells as the target of the preconditioning phenomenon during the warm ischaemia/reperfusion injury. Accordingly, modulation of Kupffer cell activity was associated with a well-preserved hepatocyte integrity, together with low levels of pro-oxidant generation during reperfusion. As activated Kupffer cells can generate and release potentially toxic substances, their modulation by ischaemic preconditioning could help to provide new surgical and/or pharmacological strategies to protect the liver against reperfusion damage.     

Antioxidants and gadolinium chloride attenuate hepatic parenchymal and endothelial cell injury induced by low flow ischemia and reperfusion in perfused rat livers

The objective of this study was to determine whether Kupffer cells contribute to parenchymal and endothelial cell damage induced by ischemia-reperfusion in perfused rat livers. Parenchymal and endothelial cell injury were determined by measuring activities of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP), respectively, in the effluent perfusate of livers subjected to 60 min of low flow ischemia followed by 30 min of reperfusion. Upon reperfusion, LDH and PNP activities increased significantly within the first 10 min of reperfusion and remained elevated over control values throughout the duration of reperfusion. Pretreatment with gadolinium chloride, an inhibitor of Kupffer cell function, significantly decreased LDH and PNP efflux during reperfusion by approximately 60% and 50%, respectively. When Kupffer cells were stimulated by vitamin A pretreatment, PNP efflux was doubled during reperfusion. Vitamin E pretreatment attenuated LDH and PNP release by approximately 70% during reperfusion compared to enzyme release in untreated livers. Moreover, the water-soluble antioxidants superoxide dismutase and desferrioxamine reduced reperfusion injury, whereas catalase had no effect on enzyme release. These results demonstrate that superoxide anions released from Kupffer cells are involved in oxidative damage to endothelial cells as well as hepatocytes during the early stages of hepatic reperfusion.     

Antioxidants and gadolinium chloride attenuate hepatic parenchymal and endothelial cell injury induced by low flow ischemia and reperfusion in perfused rat livers

The objective of this study was to determine whether Kupffer cells contribute to parenchymal and endothelial cell damage induced by ischemia-reperfusion in perfused rat livers. Parenchymal and endothelial cell injury were determined by measuring activities of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP), respectively, in the effluent perfusate of livers subjected to 60 min of low flow ischemia followed by 30 min of reperfusion. Upon reperfusion, LDH and PNP activities increased significantly within the first 10 min of reperfusion and remained elevated over control values throughout the duration of reperfusion. Pretreatment with gadolinium chloride, an inhibitor of Kupffer cell function, significantly decreased LDH and PNP efflux during reperfusion by approximately 60% and 50%, respectively. When Kupffer cells were stimulated by vitamin A pretreatment, PNP efflux was doubled during reperfusion. Vitamin E pretreatment attenuated LDH and PNP release by approximately 70% during reperfusion compared to enzyme release in untreated livers. Moreover, the water-soluble antioxidants superoxide dismutase and desferrioxamine reduced reperfusion injury, whereas catalase had no effect on enzyme release. These results demonstrate that superoxide anions released from Kupffer cells are involved in oxidative damage to endothelial cells as well as hepatocytes during the early stages of hepatic reperfusion.     

Ethanol-dependent induction of bilirubin UDP-glucuronosyl-transferase in rat liver is mediated by Kupffer cells

Recently we have reported that bilirubin UDP-glucuronosyltransferase (UGT1A1) is induced in rat liver by chronic ethanol treatment. Several studies have shown that Kupffer cells play a central role in the mediation of various hepatic effects of chronic alcohol consumption. In the present work, the participation of Kupffer cells in the ethanol dependent induction of UGT1A1 was investigated. A group of rats was pretreated with gadolinium chloride, a known Kupffer-cell-depleting agent. We compared the effect of chronic ethanol ingestion on UGT1A1 expression in the liver of normal and gadolinium chloride treated rats. The effect of ethanol on bilirubin glucuronidation was completely prevented in Kupffer cell deficient rats. The western and northern blot analyses showed that the increase of both the protein and mRNA of UGT1A1 was prevented in these animals. These results suggest that Kupffer cells play a major role in the mediation of ethanol-stimulated induction of UGT1A1 in liver parenchymal cells.     

Acetaminophen-induced liver oxidative stress and hepatotoxicity: influence of Kupffer cell activity assessed in the isolated perfused rat liver

Summary

The influence of acetaminophen (APAP) treatment (400 mg/kg) on Kupffer cell function was studied in the isolated perfused liver by colloidal carbon infusion, concomitantly with parameters related to oxidative stress (thiobarbituric acid reactants (TBARS) formation and glutathione (GSH) content) and tissue injury (sinusoidal efflux of lactate dehydrogenase (LDH)). APAP led to increased rates of hepatic TBARS formation, GSH depletion, and higher sinusoidal LDH efflux compared to control values, without changes in the basal rate of O₂ consumption. In addition, APAP significantly enhanced the rate of carbon uptake by perfused livers and the associated carbon-induced O₂ consumption, with carbon-induced LDH effluxes being increased by 411% over control values or by 124% compared to basal LDH release in APAP-treated rats. APAP-induced changes in liver TBARS formation and GSH levels were attenuated by gadolinium chloride (GdCl₃) pretreatment, whereas those in carbon uptake, carbon-induced respiration, and LDH efflux were abolished. GdCl₃ pretreatment decreased liver O₂ consumption irrespectively of APAP treatment, an effect that seems to be due to depression of mitochondrial respiration. It is concluded that APAP intoxication enhances Kupffer cell function as assessed in the intact liver, which may represent an important source of reactive O₂ species and chemical mediators conditioning the increased oxidative stress status and the tissue injury which developed.     

Superoxide Generation by Kupffer Cells and Priming of Neutrophils During Reperfusion After Hepatic Ischemia

The objective of this study was to identify the cellular source of the vascular oxidant stress in hepatic ischemia-reperfusion injury in male Fischer rats. Nonparenchymal cells (Kupffer cells, endothelial cells) and neutrophils were isolated from postischemic liver lobes by collagenase-pronase digestion followed by centrifugal elutriation. The spontaneous and stimulated generation of superoxide by these cells were subsequently quantified in vitro. Large Kupffer cells from the postischemic lobes spontaneously generated 300% more superoxide than similar cells from control animals. No difference in spontaneous superoxide formation was found when the small Kupffer cells were compared. No other cells isolated from the postischemic lobes or control liver including neutrophils released any detectable superoxide spontaneously. In contrast, small Kupffer cells and neutrophils from the postischemic liver generated significantly more superoxide after stimulation with phorbol ester or opsonized zymosan than the controls. The considerably higher response with zymosan stimulation compared to phorbol ester indicates a particular priming for a receptor-mediated signal transduction pathway during reperfusion. These studies demonstrate that Kupffer cells are the principal source of the oxidant stress during the initial reperfusion phase after hepatic ischcmia. The priming of neutrophils during this time may be an important factor for the later neutrophil-induced injury phase.     

Derangement of Kupffer cell functioning and hepatotoxicity in hyperthyroid rats subjected to acute iron overload

Liver oxidative stress, Kupffer cell functioning, and cell injury were studied in control rats and in animals subjected to L-3,3',5-tri-iodothyronine (T3) and/or acute iron overload. Thyroid calorigenesis with increased rates of hepatic O2 uptake was not altered by iron treatment, whereas iron enhanced serum and liver iron levels independently of T3. Liver thiobarbituric acid reactants formation increased by 5.8-, 5.7-, or 11.0-fold by T3, iron, or their combined treatment, respectively. Iron enhanced the content of protein carbonyls independently of T3 administration, whereas glutathione levels decreased in T3- and iron-treated rats (54%) and in T3Fe-treated animals (71%). Colloidal carbon infusion into perfused livers elicited a 109% and 68% increase in O2 uptake in T3 and iron-treated rats over controls. This parameter was decreased (78%) by the joint T3Fe administration and abolished by gadolinium chloride (GdCl3) pretreatment in all experimental groups. Hyperthyroidism and iron overload did not modify the sinusoidal efflux of lactate dehydrogenase, whereas T3Fe-treated rats exhibited a 35-fold increase over control values, with a 54% reduction by GdCl3 pretreatment. Histological studies showed a slight increase in the number or size of Kupffer cells in hyperthyroid rats or in iron overloaded animals, respectively. Kupffer cell hypertrophy and hyperplasia with presence of inflammatory cells and increased hepatic myeloperoxidase activity were found in T3Fe-treated rats. It is concluded that hyperthyroidism increases the susceptibility of the liver to the toxic effects of iron, which seems to be related to the development of a severe oxidative stress status in the tissue, thus contributing to the concomitant liver injury and impairment of Kupffer cell phagocytosis and particle-induced respiratory burst activity.     

Influence of Hyperthyroidism on the Activity of Liver Nitric Oxide Synthase in the Rat

Hyperthyroidism enhances the prooxidant activity of the liver by elevating superoxide radical and/or hydrogen peroxide generation in microsomal, mitochondrial, and peroxisomal fractions, with an increased respiratory burst of Kupffer cells. In this study, the influence of daily doses of 0.1 mg 3,3′,5-triiodothyronine (T₃)/kg for three consecutive days on liver nitric oxide (NO) synthase (NOS) was assessed, as a possible contributory mechanism to T₃-induced liver prooxidant activity. Thyroid calorigenesis was paralleled by a progressive increment in the rate of NO generation, with significant increases after 2 (47%) and 3 days (70%) of T₃treatment, and a net 45% (P< 0.05) enhancement in theN^G-methyl-l-arginine-sensitive NO production, compared to control values. These enhancement effects were reversed to control levels after 3 days of hormone withdrawal, concomitantly with the normalization of hepatic respiration. Enhancement of liver NOS activity in hyperthyroid animals was diminished by 27% (P< 0.05) by the selectivein vivoinactivation of Kupffer cells by gadolinium chloride (GdCl₃), without direct actions of GdCl₃on the enzyme. These data demonstrate that hyperthyroidism leads to a significant and reversible enhancement in rat liver NOS activity, an effect that is exerted at hepatocyte and Kupffer cell levels, thus representing an additional source of prooxidants to those of reactive oxygen species.     

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

The liver, the largest organ with multiple synthesis and secretion functions in mammals, consists of hepatocytes and Kupffer, stem, endothelial, stellate and other parenchymal cells. Because of early and extensive contact with the external environment, hepatic ischaemia reperfusion (IR) may result in mitochondrial dysfunction, autophagy and apoptosis of cells and tissues under various pathological conditions. Because the liver requires a high oxygen supply to maintain normal detoxification and synthesis functions, it is extremely susceptible to ischaemia and subsequent reperfusion with blood. Consequently, hepatic IR leads to acute or chronic liver failure and significantly increases the total rate of morbidity and mortality through multiple regulatory mechanisms. An increasing number of studies indicate that mitochondrial structure and function are impaired after hepatic IR, but that the health of liver tissues or liver grafts can be effectively rescued by attenuation of mitochondrial dysfunction. In this review, we mainly focus on the subsequent therapeutic interventions related to the conservation of mitochondrial function involved in mitigating hepatic IR injury and the potential mechanisms of protection. Because mitochondria are abundant in liver tissue, clarification of the regulatory mechanisms between mitochondrial dysfunction and hepatic IR should shed light on clinical therapies for alleviating hepatic IR‐induced injury.     

Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance

Macrophage infiltration and activation in metabolic tissues underlie obesity-induced insulin resistance and type 2 diabetes. While inflammatory activation of resident hepatic macrophages potentiates insulin resistance, the functions of alternatively activated Kupffer cells in metabolic disease remain unknown. Here we show that in response to the Th2 cytokine interleukin-4 (IL-4), peroxisome proliferator-activated receptor delta (PPARdelta) directs expression of the alternative phenotype in Kupffer cells and adipose tissue macrophages of lean mice. However, adoptive transfer of PPARdelta(-/-) (Ppard(-/-)) bone marrow into wild-type mice diminishes alternative activation of hepatic macrophages, causing hepatic dysfunction and systemic insulin resistance. Suppression of hepatic oxidative metabolism is recapitulated by treatment of primary hepatocytes with conditioned medium from PPARdelta(-/-) macrophages, indicating direct involvement of Kupffer cells in liver lipid metabolism. Taken together, these data suggest an unexpected beneficial role for alternatively activated Kupffer cells in metabolic syndrome and type 2 diabetes.     

Increases in tumor necrosis factor-alpha in response to thyroid hormone-induced liver oxidative stress in the rat

Thyroid hormone-induced calorigenesis contributes to liver oxidative stress and promotes an increased respiratory burst activity in Kupffer cells, which could conceivably increase the expression of redox-sensitive genes, including those coding for cytokines. Our aim was to test the hypothesis that L-3,3',5-triiodothyronine (T3)-induced liver oxidative stress would markedly increase the production of TNF-alpha by Kupffer cells and its release into the circulation. Sprague-Dawley rats receive a single dose of 0.1 mg T3/kg or vehicle (controls) and determinations of liver O2 consumption, serum TNF-alpha, rectal temperature, and serum T3 levels, were carried out at different times after treatment. Hepatic content of total reduced glutathione (GSH) and biliary glutathione disulfide (GSSG) efflux were measured as indices of oxidative stress. In some studies, prior to T3 injection animals were administered either (i) the Kupffer cell inactivator gadolinium chloride (GdCl3), (ii) the antioxidants alpha-tocopherol and N-acetyl-L-cysteine (NAC), or (iii) an antisense oligonucleotide against TNF-alpha (ASO TJU-2755). T3 elicited an 80-fold increase in the serum levels of TNF-alpha at 22h after treatment, which coincided with the onset of thyroid calorigenesis. Pretreatment with GdCl3, alpha-tocopherol, NAC, and ASO TJU-2755 virtually abolished this effect and markedly reduced T3-induced liver GSH depletion and the increases in biliary GSSG efflux. It is concluded that the hyperthyroid state in the rat increases the circulating levels of TNF-alpha by actions exerted at the Kupffer cell level and these are related to the oxidative stress status established in the liver by thyroid calorigenesis.     

The acute-phase response of the liver in relation to thyroid hormone-induced redox signaling

Recently, we reported that 3,3',5-triiodothyronine (T3) induces the expression of redox-sensitive genes as a nongenomic mechanism of T3 action. In this study, we show that T3 administration to rats (daily doses of 0.1 mg/kg ip for 3 consecutive days) induced a calorigenic response and liver glutathione depletion as an indication of oxidative stress, with higher levels of interleukin (IL)-6 in serum (ELISA) and hepatic STAT3 DNA binding (EMSA), which were maximal at 48-72 h after treatment. Under these conditions, the protein expression of the acute-phase proteins haptoglobin and beta-fibrinogen is significantly augmented, a change that is suppressed by pretreatment with alpha-tocopherol (100 mg/kg ip) or gadolinium chloride (10 mg/kg iv) before T3. It is concluded that T3 administration induces the acute-phase response in rat liver by a redox mechanism triggered at the Kupffer cell level, in association with IL-6 release and activation of the STAT3 cascade, a response that may contribute to reestablishing homeostasis in the liver and extrahepatic tissues exhibiting oxidative stress.     

Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death

Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB1/2 receptors.     

Tri-iodothyronine differentially induces Kupffer cell ED1/ED2 subpopulations

Thyroid calorigenesis is carried out by activation of cytochrome-c oxidase, as well as by induction of mitochondrial and nuclear genes that code for cell respiratory apparatus components and uncoupling proteins. These effects operate increments in basal metabolic rate and also lead to increased production of oxygen and nitrogen reactive species in liver parenchymal cells. The hepatic antioxidant system is also compromised, since superoxide dismutase and catalase activities, glutathione content and lipid soluble antioxidants are reduced. Liver macrophages contribute to the hepatic oxidative stress observed in T(3)-treated rats, and both Kupffer cell hyperplasia and hypertrophy are reported. Kupffer cells constitute the main fixed macrophage population in the body and are a heterogeneous group of cells, derived from a less numerous population of local precursors, which are morphologically fairly distinguishable from the mature lineage elements. ED1 and ED2 antigens have been particularly useful in the characterization of Kupffer cell subpopulations. In particular, antibodies against these antigens provided evidence that T(3)- induced Kupffer cell hyperplasia causes a shift on liver macrophage population phenotype, leaning towards younger cell types. Despite the fact that sinusoidal environment itself stimulates the proliferation of macrophage precursors and their differentiation into Kupffer cells, increased Kupffer cell turnover rates modify the sinusoidal environment and may imply further functional effects. Thus, Kupffer cell hyperplasia secondary to increased T(3) levels is potentially a pro-inflammatory event, which involves both, the expansion of Kupffer cell precursor population by means of circulating monocyte recruitment, and the differentiation of preexisting local Kupffer cell precursors into mature liver macrophages.     

Zymosan-induced changes in glucose release and fatty acid oxidation in the perfused rat liver

The aim of the present study was to investigate the actions of zymosan on glucose release and fatty acid oxidation in perfused rat livers and to determine if Kupffer cells and Ca2+ ions are implicated in these actions. Zymosan caused stimulation of glycogenolysis in livers from fed rats. In livers from fasted rats zymosan caused gradual inhibition of glucose production and oxygen consumption from lactate plus pyruvate. Ketogenesis, oxygen consumption, and [14C-]-CO2 production were inhibited by zymosan when the [1-14C]-palmitate was supplied exogenously. However, ketogenesis and oxygen consumption from endogenous sources were not inhibited. An interference with substrate-uptake by the liver may be the cause of the changes in gluconeogenesis and oxidation of fatty acids from exogenous sources. The pretreatment of the rats with gadolinium chloride and the removal of Ca2+ ions did not suppress the effects of zymosan on glucose release, a finding that argues against the participation of Kupffer cells or Ca2+ ions in the liver responses. The hepatic metabolic changes caused by zymosan could play a role in the systemic metabolic alterations reported to occur after in vivo zymosan administration.     

Short term regulation of hepatocyte glutathione content by hepatic sinusoidal cells in co-culture

An inadequate balance between oxidant species and antioxidant mechanisms may constitute the primary mechanisms of a number of pathologies. The liver plays a central role in this balance: parenchymal hepatic cells contain and export especially high levels of the antioxidant glutathione and activated Kupffer cells release inflammation mediators and reactive oxygen species. There is growing evidence of a paracrine regulation of hepatic function by means of a fluent intercellular communication which must still be fully elucidated, especially in basal conditions. In vivo models provide often too complex results but, in vitro, tissue interactions are left aside; therefore it is important to find new experimental models to address cell communication studies. Here we propose the complementary use of three models to study liver glutathione system regulation in basal conditions: pure parenchymal cells primary cultures, addition of sinusoidal cell conditioned media to parenchymal cells and co-culture of sinusoidal cells using porous membranes. We have also developed a high specifity immunofluorescent method for the complete characterization of sinusoidal cell populations by flow cytometry and confocal microscopy. Our results show that Kupffer cells possess higher levels of reactive oxygen species than sinusoidal endothelial cells even in basal conditions. We also report that the glutathione content of hepatic parenchymal cells in basal conditions is regulated by a sinusoidal-parenchymal cells cross-talk and suggest the existence of a paracrine circuit in the management of liver oxidative stress.     

Green tea extract supplement reduces D-galactosamine-induced acute liver injury by inhibition of apoptotic and proinflammatory signaling

Oxidative stress and inflammation contributed to the propagation of acute liver injury (ALI). The present study was undertaken to determine whether D-galactosamine (D-GalN) induces ALI via the mitochondrial apoptosis- and proinflammatory cytokine-signaling pathways, and possible mechanism(s) by which green tea (GT) extract modulates the apoptotic and proinflammatory signaling in rat. D-GalN induced hepatic hypoxia/hypoperfusion and triggered reactive oxygen species (ROS) production from affected hepatocytes, infiltrated leukocytes, and activated Kupffer cells. D-GalN evoked cytosolic Bax and mitochondrial cytochrome C translocation and activated proinflammatory nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) translocation, contributing to the increase of intercellular adhesion molecule-1 expression, terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL)-positive hepatocytes, multiple plasma cytokines and chemokines release, and alanine aminotransferase (ALT) activity. An altered biliary secretion profile of several acute phase proteins directly indicates oxidative stress affecting intracellular trafficking in the hepatocyte. GT pretreatment attenuated ROS production, mitochondrial apoptosis- and proinflammatory cytokine-signaling pathway, plasma ALT and cytokines levels, biliary acute phase proteins secretion and hepatic pathology by the enhancement of anti-apoptotic mechanisms. In conclusion, D-GalN induced ALI via hypoxia/hypoperfusion-enhanced mitochondrial apoptosis- and proinflammatory cytokine-signaling pathway, contributing to oxidative stress and inflammation in the liver. GT can counteract the D-GalN-induced ALI via the attenuation of apoptotic and proinflammatory signaling by the upregulation of anti-apoptotic mechanism.     

Enhancement of lindane-induced liver oxidative stress and hepatotoxicity by thyroid hormone is reduced by gadolinium chloride

The role of Kupffer cells in the hepatocellular injury and oxidative stress induced by lindane (20 mg/kg; 24h) in hyperthyroid rats (daily doses of 0.1 mg L-3,3',5-triiodothyronine (T3)/kg for three consecutive days) was assessed by the simultaneous administration of gadolinium chloride (GdCl3; 2 doses of 10mg/kg on alternate days). Hyperthyroid animals treated with lindane exhibit enhanced liver microsomal superoxide radical (O2.-) production and NADPH cytochrome c reductase activity, with lower levels of cytochrome P450, superoxide dismutase (SOD) and catalase activity, and glutathione (GSH) content over control values. These changes are paralleled by a substantial increase in the lipid peroxidation potential of the liver and in the O2.- generation/ SOD activity ratio, thus evidencing a higher oxidative stress status that correlates with the development of liver injury characterized by neutrophil infiltration and necrosis. Kupffer cell inactivation by GdCl3 suppresses liver injury in lindane/T3-treated rats with normalization of altered oxidative stress-related parameters, excepting the reduction in the content of GSH and in catalase activity. It is concluded that lindane hepatotoxicity in hyperthyroid state, that comprises an enhancement in the oxidative stress status of the liver, is largely dependent on Kupffer cell function, which may involve generation of mediators leading to pro-oxidant and inflammatory processes.