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.

Role of beta2-glycoprotein I, LDL-, and antioxidant levels in hypercholesterolemic elderly subjects.

The levels of electronegative low-density lipoprotein (LDL-), LDL cholesterol oxidability, and plasma levels of molecular antioxidants and of beta(2)-glycoprotein I (beta(2) GPI) were studied in a group of 10 hypercholesterolemic (HC) and 10 normocholesterolemic (NC) elderly subjects. HC subjects showed significantly higher levels of cholesterol, LDL cholesterol, LDL-, and beta(2)GPI than NC, whereas high-density lipoprotein cholesterol and alpha-tocopherol levels were lower in HC as compared with NC subjects. Correlations among LDL- levels, LDL oxidation lag time, beta(2)GPI, and antioxidant plasma levels were studied in 100 HC elderly subjects. Lag time for in vitro LDL oxidation positively correlated with ubiquinol-10 levels (p = 0.008), but not with other antioxidants studied or beta(2)GPI. LDL- and alpha-tocopherol levels showed an inverse and significant correlation (p = 0.018). beta(2)GPI and LDL cholesterol levels were correlated (p = 0.001), whereas no significance was found between LDL- and beta(2)GPI levels (p = 0.057). The physiological significance of alpha-tocopherol and ubiquinol-10 levels on LDL- levels, and the presence of high levels of beta(2)-GPI, are discussed in terms of protective mechanisms operating during the overall atherosclerosis process.

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.