lithium-chloride and Liver-Cirrhosis

In decompensated cirrhosis, the early innate immune response to the Toll-like receptor 4 (TLR4) agonist, lipopolysaccharides (LPS), is characterized by a hyper-production of pro-inflammatory cytokines and hypo-production of the anti-inflammatory cytokine IL-10. In LPS-stimulated non-cirrhotic immune cells, the constitutively active glycogen synthase kinase (GSK) 3 favors pro- vs. anti-inflammatory cytokines, by acting on gene induction. However, in these cells, TLR4 dampens its own pro-inflammatory response by inducing early (within minutes) AKT-mediated phosphorylation of GSK3β (one of two GSK3 isoforms) on Ser9. Phosphorylation of GSK3β (Ser9) inhibits its activity, decreases pro-inflammatory cytokines, and increases IL-10. Thus, we investigated the role of GSK3 in LPS-induced cytokine production by peripheral blood mononuclear cells (PBMCs) or monocytes from patients with advanced cirrhosis and normal subjects.. Cells were pre-incubated with or without GSK3 inhibitor (SB216763 or lithium chloride) for 1h and then stimulated with LPS. Cytokine production was assessed at mRNA and secreted proteins levels, by real-time RT-PCR at 1h and ELISA at 20 h, respectively. GSK3β phosphorylation was assessed using Western blotting.. In cirrhotic and normal PBMCs pretreated with GSK3 inhibitors, LPS-induced production of pro-inflammatory proteins TNF-α and IL-12p40 was significantly decreased while that of IL-10 was increased. LPS-induced, AKT-mediated phosphorylation of GSK3β on Ser9 found in normal monocytes, was abolished in cirrhotic cells.. GSK3 is involved in the early TLR4-mediated pro-inflammatory response in patients with decompensated cirrhosis. This was associated with a defect in AKT-mediated GSK3β phosphorylation resulting in unrestricted 'pro-inflammatory' activity of the enzyme.

Topics: Adjuvants, Immunologic; Adult; Aged; Cells, Cultured; Female; Gene Expression Regulation, Enzymologic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hepatitis; Humans; Indoles; Interleukin-10; Interleukin-12; Lipopolysaccharides; Lithium Chloride; Liver Cirrhosis; Male; Maleimides; Middle Aged; Monocytes; Proto-Oncogene Proteins c-akt; Severity of Illness Index; Signal Transduction; Toll-Like Receptor 4

In normal humans, plasma dopamine levels rise during head-out water immersion or saline intravenous infusion. Dopamine inhibits Na+,K+-ATPase activity in the proximal tubule and blunts aldosterone secretion leading to increased diuresis and natriuresis. The aim of this study is to evaluate the role of endogenous dopaminergic activity in the intrarenal sodium handling in patients with compensated liver cirrhosis. We studied nine healthy controls and 12 patients with Child-Pugh A cirrhosis during a normosodic diet for (1) dopaminergic activity, as measured by the incremental aldosterone responses 30 and 60 min after intravenous metoclopramide administration; (2) basal plasma levels of active renin and aldosterone; (3) 4-hr renal clearance of lithium (an index of fluid delivery to the distal tubule), creatinine, sodium, and potassium, first without and then with dopaminergic blockade with intravenous metoclopramide. The patients displayed greater endogenous dopaminergic activity, evidenced by higher incremental aldosterone responses compared with controls (+30 min: 160.2 +/- 68.8 vs 83.6 +/- 35.2 pg/ml, P < 0.01; +60 min: 140.5 +/- 80.3 vs 36.8 +/- 39.1 pg/ml, P < 0.01, respectively). In spite of this, patients and controls did not show significantly different basal aldosterone plasma levels, delivery of sodium to the distal nephron, or urinary excretion of sodium. In both groups the dopaminergic blockade with metoclopramide determined no change in sodium and potassium urinary excretion, but it caused a fall of the fluid and sodium delivery from the proximal tubule to the distal nephron among the patients (from 30.7 +/- 9.3 to 14.4 +/- 4.5 ml/min, P < 0.001; and from 4.25 +/- 1.30 to 2.00 +/- 0.64 meq/min, P < 0.001, respectively). In this group the natriuresis was maintained due to a reduction of the reabsorbed fraction of the distal sodium delivery (from 97.5 +/- 1.9% to 89.8 +/- 12.4%, P < 0.05). In conclusions, compensated cirrhotic patients display an increased endogenous dopaminergic activity compared with controls. This function is critical in maintaining the delivery of sodium to the distal nephron.

Topics: Adult; Aged; Aldosterone; Case-Control Studies; Dopamine; Dopamine Antagonists; Female; Humans; Immersion; Kidney Tubules; Lithium Chloride; Liver Cirrhosis; Male; Metoclopramide; Middle Aged; Natriuresis; Sodium