The role of Kupffer cells after major liver surgery.

BACKGROUND: Kupffer cells (KCs) are the resident macrophages of the liver. KCs have an enormous endotoxin eliminating capacity. Endotoxins play an important role in the development of systemic complications after partial hepatectomy by activating KCs. The role of KCs and endotoxins after partial hepatectomy is investigated. METHODS: Wistar rats (n = 16, 250-275 g) were randomly assigned to have 1 mL dichloromethylene-diphosphonate (CL2MDP) or 1 mL NaCl 0.9% i.v. Forty-eight hours later, all rats received a two-thirds liver resection. Twenty-four hours later, rats received at random 50 microg/kg endotoxin (LPS) in 1 mL or 1 mL of NaCl 0.9% IV. The rats were killed 4 hours after LPS or SAL infusion. RESULTS: CL2MDP infusion resulted in a complete KC elimination. KC-depleted rats had the lowest mean arterial pressure, the highest heart and ventilatory rate after endotoxemia. All rats were able to maintain pH in normal ranges. The KC-depleted rats after partial hepatectomy had the lowest CO2 levels and the highest levels of lactate during endotoxemia. Oxygen levels were similar in all groups. Hepatic, pulmonary, and renal mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta were decreased in KC-depleted rats. Plasma levels of TNF-alpha were significantly decreased in KC-depleted rats. Furthermore, the highest influx of macrophages and polymorphonuclear cells in the lung and kidney were measured in KC-depleted rats during endotoxemia. CONCLUSIONS: Partial hepatectomy in KC-depleted rats result in a more pronounced endotoxin-mediated systemic inflammation and decreased synthesis of cytokines.

Kupffer cell-depleted rats have a diminished acute-phase response following major liver resection.

Partial hepatectomy (PH)-induced Kupffer cell (KC) activation results in a rapid release of cytokines inducing the acute-phase response (APR). This study was done to evaluate the role of Kupffer cells (KCs) in the course of the APR following PH and a consecutive endotoxin challenge. KC depletion was performed in rats by i.v. administration of 1 mL liposome-encapsulated dichloromethylene diphosohonate (Cl2MDP). Control rats received 1 mL NaCl 0.9%. Forty-eight hours later, PH was performed. At 24 h after PH, rats were randomized to receive either 1 mL NaCl 0.9% (saline) or 50 microg/kg LPS i.v. in 1 mL. Animals were sacrificed at 4 h after LPS or saline infusion. The APR was determined by measuring hepatic gene expression of alpha 2-macroglobulin, alpha 1-acid glycoprotein, and IL-6 and expression of hepatic albumin. The APR was significantly depressed in KC-depleted rats. Despite increased IL-6 mRNA synthesis in response to low-dose LPS, no enhancement of acute-phase protein synthesis (APP) was found in KC-depleted rats. Hepatic failure was most profound in KC-depleted rats, as indicated by elevated plasma levels of liver transaminases and ammonia. We conclude that after PH, KC function in the remnant liver is important for the acute-phase reaction and reduces endotoxin-induced hepatocyte damage.

Feedback inhibition controls spike transfer in hybrid thalamic circuits.

Sensory information reaches the cerebral cortex through the thalamus, which differentially relays this input depending on the state of arousal. Such 'gating' involves inhibition of the thalamocortical relay neurons by the reticular nucleus of the thalamus, but the underlying mechanisms are poorly understood. We reconstructed the thalamocortical circuit as an artificial and biological hybrid network in vitro. With visual input simulated as retinal cell activity, we show here that when the gain in the thalamic inhibitory feedback loop is greater than a critical value, the circuit tends towards oscillations -- and thus imposes a temporal decorrelation of retinal cell input and thalamic relay output. This results in the functional disconnection of the cortex from the sensory drive, a feature typical of sleep states. Conversely, low gain in the feedback inhibition and the action of noradrenaline, a known modulator of arousal, converge to increase input output correlation in relay neurons. Combining gain control of feedback inhibition and modulation of membrane excitability thus enables thalamic circuits to finely tune the gating of spike transmission from sensory organs to the cortex.