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Abstract
The devastating consequences of hepatic failure include hepatic encephalopathy, a severe, life threatening impairment of neuronal function. Hepatic encephalopathy is caused by impaired hepatic clearance of NH4+. Cellular NH4+ uptake is accomplished mainly by the Na+,K+,2Cl− cotransporter. Here we show that hepatic clearance of NH4+ is impaired in TNFα deficient as well as TNFR1&TNFR2 double knockout mice, which both develop hyperammonemia. Despite impaired hepatic clearance of NH4+, TNFα deficient mice and TNFR1 deficient mice were protected against acute ammonia intoxication. While 54% of the wild-type mice and 60% of TNFR2 deficient mice survived an NH4+ load, virtually all TNFα deficient mice and TNFR1 deficient mice survived the treatment. Conversely, TNFα treatment of wild type mice sensitized the animals to the toxic effects of an NH4+ load. The protection of TNFα-deficient mice against an NH4+ load was paralleled by decreased cerebral expression of NKCC1. According to the present observations, inhibition of TNFα formation and/or NKCC1 may be strategies to favorably influence the clinical course of hepatic encephalopathy.
Highlights
Ammonia detoxification in the liver is critical to prevent toxic effects in the brain[1]
This increased ammonia concentration was dependent on both, tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2) signaling, as only TNFR1&TNFR2 double knockout showed increased ammonia levels in the blood stream (Fig. 1b)
TNFα-deficient and TNFR1-deficient animals were protected against acute ammonia intoxication
Summary
Ammonia detoxification in the liver is critical to prevent toxic effects in the brain[1]. Increased ammonia levels in the peripheral blood are associated with hepatic encephalopathy, a devastating clinical condition following liver failure[1]. Remaining ammonia, which escapes the urea cycle, is taken up by perivenous scavenger cells and metabolized to glutamine by glutamine synthetase[4,5,6] This high affinity ammonia metabolizing mechanism prevents toxic increase of ammonia in the circulation. Defects in these perivenous scavenger cells result in increased ammonia concentrations in the blood[4, 7]. In the brain TNFα triggered NKCC1 expression and augmented NH4+ toxicity Along those lines TNFR1-deficient animals were resistant to acute ammonia intoxication. Therapeutic regimens targeting TNFα, TNFR1 or NKCC1 may counteract hepatic encephalopathy
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