The Role of Transforming Growth Factor Beta in Hepatic Encephalopathy Pathogeneis



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Hepatic encephalopathy (HE) is a neurological complication that arises due to liver dysfunction and is associated with increased circulating ammonia and a systemic immune response. Treatment paradigms have attempted to minimize the metabolic and inflammatory consequences of liver failure. However, investigations into the specific cell signaling mechanisms between the liver and brain that induce these pathological processes are currently lacking. Both TGF?1 and Shh are known to be upregulated in the liver and present in the circulation following liver damage. These studies employed the azoxymethane (AOM) model of acute liver failure in mice, the bile duct ligation (BDL) model of minimal HE in rats, and patients with liver cirrhosis who had HE to study cell signaling and pathological processes present during HE. Studies of specific cellular signaling mechanisms were performed in isolated primary neurons and immortalized brain endothelial cells. All pharmacological manipulations of hedgehog signaling, TGF? signaling, and clodronate-liposome depletion of microglia were performed in AOM mice. Gli1 was upregulated in AOM, BDL, and HE patient cortices. Shh was upregulated in the liver and serum during HE, but had no effect on neurological decline. Liver TGF?1 signaling was upregulated and had increased expression in cortical neurons. TGF?1 suppressed neuronal Gli1 via SMAD3. The use of neutralizing antibodies against TGF? generated neuroprotection during HE. The BBB was disrupted during AOM-induced HE and neutralizing antibodies against TGF? significantly reduced permeability. Studies using bEnd.3 cells found that TGF?1 suppressed Claudin-5 and increased MMP9 through a SMAD3-dependent mechanism. Depletion of microglia with clodronate liposomes in AOM mice was protective. Cortical CCL3/CCR1 axis signaling was elevated during HE and was reduced with neutralizing antibodies against TGF?. Also, treatment with neutralizing antibodies against TGF? reduced microgliosis and microglia activation. CCL3 KO mice had no changes in neurological decline compared to wild-type mice. Elevation of Gli1 or suppression of TGF?1 was neuroprotective during HE. TGF?1 increased BBB permeability and generated microglia activation and microgliosis during HE though this effect was not through the CCL3/CCR1 signaling axis. Gli1 or TGF?1 may be therapeutic targets for the treatment and management of HE.