title: Neuroinflammation in hepatic encephalopathy: mechanistic aspects.
abstract: Hepatic encephalopathy (HE) is a major neurological complication of severe liver disease that presents in acute and chronic forms. While elevated brain ammonia level is known to be a major etiological factor in this disorder, recent studies have shown a significant role of neuroinflammation in the pathogenesis of both acute and chronic HE. This review summarizes the involvement of ammonia in the activation of microglia, as well as the means by which ammonia triggers inflammatory responses in these cells. Additionally, the role of ammonia in stimulating inflammatory events in brain endothelial cells (ECs), likely through the activation of the toll-like receptor-4 and the associated production of cytokines, as well as the stimulation of various inflammatory factors in ECs and in astrocytes, are discussed. This review also summarizes the inflammatory mechanisms by which activation of ECs and microglia impact on astrocytes leading to their dysfunction, ultimately contributing to astrocyte swelling/brain edema in acute HE. The role of microglial activation and its contribution to the progression of neurobehavioral abnormalities in chronic HE are also briefly presented. We posit that a better understanding of the inflammatory events associated with acute and chronic HE will uncover novel therapeutic targets useful in the treatment of patients afflicted with HE.
authors.affiliation: Laboratory of Neuropathology, Veterans Affairs Medical Center, Miami, FL, USA.
authors.forename: Arumugam R
authors.initials: AR
authors.lastname: Jayakumar
authors.affiliation: Department of Pathology, University of Miami School of Medicine, Miami, FL, USA.
authors.forename: Kakulavarapu V
authors.initials: KV
authors.lastname: Rama Rao
authors.affiliation: Laboratory of Neuropathology, Veterans Affairs Medical Center, Miami, FL, USA ; Department of Pathology, University of Miami School of Medicine, Miami, FL, USA ; Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Norenberg
keywords: AHE, acute hepatic encephalopathy; ALF, acute liver failure; BBB, blood–brain barrier; BDL, bile duct ligation; COX2, cyclooxygenase-2; ECs, endothelial cells; FHF, fulminant hepatic failure; HE, hepatic encephalopathy; HO, hemoxygenase; IL, interleukin; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-kappaB; NOX, NADPH oxidase; ONS, oxidative/nitrative stress; PLA2, phospholipase-A2; RONS, reactive oxygen and nitrogen species; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-alpha; Tg, transgenic; WT, wild type; ammonia; cNOS, constitutive nitric oxide synthase; hepatic encephalopathy; iNOS, inducible nitric oxide synthase; neuroinflammation