Abstract
Background and aimsWe developed a bio-artificial liver (BAL) using a radial-flow bioreactor and rescued mini-pig models with lethal acute liver failure (ALF). The point of the rescue is the recovery from hepatic encephalopathy (HE). HE on ALF has sometimes resulted in brain death following brain edema with astrocyte swelling. Several factors, including ammonia and glutamine, have been reported to induce astrocyte swelling and injury. However, many clinicians believe that there are any other factors involved in the development of HE. Therefore, the aim of this study was to identify novel HE-inducible factors, particularly those inducing astrocyte dysfunction.MethodsMini-pig plasma samples were collected at three time points: before the administration of toxins (α-amanitin and LPS), when HE occurred after the administration of toxins, and after treatment with extracorporeal circulation (EC) by the BAL. To identify the causative factors of HE, each plasma sample was subjected to a comparative proteome analysis with two-dimensional gel electrophoresis and mass spectrometry. To assess the direct effects of candidate factors on the astrocyte function and injury, in vitro experiments with human astrocytes were performed.ResultsUsing a proteome analysis, we identified alpha-1 antichymotrypsin (ACT), which was increased in plasma samples from mini-pigs with HE and decreased in those after treatment with EC by BAL. In in vitro experiments with human astrocytes, ACT showed growth-inhibitory and cytotoxic effects on astrocytes. In addition, the expression of water channel protein aquaporin-4, which is induced in injured astrocytes, was increased following ACT treatment. Interestingly, these effects of ACT were additively enhanced by adding arginine-vasopressin (AVP) and were canceled by adding an AVP receptor antagonist.ConclusionsThese results suggest that ACT is involved in astrocyte injury and dysfunction in concert with AVP during the development of acute HE.
Highlights
Hepatic encephalopathy (HE) is a major clinical complication in patients with severe liver disease and refers to the reversible neuropsychiatric disorder observed in acute liver failure (ALF) [1, 2]
Mini-pig plasma samples were collected at three time points: before the administration of toxins (α-amanitin and LPS), when hepatic encephalopathy (HE) occurred after the administration of toxins, and after treatment with extracorporeal circulation (EC) by the bio-artificial liver (BAL)
We identified alpha-1 antichymotrypsin (ACT), which was increased in plasma samples from mini-pigs with HE and decreased in those after treatment with EC by BAL
Summary
Hepatic encephalopathy (HE) is a major clinical complication in patients with severe liver disease and refers to the reversible neuropsychiatric disorder observed in acute liver failure (ALF) [1, 2]. We previously reported that a mini-pig model of ALF induced by α-amanitin, a mushroom-derived poison, and lipopolysaccharide (LPS) died from marked cerebral edema with increased S-100β protein in plasma, a marker of astrocytic damage, whereas minipigs with induced ALF that were treated with extracorporeal circulation (EC) using a bio-artificial liver (BAL) were able to recover from lethal HE. The induction of AVP was shown to exacerbate the ammonia-induced increase in cerebral blood flow and to hasten the development of brain edema in a model of ALF [10, 11]. We developed a bio-artificial liver (BAL) using a radial-flow bioreactor and rescued mini-pig models with lethal acute liver failure (ALF). The aim of this study was to identify novel HE-inducible factors, those inducing astrocyte dysfunction
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
