No changes in expression of tight junction proteins or blood–brain barrier permeability in azoxymethane-induced experimental acute liver failure

Bémeur, Chantal; Chastre, Anne; Desjardins, Paul; Butterworth, Roger F.

doi:10.1016/j.neuint.2009.11.012

Cited by 10 publications

(9 citation statements)

References 14 publications

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“…In our study, we demonstrate that vasogenic brain edema is an important pathophysiological component in the development of intracranial hypertension in ALF. Our study has recently been supported by Chen and colleagues [20] who demonstrated disruptions of tight junction proteins implicated in the integrity of the BBB in mice with ALF. Kato et al published the only human study over 15 years ago, looking at ultrastructural changes of the brain in patients who died of ALF [7].…”

Section: Discussionsupporting

confidence: 70%

Neuropathological changes in the brain of pigs with acute liver failure

Kristiansen

Lindal

Myreng

et al. 2010

Scandinavian Journal of Gastroenterology

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Kristiansen, R.G. et al., 2010. Neuropathological changes in the brain of pigs with acute liver failure. Scandinavian journal of gastroenterology, 45(7-8) ABSTRACTObjective. Cerebral edema is a serious complication of acute liver failure (ALF), which may lead to intracranial hypertension and death. An accepted tenet has been that the blood-brain barrier is intact and that brain edema is primarily caused by a cytotoxic etiology due to hyperammonemia. However, the neuropathological changes in ALF have been poorly studied. Using a well characterized porcine model we aimed to investigate ultrastructural changes in the brain from pigs suffering from ALF. Materials and methods. Sixteen female Norwegian Landrace pigs weighing 27-35 kg were randomised into two groups: ALF (n = 8) and sham operated controls (n = 8). ALF was induced with an end-to-side portacaval shunt followed by ligation of the hepatic arteries. Biopsies were harvested from three different areas of the brain (frontal lobe, cerebellum, and brain stem) following eight hours of ALF and analyzed using electron microscopy. Results. Profound perivascular and interstitial edema were found in all three areas. Disruption of pericytic and astrocytic processes were seen, reflecting breakdown/lesion of the blood-brain barrier in animals suffering from ALF. Furthermore, neurons and axons were edematous and surrounded by vesicles. Severe damage to Purkinje neuron (necrosis) and damaged myelin were seen in the cerebellum and brain stem, respectively. Biopsies from sham operated animals were normal. Conclusions. Our data support the concept that vasogenic brain edema plays an important role in the development of intracranial hypertension in pigs with ALF.

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Section: Discussionsupporting

confidence: 70%

Neuropathological changes in the brain of pigs with acute liver failure

Kristiansen

Lindal

Myreng

et al. 2010

Scandinavian Journal of Gastroenterology

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“…One group of researchers found that AOM-treated mice have disruptions of occludin, claudin-5, zona occludens-1, and zona occludens-2 protein expression as assessed with western blots(11). Conversely, other researchers have used the AOM model and observed no changes in immunoblot tight junction protein expression(34). Our studies focused only on the effects of TGFβ1 on claudin-5 expression and demonstrated that treatment of bEnd.3 cells with rTGFβ1 downregulated claudin-5 and led to the translocation of this protein from the cell membrane to the cytosol.…”

Section: Discussionmentioning

confidence: 99%

TGFβ1 exacerbates blood–brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5

McMillin

Frampton

Seiwell

et al. 2015

Laboratory Investigation

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Recent studies have found that vasogenic brain edema is present during hepatic encephalopathy following acute liver failure and is dependent upon increased matrix metalloproteinase 9 (MMP9) activity and downregulation of tight junction proteins. Furthermore, circulating transforming growth factor β1 (TGFβ1) is increased following liver damage and may promote endothelial cell permeability. This study aimed to assess if increased circulating TGFβ1 drives changes in tight junction protein expression and MMP9 activity following acute liver failure. Blood-brain barrier permeability was assessed in azoxymethane (AOM)-treated mice at 6, 12, and 18 hours post-injection via Evan’s blue extravasation. Monolayers of immortalized mouse brain endothelial cells (bEnd.3) were treated with recombinant TGFβ1 (rTGFβ1) and permeability to fluorescein isothiocyanate-dextran (FITC-dextran), MMP9 and claudin-5 expression were assessed. Antagonism of TGFβ1 signaling was performed in vivo to determine its role in blood-brain barrier permeability. Blood-brain barrier permeability was increased in mice at 18 hours following AOM injection. Treatment of bEnd.3 cells with rTGFβ1 led to a dose-dependent increase of MMP9 expression as well as a suppression of claudin-5 expression. These effects of rTGFβ1 on MMP9 and claudin-5 expression could be reversed following treatment with a SMAD3 inhibitor. AOM-treated mice injected with neutralizing antibodies against TGFβ demonstrated significantly reduced blood-brain barrier permeability. Blood-brain barrier permeability is induced in AOM mice via a mechanism involving the TGFβ1-driven SMAD3-dependent upregulation of MMP9 expression and decrease of claudin-5 expression. Therefore, treatment modalities aimed at reducing TGFβ1 levels or SMAD3 activity may be beneficial in promoting blood-brain barrier integrity following liver failure.

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“…The subject of permeability of the BBB in ALF was re assessed in the azoxymethane hepatotoxicity model but, again, findings are equivocal. Whereas there is excellent general agreement that the BBB remains grossly intact in this animal model, [49][50][51][52] some investigators have reported subtle changes in expression of BBB tight junction proteins. 53,54 These alterations in expression are caused by activation of epidermal growth factor receptor resulting in increased permeability to Evans blue dye, which could indicate increased permeability of the BBB to small molecules such as ammonia and water.…”

Section: Blood-brain Barrier Permeabilitymentioning

confidence: 95%

“…55 It should be noted, however, that these findings were not confirmed by others. 51,52 Certainly, accumulation of ammonia and water does occur in ALF, but whether this is the consequence of increased BBB permeability awaits further studies.…”

Section: Blood-brain Barrier Permeabilitymentioning

confidence: 99%

The liver–brain axis in liver failure: neuroinflammation and encephalopathy

Butterworth

2013

Nat Rev Gastroenterol Hepatol

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174

128

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Systemic inflammation is common in liver failure and its acquisition is a predictor of hepatic encephalopathy severity. New studies provide convincing evidence for a role of neuroinflammation (inflammation of the brain per se) in liver failure; this evidence includes activation of microglia, together with increased synthesis in situ of the proinflammatory cytokines TNF, IL-1β and IL-6. Liver-brain signalling mechanisms in liver failure include: direct effects of systemic proinflammatory molecules, recruitment of monocytes after microglial activation, brain accumulation of ammonia, lactate and manganese, and altered permeability of the blood-brain barrier. Ammonia and cytokines might act synergistically. Existing strategies to reduce ammonia levels (including lactulose, rifaximin and probiotics) have the potential to dampen systemic inflammation, as does albumin dialysis, mild hypothermia and N-acetylcysteine, the latter two agents acting at both peripheral and central sites. Minocycline, an agent with potent central anti-inflammatory properties, reduces neuroinflammation, brain oedema and encephalopathy in liver failure, as does the anti-TNF agent etanercept.

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No changes in expression of tight junction proteins or blood–brain barrier permeability in azoxymethane-induced experimental acute liver failure

Cited by 10 publications

References 14 publications

Neuropathological changes in the brain of pigs with acute liver failure

Neuropathological changes in the brain of pigs with acute liver failure

TGFβ1 exacerbates blood–brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5

The liver–brain axis in liver failure: neuroinflammation and encephalopathy

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