Subtle BBB alterations in brain edema associated with acute liver failure

Abstract

Vasogenic mechanism of brain edema in acute liver failure (ALF) remains poorly understood. Recent work demonstrates that matrix metalloproteinase-9 (MMP-9) contributes to the development of brain edema in experimental ALF (J Hepatol 44:1105, 2006). Importantly, MMP-9 blockage with specific monoclonal antibodies and/or synthetic inhibitor, the edema is attenuated. Specifically, utrastructural evaluations demonstrate intact blood-brain barrier and its tight junction. These results suggest that subtle alterations in BBB are likely to involve in the brain edema associated with ALF.

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

“…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. 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.…”

Matrix metalloproteinase‐9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy: A pilot study in mice

“…However, the onset of coma and advanced stages of encephalopathy marks the beginning of the lethal course of FLF . It is during the early stage that the blood–brain barrier (BBB) becomes permeable to small molecules . If the BBB dysfunction persists, brain edema and herniation will result .…”

“…39 It is during the early stage that the blood-brain barrier (BBB) becomes permeable to small molecules. [40][41][42] If the BBB dysfunction persists, brain edema and herniation will result. 28,34 Our previous reports 28,30,31,34,35,[41][42][43][44] are consistent with previous reports [45][46][47][48] on the brain damage during FLF, and our previous findings collectively corroborate that MMP-9 induces significant alterations in brain endothelial cells during FLF, and that BBB dysfunction is associated with increased permeability only to small molecules and ammonia, but is not necessarily associated with a structural breakdown.…”

“…[40][41][42] If the BBB dysfunction persists, brain edema and herniation will result. 28,34 Our previous reports 28,30,31,34,35,[41][42][43][44] are consistent with previous reports [45][46][47][48] on the brain damage during FLF, and our previous findings collectively corroborate that MMP-9 induces significant alterations in brain endothelial cells during FLF, and that BBB dysfunction is associated with increased permeability only to small molecules and ammonia, but is not necessarily associated with a structural breakdown. 28,30,31,34,35,[41][42][43][44] Recently, other researchers have demonstrated that a leaky BBB could result from subtle alterations in tight junctions, [49][50][51][52] and we also consider that the regulation of tight junction integrity and the activation of epidermal growth factor receptors in FLF are important for preventing brain edema in FLF.…”