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(J Hepatol 44: , 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. KeywordsBlood-brain barrier; Brain edema; Acute liver failure Dear Editors, I have read the article (Sawara et al., 2009) with great interest. However, I would like to call your attention to the statement in the article, "In contrast to the present study, azoxymethane-treated mice manifest clear signs of physical breakdown of the BBB including extravasation of sodium fluorescein and Evans blue." We believe this is an incorrect interpretation of the cited work.In our report, "Matrix metalloproteinase-9 contributes to the brain extravasation and edema in fulminant hepatic failure mice," (Nguyen et al., 2006) we demonstrated the first evidence that a vasogenic mechanism takes part in the development of brain edema in acute liver failure (ALF). The original characterization of this mouse model of ALF by Matkowskyj et al. (1999) and recent further examination of this model by Dr. Butterworth's lab confirmed that this mouse model recapitulates the ALF in humans (Belanger et al., 2006). We further demonstrated the increased BBB permeability to Evans blue dye and water in azoxymethane-induced ALF in mice (Nguyen et al., 2006). The leakage of Evans blue was visualized as brain extravasation. When we examined the brains under fluorescent microscopy, the extravasated dye was observed in the immediate surrounding region of the brain capillary. More importantly, the electron microscopic evaluations showed intact BBB (Fig. 1). The evidence of astrocytic swelling is obvious. We did not observe any significant structural alterations of the brain capillaries of the azoxymethane-induced ALF mice under electron microscopy (Fig. 1a) as compared to the brain of the normal control mice (Fig. 1b). The tight junction was intact. The results from our lab are consistent with the previous

Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

“…Some researchers have focused on postoperative behavior of TIMP-1 [28] . In particular, TIMP-1 has extrahepatic effects during liver failure [23,[49][50][51][52] and therefore we initially expected that TIMP-1 would show differences in the liver samples. However, zymography for TIMP-1 did not show any differences, although groups with shear stress and portal hypertension (i.e., 60% hepatectomy and 40% SOLT) showed increased protein expression of TIMP-1 in western blotting.…”