Chastre Anne, Bélanger Mireille, Nguyen Bich N, Butterworth Roger F
Neuroscience Research Unit, Saint-Luc Hospital, CRCHUM, Montreal, QC, Canada.
Liver Int. 2014 Mar;34(3):353-61. doi: 10.1111/liv.12252. Epub 2013 Aug 2.
BACKGROUND & AIMS: Acute liver failure (ALF) is frequently complicated by infection leading to precipitation of central nervous system complications such as hepatic encephalopathy (HE) and increased mortality. There is evidence to suggest that when infection occurs in ALF patients, the resulting pro-inflammatory mechanisms may be amplified that could, in turn, have a major impact on blood-brain barrier (BBB) function. The aim of this study was to investigate the role of endotoxemia on the progression of encephalopathy in relation to BBB permeability during ALF.
Adult male C57-BL6 mice with ALF resulting from azoxymethane-induced toxic liver injury were administered trace amounts of the endotoxin component lipopolysaccharide (LPS). Effects on the magnitude of the systemic inflammatory response, liver pathology and BBB integrity were measured as a function of progression of HE, defined as time to loss of corneal reflex (coma).
Lipopolysaccharide caused additional two- to seven-fold (P < 0.001) increases in circulating pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), worsening liver pathology and associated increases of circulating transaminases as well as increased hyperammonaemia consistent with a further loss of viable hepatocytes. LPS treatment of ALF mice led to a rapid precipitation of hepatic coma and the BBB became permeable to the 25-kDa protein immunoglobulin G (IgG). This extravasation of IgG was accompanied by ignificant up-regulation of matrix metalloproteinase-9 (MMP-9), an endopeptidase known to modulate opening of the BBB in a wide range of neurological disorders.
These findings represent the first direct evidence of inflammation-related BBB permeability changes in ALF.
急性肝衰竭（ALF）常并发感染，进而引发中枢神经系统并发症如肝性脑病（HE），并增加死亡率。有证据表明，ALF患者发生感染时，由此产生的促炎机制可能会被放大，进而可能对血脑屏障（BBB）功能产生重大影响。本研究的目的是探讨内毒素血症在ALF期间与BBB通透性相关的脑病进展中的作用。
给因偶氮甲烷诱导的中毒性肝损伤导致急性肝衰竭的成年雄性C57-BL6小鼠注射微量内毒素成分脂多糖（LPS）。根据HE进展情况（定义为角膜反射消失[昏迷]的时间），测量对全身炎症反应程度、肝脏病理和BBB完整性的影响。
脂多糖使循环促炎细胞因子（TNF-α、IL-1β、IL-6）增加了额外的2至7倍（P<0.001），肝脏病理恶化，循环转氨酶相关增加，高氨血症增加，这与存活肝细胞的进一步丧失一致。LPS治疗急性肝衰竭小鼠导致肝昏迷迅速发生，BBB对25 kDa蛋白免疫球蛋白G（IgG）变得通透。IgG的这种外渗伴随着基质金属蛋白酶-9（MMP-9）的显著上调，MMP-9是一种已知在多种神经系统疾病中调节BBB开放的内肽酶。
这些发现代表了急性肝衰竭中炎症相关血脑屏障通透性变化的首个直接证据。
