Department of Pathology, University of Miami, Miller School of Medicine, PO Box 016960, Miami, Fl 33101, USA.
Am J Pathol. 2010 Mar;176(3):1400-8. doi: 10.2353/ajpath.2010.090756. Epub 2010 Jan 14.
Brain edema and the associated increase in intracranial pressure are potentially lethal complications of acute liver failure (ALF). Astrocyte swelling (cytotoxic edema) represents a significant component of the brain edema in ALF, and elevated blood and brain ammonia levels have been strongly implicated in its formation. We earlier showed in cultured astrocytes that oxidative stress (OS) and the mitochondrial permeability transition (mPT) play major roles in the mechanism of ammonia-induced astrocyte swelling. Glutamine, a byproduct of ammonia metabolism, has also been shown to induce OS, the mPT, and astrocyte swelling. Such effects of glutamine were suggested to be mediated by its hydrolysis in mitochondria, potentially yielding high levels of ammonia in this organelle and leading to OS and the mPT. L-histidine, an inhibitor of mitochondrial glutamine transport, was recently shown to mitigate OS, mPT, and cell swelling in cultured astrocytes treated with ammonia. The present study examined whether L-histidine similarly abolishes OS, the mPT, and brain edema in a rat model of ALF. Treatment of rats with thioacetamide caused a significant degree of brain edema, which was associated with induction of OS and the mPT. These changes were completely abolished by L-histidine, supporting a key role of mitochondrial glutamine transport and hydrolysis in the mechanism of the brain edema associated with ALF.
脑水肿和随之而来的颅内压升高是急性肝衰竭（ALF）的潜在致命并发症。星形胶质细胞肿胀（细胞毒性水肿）是 ALF 脑水肿的重要组成部分，血液和脑内氨水平升高强烈提示其形成。我们之前在培养的星形胶质细胞中表明，氧化应激（OS）和线粒体通透性转换（mPT）在氨诱导的星形胶质细胞肿胀机制中起主要作用。氨代谢的副产物谷氨酰胺也被证明会诱导 OS、mPT 和星形胶质细胞肿胀。谷氨酰胺的这种作用被认为是通过其在线粒体中的水解介导的，可能导致该细胞器中氨水平升高，并导致 OS 和 mPT。最近的研究表明，线粒体谷氨酰胺转运抑制剂 L-组氨酸可减轻氨处理的培养星形胶质细胞中的 OS、mPT 和细胞肿胀。本研究探讨了 L-组氨酸是否同样可以消除 ALF 大鼠模型中的 OS、mPT 和脑水肿。用硫代乙酰胺处理大鼠会导致明显程度的脑水肿，这与 OS 和 mPT 的诱导有关。L-组氨酸完全消除了这些变化，支持线粒体谷氨酰胺转运和水解在与 ALF 相关的脑水肿机制中起关键作用。
