Mechanisms of sepsis-induced cholestatic liver injury

我们探讨了脓毒症所致胆汁淤积性肝损伤的作用和机制。我们发现胆红素和胆汁酸从血液中清除，它们进入胆汁的输出量在感染时减少。这一现象的主要原因之一被认为是细菌产生的脂多糖和多糖肽。接下来，我们用大鼠注射脂多糖的模型来研究细胞学机制。注射脂多糖可诱导时间和剂量依赖的肝细胞凋亡，并伴有肝细胞内caspase-3的激活。Kupffer细胞灭活后，未见细胞凋亡。加入抗肿瘤坏死因子α抗体后，半胱氨酸天冬氨酸氨基转移酶-3活性降低，肝细胞凋亡减少。即使在存活的肝细胞中，注射LPS后胆汁酸和胆红素的转运蛋白如NTCP、OATP和CMOAT的表达也呈时间和剂量依赖性地下降。这些转运蛋白的降解率也被Kupffer细胞灭活所抑制。加入抗IL-1α抗体，但不能抑制抗肿瘤坏死因子α抗体对NtCP、OATP和Cmoat表达的抑制作用。通过加入内毒素，MAP激酶(ERK、JNK和p38 MAP激酶)的激活已被证实，我们发现这些激酶的抑制剂抑制了这些转运蛋白的表达下降。这些结果提示，内毒素诱导肝细胞凋亡(肝细胞数量减少)，胆汁酸和胆红素转运体的表达减少是通过激活的枯否细胞分泌的细胞因子来实现的。因此，可以认为肝脏的胆汁分泌减少。

We have examined the effect and mechanism of sepsis-induced cholestatic liver injury. We showed bilirubin and bile acid clearance from the blood and their output into the bile were reduced in the presence of infection. One of main causes of this phenomenon has been considered to be lipopolysaccharide (LPS) and peptidglycan from bacteria. Next, we examined cytological mechanisms using LPS-injection model of rats. Injection of LPS induced time- and dose-dependent hepatocyte apoptosis with concomitant activation of caspase-3 in hepatocytes. When Kupffer cells were inactivated, there was no apoptosis. Addition of anti-TNFα antibody decreased activation of caspase-3 as well as apoptosis of hepatocytes. Even in survived hepatocytes, expression of transport proteins for bile acids and bilirubin, such as NTCP, OATP and CMOAT, was time- and dosedependently decreased after injection of LPS.Decrease in these transport proteins was also suppressed by Kupffer cell inactivation. The decrease in NTCP, OATP and CMOAT expression was inhibited by addition of anti-IL-1α antibody, but not anti-TNFα antibody. By LPS addition, activation of MAP kinases (ERK, JNK and p38 MAP kinases) has been confirmed and we showed that inhibitors of these kinases inhibited decrease in expression of these transporters. These results suggested that LPS induced hepatocyte apoptosis (decrease in the number of hepatocytes) and decreased in expression of bile acid and bilirubin transporters via cytokines secreted from activated Kupffer cells. Consequently, it may be considered that bile secretion of the liver is decreased.