权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of sepsis-induced cholestatic liver injury

脓毒症所致胆汁淤积性肝损伤的机制

基本信息

批准号：
11671162
负责人：
NISHIDA Toshirou
金额：
$ 2.3万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671162/
关键词：
Endotoxin Apotosis Hepatocyte Kupffer cell Bilirubin Bile Acids Caspase-3 MAP Kinases 肝障害胆汁鬱滞

项目摘要

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.

我们研究了脓毒症引起的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的清除率和它们进入胆汁的输出量在感染的存在下减少。这种现象的主要原因之一被认为是细菌的脂多糖（LPS）和肽聚糖。接下来，我们使用LPS注射大鼠模型研究细胞学机制。注射LPS可诱导时间和剂量依赖性肝细胞凋亡，同时激活肝细胞中的caspase-3。当枯否细胞失活时，没有凋亡。抗TNF α抗体的加入降低了caspase-3的活化以及肝细胞的凋亡。即使在存活的肝细胞中，NTCP、OATP和CMOAT等胆汁酸和胆红素转运蛋白的表达也随着LPS的注射而呈时间和剂量依赖性下降，枯否细胞失活也抑制了这些转运蛋白的表达。NTCP、OATP和CMOAT表达的降低可被抗IL-1α抗体抑制，但不被抗TNF α抗体抑制。通过加入LPS，MAP激酶（ERK、JNK和p38 MAP激酶）的激活已经被证实，并且我们表明这些激酶的抑制剂抑制这些转运蛋白表达的降低。这些结果表明，LPS诱导肝细胞凋亡（肝细胞数量减少），并通过激活的枯否细胞分泌的细胞因子降低胆汁酸和胆红素转运蛋白的表达。因此，可以认为肝脏的胆汁分泌减少。