Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice
Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice
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DOI：
10.1152/ajpgi.00318.2003
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发表时间：
2004-03-01
影响因子：
4.5
通讯作者：
Jaeschke, H
中科院分区：
文献类型：
--
作者：
Gujral, JS;Liu, J;Jaeschke, H
胆汁淤积诱导的肝损伤在胆管梗阻引起急性炎症反应。为了进一步表征胆管结扎（BDL）模型中嗜酸性粒细胞诱导的细胞损伤的机制，我们使用野生型（WT）和ICAM-1缺陷型小鼠进行了实验。在BDL 3天后，观察到WT动物肝脏中沿着窦状隙、沿着门静脉和肝细胞上ICAM-1表达增加。中性粒细胞聚集在窦状隙中[358 +/- 44个中性粒细胞/20个高倍视野（HPF）]，>50%外渗到实质组织中。血浆丙氨酸转氨酶（ALT）水平升高23倍，观察到严重的肝细胞坏死（占总细胞的47 +/- 11%）。在这些肝脏中检测到氯酪氨酸-蛋白加合物（嗜铬细胞瘤衍生的次氯酸的标记物）和4-羟基壬烯醛加合物（脂质过氧化产物）。中性粒细胞也聚集在门静脉和外渗到门静脉束。然而，没有证据表明，氯酪氨酸或4-羟基壬烯醛蛋白加合物中检测到的门脉束。与WT动物相比，ICAM-1缺陷小鼠在BDL后血浆ALT水平降低67%，坏死减少83%。肝脏中中性粒细胞总数减少（126 +/- 25/20 HPF），85%的白细胞保留在血窦中。此外，这些肝脏显示出氯酪氨酸和4-羟基壬烯醛加合物的最小染色，表明氧化应激显著降低和细胞因子反应减弱。因此，与BDL小鼠急性胆汁淤积性肝损伤加重相关的中性粒细胞聚集在肝窦中，依赖于ICAM-1外渗到组织中，并引起涉及活性氧形成的细胞损伤。
Cholestasis-induced liver injury during bile duct obstruction causes an acute inflammatory response. To further characterize the mechanisms underlying the neutrophil-induced cell damage in the bile duct ligation (BDL) model, we performed experiments using wild-type (WT) and ICAM-1-deficient mice. After BDL for 3 days, increased ICAM-1 expression was observed along sinusoids, along portal veins, and on hepatocytes in livers of WT animals. Neutrophils accumulated in sinusoids [358 +/- 44 neutrophils/20 high-power fields (HPF)] and >50% extravasated into the parenchymal tissue. Plasma alanine transaminase (ALT) levels increased by 23-fold, and severe liver cell necrosis (47 +/- 11% of total cells) was observed. Chlorotyrosine-protein adducts (a marker for neutrophil-derived hypochlorous acid) and 4-hydroxynonenal adducts (a lipid peroxidation product) were detected in these livers. Neutrophils also accumulated in the portal venules and extravasated into the portal tracts. However, no evidence for chlorotyrosine or 4-hydroxynonenal protein adducts was detected in portal tracts. ICAM-1-deficient mice showed 67% reduction in plasma ALT levels and 83% reduction in necrosis after BDL compared with WT animals. The total number of neutrophils in the liver was reduced (126 +/- 25/20 HPF), and 85% of these leukocytes remained in sinusoids. Moreover, these livers showed minimal staining for chlorotyrosine and 4-hydroxynonenal adducts, indicating a substantially reduced oxidant stress and a diminished cytokine response. Thus neutrophils relevant for the aggravation of acute cholestatic liver injury in BDL mice accumulate in hepatic sinusoids, extravasate into the tissue dependent on ICAM-1, and cause cell damage involving reactive oxygen formation.