CYTOKINE-INDUCED UP-REGULATION OF HEPATIC INTERCELLULAR-ADHESION MOLECULE-1 MESSENGER-RNA EXPRESSION AND ITS ROLE IN THE PATHOPHYSIOLOGY OF MURINE ENDOTOXIN-SHOCK AND ACUTE LIVER-FAILURE
CYTOKINE-INDUCED UP-REGULATION OF HEPATIC INTERCELLULAR-ADHESION MOLECULE-1 MESSENGER-RNA EXPRESSION AND ITS ROLE IN THE PATHOPHYSIOLOGY OF MURINE ENDOTOXIN-SHOCK AND ACUTE LIVER-FAILURE
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DOI：
10.1002/hep.1840210623
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发表时间：
1995-06-01
期刊：
影响因子：
13.5
通讯作者：
JAESCHKE, H
中科院分区：
文献类型：
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作者：
ESSANI, NA;FISHER, MA;JAESCHKE, H
内毒素血症时中性粒细胞诱导的肝损伤依赖于中性粒细胞上的粘附分子Mac-1（CD 11b/CD 18）。在半乳糖胺致敏小鼠（Gal）中给予100 μ g/kg马流产沙门氏菌内毒素（ET）后，研究了其反受体细胞间粘附分子-1（ICAM-1）在发病机制中的潜在参与。在产生大量肿瘤坏死因子-α（TNF-α）的ET-敏感小鼠（C3 Heb/FeJ）中，观察到大量中性粒细胞浸润和严重的肝损伤。在不产生TNF-α的ET-抗性株（C3 H/HeJ）中，Gal/ET未能引起中性粒细胞积聚或损伤。Gal/ET可选择性地诱导ET敏感小鼠ICAM-1 mRNA的表达，而对照组肝脏ICAM-1 mRNA的表达可忽略不计。静脉注射小鼠TNF-α、白细胞介素-1 α（IL-1a）或IL-1 β（13至23 μ g/kg）强烈诱导两种菌株中的ICAM-1信息，显示出相当的ICAM-1 mRNA合成能力。所有的细胞因子引起类似的中性粒细胞在肝脏中的积累;然而，只有Gal/TNF-α也引起循环中性粒细胞上Mac-1的上调和肝损伤。与同种型匹配的对照抗体治疗的动物相比，抗鼠ICAM-1单克隆抗体YN.1（3 mg/kg）使ET敏感小鼠的肝损伤减轻了67%至90%，但没有减少肝窦中的中性粒细胞蓄积。我们的数据表明，细胞因子TNF-α和IL-1是负责上调ICAM-1 mRNA在肝脏内毒素血症的主要介质。两种粘附分子ICAM-1和Mac-1的上调是嗜中性粒细胞诱导的肝损伤发生所必需的。阻断ICAM-1和/或干扰ICAM-1诱导可能是预防脓毒症相关炎性肝损伤的成功治疗策略。
Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecule Mac-1 (CD11b/ CD18) on neutrophils. The potential involvement of its counterreceptor, intercellular adhesion molecule-1 (ICAM-1), in the pathogenesis was investigated after administration of 100 mu g/kg Salmonella abortus equi endotoxin (ET) in galactosamine-sensitized mice (Gal). In ET-sensitive mice (C3Heb/FeJ), which generated large amounts of tumor necrosis factor-alpha (TNF-alpha), massive neutrophil infiltration and severe liver injury were observed. In an ET-resistant strain (C3H/HeJ), which did not generate TNF-alpha, Gal/ET failed to cause neutrophil accumulation or injury. ICAM-1 messenger RNA (mRNA), negligible in control livers, was selectively induced by Gal/ET in ET-sensitive mice. Intravenous injection of murine TNF-alpha, interleukin-1 alpha (IL-1a) or IL-1 beta (13 to 23 mu g/kg) strongly induced the ICAM-1 message in both strains, showing a comparable capacity for ICAM-1 mRNA synthesis. All cytokines caused similar neutrophil accumulation in the liver; however, only Gal/ TNF-alpha also caused upregulation of Mac-1 on circulating neutrophils and liver injury. The anti-murine ICAM-1 monoclonal antibody YN.1 (3 mg/kg) attenuated liver injury in ET-sensitive mice by 67% to 90% compared with isotype-matched control antibody-treated animals but did not reduce neutrophil accumulation in hepatic sinusoids. Our data suggest that the cytokines TNF-alpha and IL-1 are the main mediators responsible for upregulation of ICAM-1 mRNA in the liver during endotoxemia. The upregulation of both adhesion molecules, ICAM-1 and Mac-1, is necessary for a neutrophil-induced liver injury to occur. Blocking ICAM-1 and/or interfering with ICAM-1 induction could be a successful therapeutic strategy to prevent sepsis related inflammatory liver injury.