Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia
Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia
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DOI：
10.1152/ajpgi.00317.2004
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发表时间：
2005-05-01
影响因子：
4.5
通讯作者：
Jaeschke, H
中科院分区：
文献类型：
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作者：
Dorman, RB;Gujral, JS;Jaeschke, H
用氨基半乳糖(Gal，700 mg/kg)、内毒素(ET，100µg/kg)或Gal+ET(Gal/ET)治疗C3Heb/FEJ小鼠，验证了中性粒细胞趋化因子KC和巨噬细胞炎症蛋白-2(MIP-2)参与中性粒细胞迁移和肝损伤的假说。Gal/ET或ET单独作用1.5h后，肝组织KC和MIP-2mRNA水平及血浆CXC趋化因子水平显著升高，并逐渐下降至7h，小鼠重组细胞因子(TNF-α、IL-1α和IL-1β)诱导产生CXC趋化因子，而Gal/ET无此作用。为了评估KC和MIP-2的功能重要性，C3Heb/FEJ小鼠分别用Gal/ET和对照免疫球蛋白G或联合使用抗KC和MIP-2抗体。抗CXC趋化因子抗体在7h不能减轻肝细胞凋亡、中性粒细胞窦渗出和肝损伤，而且Gal/ET对BALB/CJ野生型和CXC受体2基因敲除(CXCR2(-/-))小鼠的肝损伤无明显影响。Gal/ET后，CXCR2(-/-)小鼠肝脏中性粒细胞计数高于野生型小鼠，是由于未经处理的CXCR2(-/-)小鼠肝窦内中性粒细胞数量增加所致。Pancaspase抑制剂Z-Val-Ala-Asp-氟甲基酮可抑制Gal/ET诱导的细胞凋亡、中性粒细胞外溢和损伤，但不能消除CXC趋化因子的形成。因此，Gal/ET在肝脏中诱导大量依赖细胞因子的CXC趋化因子的形成。然而，中性粒细胞外溢和损伤发生在6-7h的细胞凋亡性损伤中，并且不依赖于CXC趋化因子的形成。
The hypothesis that the neutrophil chemoattractant CXC chemokines KC and macrophage inflammatory protein-2 (MIP-2) are involved in neutrophil transmigration and liver injury was tested in C3Heb/FeJ mice treated with galactosamine ( Gal, 700 mg/kg), endotoxin (ET, 100 mu g/kg), or Gal + ET (Gal/ET). Hepatic KC and MIP-2 mRNA levels and plasma CXC chemokine concentrations were dramatically increased 1.5 h after Gal/ET or ET alone and gradually declined up to 7 h. Murine recombinant cytokines (TNF-alpha, IL-1 alpha, and IL-1 beta), but not Gal/ET, induced CXC chemokine formation in the ET-resistant C3H/HeJ strain. To assess the functional importance of KC and MIP-2, C3Heb/FeJ mice were treated with Gal/ET and control IgG or a combination of anti-KC and anti-MIP-2 antibodies. Anti-CXC chemokine antibodies did not attenuate hepatocellular apoptosis, sinusoidal neutrophil sequestration and extravasation, or liver injury at 7 h. Furthermore, there was no difference in liver injury between BALB/cJ wild-type and CXC receptor-2 gene knockout (CXCR2(-/-)) mice treated with Gal/ET. The higher neutrophil count in livers of CXCR2(-/-) than in wild-type mice after Gal/ET was caused by the elevated number of neutrophils located in sinusoids of untreated CXCR2(-/-) animals. The pancaspase inhibitor Z-Val-Ala-Asp-fluoromethylketone eliminated Gal/ET-induced apoptosis and neutrophil extravasation and injury but not CXC chemokine formation. Thus Gal/ET induced massive, cytokine-dependent CXC chemokine formation in the liver. However, neutrophil extravasation and injury occurred in response to apoptotic cell injury at 6-7 h and was independent of CXC chemokine formation.