Plasminogen activator inhibitor-1 limits liver injury and facilitates regeneration after acetaminophen overdose
Plasminogen activator inhibitor-1 limits liver injury and facilitates regeneration after acetaminophen overdose
复制标题
DOI：
10.1093/toxsci/kfn091
复制
发表时间：
2008-08-01
影响因子：
3.8
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Bajt, Mary Lynn;Yan, Hui-Min;Jaeschke, Hartmut
已知纤溶酶原激活剂抑制剂 1 (PAI-1) 基因表达缺陷会在许多肝毒性模型中促进生长因子激活和再生。为了评估 PAI-1 在对乙酰氨基酚 (APAP) 肝毒性中是否具有类似作用，用 200 mg/kg APAP 治疗野生型 (WT) 和 PAI-1 基因敲除小鼠 (PAI-KO)，并评估肝损伤及其修复。在 WT 动物中，血浆丙氨酸氨基转移酶 (ALT) 活性在前 12 小时内增加，然后在 48 小时内恢复到基线。坏死面积与 ALT 值平行增加，在 12 至 24 小时之间达到峰值，并在 96 小时完全消退。坏死区外细胞的再生反应，如增殖细胞核抗原蛋白和细胞周期蛋白 D-1 基因表达所示，在 24 小时内观察到，在 48 小时达到峰值，然后下降，但一直保持升高直至 96 小时。在前 12 小时内，PAI-KO 中对 APAP 的肝损伤与 WT 动物相似。然而，在接下来的12小时内，随着大量肝内出血的发生，血浆ALT值和坏死面积进一步增加。大约 50% 的 PAI-KO 动物未能存活。尽管存活动物的肝损伤得到修复，但再生过程延迟至48小时。这种延迟的一个潜在原因可能是由于更严重的损伤和/或细胞周期抑制剂 p21 的表达增加。我们的数据表明，PAI 激活可防止过度出血，从而促进组织修复，从而限制 APAP 肝毒性期间的肝损伤和死亡率。
Deficiency in plasminogen activator inhibitor-1 (PAI-1) gene expression is known to promote growth factor activation and regeneration in a number of hepatotoxicity models. To evaluate if PAI-1 has similar effects in acetaminophen (APAP) hepatotoxicity, wild-type (WT) and PAI-1 gene knockout mice (PAI-KO) were treated with 200 mg/kg APAP and liver injury and its repair were assessed. In WT animals, plasma alanine aminotransferase (ALT) activities increased during the first 12 h and then returned to baseline within 48 h. The area of necrosis increased in parallel to the ALT values, peaked between 12 and 24 h and was completely resolved by 96 h. The regenerative response of cells outside the necrotic area, as indicated by proliferating cell nuclear antigen protein and cyclin D-1 gene expression, was observed within 24 h, peaked at 48 h and then declined but remained elevated until 96 h. Liver injury in response to APAP was similar in PAI-KO as in WT animals during the first 12 h. However, plasma ALT values and the area of necrosis further increased during the following 12 h with development of massive intrahepatic hemorrhage. Approximately, 50% of the PAI-KO animals did not survive. Although liver injury of the surviving animals was repaired, the regeneration process was delayed until 48 h. A potential reason for this delay may have been due to the more severe injury and/or the increased expression of the cell cycle inhibitor p21. Our data indicate that PAI activation limits liver injury and mortality during APAP hepatotoxicity by preventing excessive hemorrhage and thereby facilitating tissue repair.