Protective effect of Go6976, a PKD inhibitor, on LPS/d-GalN-induced acute liver injury in mice
Protective effect of Go6976, a PKD inhibitor, on LPS/d-GalN-induced acute liver injury in mice
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DOI：
10.1007/s00011-010-0278-1
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发表时间：
2011-04-01
影响因子：
6.7
通讯作者：
Liu, Y. S.
中科院分区：
文献类型：
--
作者：
Duan, G. J.;Zhu, J.;Liu, Y. S.
蛋白激酶D（PKD）是一种新近发现的丝氨酸/苏氨酸蛋白激酶，在炎症反应中起着关键作用。在本研究中，我们研究了Go 6976，PKD抑制剂，对脂多糖（LPS）和d-氨基半乳糖（d-GalN）诱导的小鼠急性肝损伤的保护作用。结果表明，LPS/d-GalN给药显著诱导肝脏PKD活化、致死和肝损伤，而PKD抑制剂Go 6976预处理显著抑制LPS诱导的PKD活化，改善LPS/d-GalN给药小鼠的存活率并减轻LPS/d-GalN诱导的肝损伤，如血清转氨酶水平降低以及组织病理学变化减少所证明的。此外，Go 6976的保护作用通过抑制丝裂原活化蛋白激酶（MAPK）的活化，降低肿瘤坏死因子-α（TNF-α）的表达而被证实。我们的实验数据表明，Go 6976，一种PKD抑制剂，通过抑制MAPKs的活化，减少TNF-α的产生，可有效预防LPS/d-GalN诱导的急性肝损伤。这表明PKD抑制剂在干预炎症性肝病中的潜在药理学价值。
Protein kinase D (PKD) is a newly described serine/threonine protein kinase that plays a pivotal role in inflammatory response. In the present study, we examined the protective effect of Go6976, a PKD inhibitor, on lipopolysaccharide (LPS) and d-galactosamine (d-GalN)-induced acute liver injury in mice.Mice were pretreated intraperitoneally with Go6976 30 min before LPS/d-GalN administration . The mortality and degree of hepatic injury was subsequently assessed.The results indicated that LPS/d-GalN administration markedly induced hepatic PKD activation, lethality and liver injury, while pretreatment of the PKD inhibitor Go6976 significantly inhibited LPS-induced PKD activation, improved the survival of LPS/d-GalN-administered mice and attenuated LPS/d-GalN-induced liver injury, as evidenced by reduced levels of serum aminotransferases as well as reduced histopathological changes. In addition, the protective effects of Go6976 were paralleled by suppressed activation of mitogen-activated protein kinases (MAPKs), decreased expression of tumor necrosis factor-alpha (TNF-alpha) and adhesion molecules, and reduced apoptosis and myeloperoxidase (MPO) activity in liver.Our experimental data indicated that Go6976, a PKD inhibitor, could effectively prevent LPS/d-GalN-induced acute liver injury by inhibition of MAPKs activation to reduce TNF-alpha production. This suggests the potential pharmacological value of PKD inhibitors in the intervention of inflammation-based liver diseases.