Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Inflamm Res. 2011 Apr;60(4):357-66. doi: 10.1007/s00011-010-0278-1. Epub 2010 Nov 10.
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 Gö6976, a PKD inhibitor, on lipopolysaccharide (LPS) and D: -galactosamine (D: -GalN)-induced acute liver injury in mice.
Mice were pretreated intraperitoneally with Gö6976 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 Gö6976 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 Gö6976 were paralleled by suppressed activation of mitogen-activated protein kinases (MAPKs), decreased expression of tumor necrosis factor-α (TNF-α) and adhesion molecules, and reduced apoptosis and myeloperoxidase (MPO) activity in liver.
Our experimental data indicated that Gö6976, a PKD inhibitor, could effectively prevent LPS/D: -GalN-induced acute liver injury by inhibition of MAPKs activation to reduce TNF-α production. This suggests the potential pharmacological value of PKD inhibitors in the intervention of inflammation-based liver diseases.
蛋白激酶 D（PKD）是一种新发现的丝氨酸/苏氨酸蛋白激酶，在炎症反应中发挥关键作用。本研究旨在探讨 PKD 抑制剂 Gö6976 对脂多糖（LPS）和 D：-半乳糖胺（D：-GalN）诱导的小鼠急性肝损伤的保护作用。
LPS/D：-GalN 给药前 30 分钟，通过腹腔内注射给予 Gö6976 预处理小鼠。随后评估死亡率和肝损伤程度。
结果表明，LPS/D：-GalN 给药显著诱导肝 PKD 激活、致死率和肝损伤，而 PKD 抑制剂 Gö6976 的预处理显著抑制 LPS 诱导的 PKD 激活，提高 LPS/D：-GalN 给药小鼠的存活率，并减轻 LPS/D：-GalN 诱导的肝损伤，表现为血清转氨酶水平降低，组织病理学变化减轻。此外，Gö6976 的保护作用与丝裂原活化蛋白激酶（MAPKs）的抑制、肿瘤坏死因子-α（TNF-α）和黏附分子表达的降低、肝凋亡和髓过氧化物酶（MPO）活性的减少平行。
我们的实验数据表明，PKD 抑制剂 Gö6976 通过抑制 MAPKs 激活减少 TNF-α 产生，可有效预防 LPS/D：-GalN 诱导的急性肝损伤。这表明 PKD 抑制剂在干预炎症相关肝病方面具有潜在的药理学价值。
