The role of cytokine and nitric oxide on multiple organ failures in hemorrhagic shock

我们通过抑制p38MAPK （FR167653）和iNOS抑制剂（氨基胍和s-甲基异硫脲）有效调节TNF-α上调，评估了TNF-α在轻度失血性休克引起的肾损害中的作用。在不进行液体复苏的情况下，麻醉雄性大鼠经颈总动脉导管以16.7%全身血液（1.09 ml/100g体重）出血20分钟，诱导轻度失血性休克。平均动脉压（MAP）和心率（HR）在出血后很快下降，但在出血后5小时内趋于恢复到基线水平。出血后1小时血清TNF-α水平明显升高。与肾功能不全程度相比，肾脏形态学改变较少被检测到。经FR167653 5mg/kg预处理后，出血引起的炎症细胞浸润和小管细胞损伤得到抑制，出血后肾功能和肠道屏障功能障碍明显改善。经氨基胍20mg/kg或s-甲基异硫脲20mg/kg预处理后，肾功能也有所改善。这些结果表明，衍生的内源性TNF-α通过轻度失血性休克时p38MAPK的激活在肾功能障碍中起关键作用，其中可能包含肠道细菌易位的参与，并且NO也可能参与肾功能障碍。此外，这些结果应有助于法医病理学家在没有明显形态学变化的实际病例中解释轻度出血所致肾功能障碍的发病机制，以确定死因。

We evaluated the role of TNF-α on the renal damage induced by mild hemorrhagic shock using a potent inhibitor of TNF-α up regulation through p38MAPK inhibition (FR167653) and iNOS inhibitors (aminoguanidine and s-methylisothiourea). Mild hemorrhagic shock was induced in anesthetized male rats by bleeding via a common carotid catheter for 20 minutes at 16.7% of total body blood, 1.09 ml/100g body weight, without fluid resuscitation. Mean arterial pressure (MAP) and heart rate (HR) decreased soon after hemorrhaging, but tended to return to baseline level up to 5 hours after bleeding. Serum TNF-α levels at one hour after bleeding significantly increased. The renal morphological changes were less detectable when compared with the degree of renal dysfunction.After pretreated with FR167653 5mg/kg, the inflammatory cell infiltrations and tubular cell injury induced by hemorrhaging were suppressed, and the renal dysfunction and gut barrier dysfunction after hemorrhaging improved dramatically. After pretreatment with aminoguanidine 20mg/kg or s-methylisothiourea 20mg/kg, the renal dysfunction also improved.These results show that derived endogenous TNF-α plays a key role in renal dysfunction through p38MAPK activation during mild hemorrhagic shock, containing the possible participation of intestinal bacterial translocation, and that NO may also contribute to renal dysfunction. Furthermore, these results should be useful for forensic pathologists to explain the pathogenesis of renal dysfunction induced by a mild hemorrhaging in identifying the cause of death in practical cases without significant morphological changes.