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

我们通过抑制p38MAPK(FR167653)和诱导型一氧化氮合酶(α)抑制剂(氨基胍和S-甲基异硫脲)，评价了肿瘤坏死因子-α在轻度失血性休克肾损伤中的作用。麻醉雄性大鼠经颈总动脉导管放血20min，失血总量16.7%，体重1.09ml/100g体重，不复苏，造成轻度失血性休克。平均动脉压(MAP)和心率(HR)在出血后不久下降，但在出血后5小时趋于恢复到基线水平。出血后1小时血清肿瘤坏死因子-α水平明显升高。FR16765 3 5 mg/kg可明显抑制失血性肾小管上皮细胞的炎症细胞浸润和肾小管细胞损伤，明显改善失血性肾功能障碍和肠屏障功能障碍。提示轻度失血性休克时，内源性肿瘤坏死因子-α可能通过激活p38MAPK参与肾功能损害，可能参与了肠道细菌移位，NO也可能参与了肾功能损害。此外，这些结果将有助于法医病理学家解释轻微出血引起的肾功能障碍的发病机制，从而在实际病例中确定死亡原因，而不会出现明显的形态变化。

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.