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

细胞因子和一氧化氮在失血性休克多器官衰竭中的作用

• 批准号: 12470110
• 负责人: TANAKA Noriyuki
• 金额: $ 2.75万
• 依托单位: University of Occupational and Environmental Health
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470110/
• 关键词: mild hemorrhagic shock; TNF-α; inflammation; renal dysfunction; FR167653; aminoguanidine; s-methylisothiourea; 出血性ショック; サイトカイン; 腸管血流量; 血行動態; 血流量

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.

我们使用通过抑制p38 MAPK而上调TNF-α的有效抑制剂（FR 167653）和iNOS抑制剂（氨基胍和s-甲基异硫脲）来评价TNF-α在轻度失血性休克诱导的肾损伤中的作用。在麻醉的雄性大鼠中，通过经颈总动脉导管以16.7%的全身血液、1.09 ml/100 g体重放血20 min，诱导轻度失血性休克，不进行液体复苏。平均动脉压（MAP）和心率（HR）在出血后很快下降，但在出血后5小时内趋于恢复至基线水平。出血后1h血清TNF-α水平显著升高。FR 167653 5 mg/kg预处理后，可明显抑制肾移植引起的炎性细胞浸润和肾小管细胞损伤，显著改善肾移植后的肾功能和肠屏障功能障碍。结果表明，内源性TNF-α通过激活p38 MAPK在轻度失血性休克时肾功能损害中起重要作用，肠道细菌移位可能参与其中，NO也可能参与肾功能损害的发生。此外，这些结果应有助于法医病理学家解释的发病机制引起的肾功能不全的轻度损伤，在确定的实际情况下，没有显着的形态学变化的死亡原因。