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

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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.