Heat Shock Protein-70 Inducers and iNOS Inhibitors as Therapeutics to Ameliorate Hemorrhagic Shock

摘要

Hemorrhagic shock is the principal cause of death of soldiers in the battlefield. Although the underlying mechanisms are still not fully understood, it has been shown that nitric oxide (NO) overproduction and inducible nitric oxide synthase (iNOS) overexpression play important roles in producing injury caused by hemorrhagic shock. In addition, polymorphonuclear neutrophils (PMN) infiltrate injured tissues and leukotriene B4 (LTB4) generation increases. In a hemorrhage/resuscitation-induced injury model, iNOS, cyclooxygenase-2, and CD14 are all upregulated. The early response genes such as iNOS and cyclooxygenase-2 then promote the inflammatory response by the rapid and excessive production of NO and prostaglandins, respectively. It has been evident that either upregulation of inducible heat shock protein 70 kDa (HSP-72) or downregulation of iNOS can limit tissue injury caused by ischemia/reperfusion or hemorrhage/resuscitation. In our laboratory, geldanamycin, a member of ansamycin family, induces HSP-70i overexpression, to inhibit iNOS expression, to reduce cellular caspase-3 activity, and to preserve cellular ATP levels. With future combat operations expecting longer evacuation times and limited availability of medical supplies far-forward, significant improvements in fluid resuscitation will be required if potentially salvageable injured are to be saved. The action of adjunct therapy agents in the resuscitation fluid that limit tissue injury will further reduce the hemorrhage-induced injury. Since HSP-70i overexpression and iNOS inhibition exhibit cytoprotection, a compound such as geldanamycin as a HSP-70i inducer as well as an iNOS inhibitor will represent a best additive to resuscitation fluids that may reduce hemorrhage- induced injury.