Pyrrolidine Dithiocarbamate Modulates HSP70, iNOS, and Apoptosis during Hemorrhagic Shock Resuscitation in Rats

ABSTRACT

Introduction: The aim of this study is to evaluate whether hemorrhage and resuscitation affect liver, intestinal, and renal expressions of heat shock protein 70 (HSP70), inducible nitric oxide synthase (iNOS), and apoptosis indexes (TUNEL, caspase-3 activation) and whether the expression of these proteins can be modulated by pyrrolidine dithiocarbamate (PDTC) after a nonlethal hemorrhagic shock (HS) in rats. Methods: Forty rats were randomized into four groups: sham-operated, only HS, HS/resuscitation with blood plus normal saline (NS), and HS/resuscitation with blood/NS plus PDTC, 15 mg/kg body weight, intravenously. Rats were subjected to HS by blood removal to a mean arterial pressure of 35–40 mmHg through the femoral artery. After 1 hr of shock, the animals were resuscitated according to the experimental protocol. HSP70, iNOS, cleaved caspase-3 expression, and TUNEL were analyzed in liver, small intestine, and kidney 3 hr after resuscitation. Results: HS upregulated HSP70, iNOS, cleaved caspase-3 expression, and induced apoptosis (TUNEL) (p < .05 to < .001). Resuscitation was not associated with further increase of their expressions. The administration of PDTC during resuscitation decreased liver, intestinal, and renal activation of iNOS and apoptosis indexes (p < .05 to < .001), and was associated with further increase in HSP70 expression (p < .05). Conclusions: Our results show that HS resuscitation with PDTC modulates several signaling pathways (HSP70, iNOS, TUNEL, and caspase-3) in a rat model. The results suggest that PDTC administration—by reducing apoptosis and iNOS expression—may have a potential role in minimizing organ damage after severe hemorrhage.

Keywords: :

• hemorrhage
• resuscitation
• systemic inflammation
• pyrrolidine dithiocarbamate
• heat shock protein
• inducible nitric oxide synthase
• caspase-3
• rat