Ethyl pyruvate ameliorates hepatic injury following blunt chest trauma and hemorrhagic shock by reducing local inflammation, NF-kappaB activation and HMGB1 release.

Abstract

The treatment of patients with multiple trauma including blunt chest/thoracic trauma (TxT) and hemorrhagic shock (H) is still challenging. Numerous studies show detrimental consequences of TxT and HS resulting in strong inflammatory changes, organ injury and mortality. Additionally, the reperfusion (R) phase plays a key role in triggering inflammation and worsening outcome. Ethyl pyruvate (EP), a stable lipophilic ester, has anti-inflammatory properties. Here, the influence of EP on the inflammatory reaction and liver injury in a double hit model of TxT and H/R in rats was explored.Female Lewis rats were subjected to TxT followed by hemorrhage/H (60 min, 35±3 mm Hg) and resuscitation/R (TxT+H/R). Reperfusion was performed by either Ringer`s lactated solution (RL) alone or RL supplemented with EP (50 mg/kg). Sham animals underwent all surgical procedures without TxT+H/R. After 2h, blood and liver tissue were collected for analyses, and survival was assessed after 24h.Resuscitation with EP significantly improved haemoglobin levels and base excess recovery compared with controls after TxT+H/R, respectively (p<0.05). TxT+H/R-induced significant increase in alanine aminotransferase levels and liver injury were attenuated by EP compared with controls (p<0.05). Local inflammation as shown by increased gene expression of IL-6 and ICAM-1, enhanced ICAM-1 and HMGB1 protein expression and infiltration of the liver with neutrophils were also significantly attenuated by EP compared with controls after TxT+H/R (p<0.05). EP significantly reduced TxT+H/R-induced p65 activation in liver tissue. Survival rates improved by EP from 50% to 70% after TxT+H/R.These data support the concept that the pronounced local pro-inflammatory response in the liver after blunt chest trauma and hemorrhagic shock is associated with NF-κB. In particular, the beneficial anti-inflammatory effects of ethyl pyruvate seem to be regulated by the HMGB1/NF-κB axis in the liver, thereby, restraining inflammatory responses and liver injury after double hit trauma in the rat.