Date Published: February 8, 2018
Publisher: Public Library of Science
Author(s): Nils Wagner, Scott Dieteren, Niklas Franz, Kernt Köhler, Katharina Mörs, Luka Nicin, Julia Schmidt, Mario Perl, Ingo Marzi, Borna Relja, Raghavan Raju.
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.
Trauma is still the most common cause of death in children and young adults, as well as one of the global leading causes of worldwide mortality [1,2]. The treatment of patients with severe and multiple traumatic injuries including blunt chest trauma and hemorrhagic shock is still challenging [3,4]. Due to the microcirculatory disturbances and the release of pathogen-associated-molecular-patterns (PAMP) e.g. lipopolysaccharide (LPS) and/or damage-associated-molecular-patterns (DAMP) such as HMGB1 caused by tissue damage, notably these hypoxic conditions result in a massive activation of the immune system, which carries a high risk for multiple organ dysfunction syndrome (MODS) and organ failure (e.g. lung, liver) [5–12].
All relevant data have been deposited to Figshare: https://figshare.com/articles/Ethyl_pyruvate_ameliorates_hepatic_injury_following_blunt_chest_trauma_and_hemorrhagic_shock_by_reducing_local_inflammation_NF-kappaB_activation_and_HMGB1_release/5616922
In the present study, we examined the effect of ethyl pyruvate as resuscitation solution in a double hit model of blunt chest trauma and hemorrhagic shock in rats. Pyruvate is the final product of glycolysis, a scavenger of reactive oxygen species (ROS) and has been tested in numerous in vitro and in vivo studies . Salahudeen et al. showed a beneficial effect of pyruvate regarding renal injury, Mongan et al. and Slovin et al. found an improved survival after sodium pyruvate infusions in models of hemorrhagic shock, and Sileri et al. investigated a protective effect of pyruvate on ischemia/reperfusion injury of the liver [37–40]. The study situation regarding a direct comparison of EP and pyruvate is inconsistent. For example, Zeng et al. examined EP and pyruvate in neonatal rat cerebrocortical slices and has found a superiority of EP . On the other hand, Sharma et al. detected a advantage of sodium pyruvate compared with EP in a hemorrhagic shock model . Our decision to use EP as a reperfusion solution is mainly based on two important issues. First, pyruvate has a limited stability in solutions, so that in an aldol-like reaction parapyruvate can arise. Second, EP has been used as a safe substance in a Phase II trial in patients with cardiac surgery, although without a significant beneficial effect . The reasons for the results of the Phase II trial remain unclear, but may certainly be caused by the applied dose of EP, selection of the study cohort or no adequate inflammatory response in this setting. However, we believe due to the encouraging in vitro and in vivo results regarding a potential therapy with EP, that further studies to investigate, understand and use the beneficial effects of EP are required.