Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock

Abstract

Administration of pyruvate, an effective scavenger of reactive oxygen species, has been shown to be salutary in numerous models of redox-mediated tissue or organ injury. Pyruvate, however, is unstable in solution and, hence, is not attractive for development as a therapeutic agent. Herein, ethyl pyruvate, which is thought to be more stable than the parent compound, was formulated in a calcium-containing balanced salt solution [Ringer ethyl pyruvate solution (REPS)] and evaluated in a murine model of hemorrhagic shock and resuscitation (HS/R). Resuscitation with REPS instead of Ringer lactate solution (RLS) significantly improved survival at 24 h and abrogated bacterial translocation to mesenteric lymph nodes and the development of increased ileal mucosal permeability to FITC-labeled dextran (4,000 Da) at 4 h. Mice treated with REPS instead of RLS also had lower circulating levels of alanine aminotransferase at 4 h. Treatment with REPS instead of RLS decreased activation of nuclear factor-κB in liver and colonic mucosa after HS/R and also decreased the expression of inducible nitric oxide synthase, tumor necrosis factor, cyclooxygenase-2, and interleukin-6 mRNA in liver, ileal mucosa, and/or colonic mucosa. These data support the view that resuscitation with REPS modulates the inflammatory response and decreases hepatocellular and gut mucosal injury in mice subjected to HS/R.

Anti-HMGB1 Neutralizing Antibody Ameliorates Gut Barrier Dysfunction and Improves Survival after Hemorrhagic Shock

“…Other anti-inflammatory therapeutic agents have been shown to ameliorate hepatocellular injury after HS/R in rodents (7,51). In the present study, however, treatment with anti-HMGB1 antibody was not demonstrably effective in this regard.…”

“…Ileal mucosal permeability to the fluorescent tracer, FITC-dextran with a mo-lecular mass of 4000 Da (FD4), was determined using an everted gut sac method, as previously described (7). Briefly, gut sacs were prepared in ice-cold modified Krebs-Henseleit bicarbonate buffer (KHBB), pH 7.4.…”

“…Intestinal barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and/or increased bacterial translocation to mesenteric lymph nodes (MLN), occurs following hemorrhagic shock and resuscitation (HS/R) in rodents (6)(7)(8)(9)(10)(11)(12)(13). These findings may have clinical implications, because increased intestinal permeability has been shown to be associated with an increased risk of complications, MODS, or even mortality in critically ill patients (14)(15)(16)(17).…”

Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation

“…EP administration significantly improved survival in standard models of lethal hemorrhagic shock (12,13). We reasoned that EP also might be protective in sepsis, because the pathogenesis of ischemia-reperfusion and hemorrhagic shock, like sepsis, depends on activation of early and late cytokine responses.…”

New Insights into the Acetaminophen Hepatotoxicity Research

“…EP inhibits LPS-stimulated macrophages to release TNF-a, IL-6 and HMGB1 [32]; EP also protects against liver injury in the following models: acute alcoholic hepatitis [50], hemorrhagic shock [51], sepsis [52], acute extrahepatic obstruction [53], and acute necrotizing pancreatitis [54]. EP reduces liver injury at 24 hours but impairs liver regeneration at 48 hrs during APAP hepatotoxicity, and the late detrimental effect is associated with decreased serum TNF-a concentration and reduced cyclin D1 expression in liver tissue.…”