Optimization of a Lethal, Combat-Relevant Model of Sterile Inflammation in Mice for Drug Candidate Screening.

This article focuses on optimizing a mouse model using tissue–bone matrix (TBX) implantation to study sterile systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) following trauma, conditions that pose significant risks to wounded military Service Members. The study found that ketamine/xylazine anesthesia accelerated lethality in this model compared to isoflurane, which better mimics the timing of human SIRS/MODS mortality. Dose-dependent TBX implantation induced moribundity within 48 hours, with 17.5% TBX identified as optimal for therapeutic testing. The toll-like receptor 4 (TLR4) antagonist Eritoran, tested at 20 mg/kg and 40 mg/kg doses, did not reduce mortality in this model, suggesting that TLR4 blockade alone may be insufficient to prevent trauma-induced SIRS/MODS. The TBX model offers a complex and relevant platform for evaluating novel therapeutics targeting trauma-related inflammation in military-relevant contexts.