{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T02:42:17Z","timestamp":1774320137018,"version":"3.50.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"Supplement_3","funder":[{"DOI":"10.13039\/100013132","name":"Combat Casualty Care Research Program","doi-asserted-by":"publisher","award":["CO210012"],"award-info":[{"award-number":["CO210012"]}],"id":[{"id":"10.13039\/100013132","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013132","name":"Combat Casualty Care Research Program","doi-asserted-by":"publisher","award":["CO210012"],"award-info":[{"award-number":["CO210012"]}],"id":[{"id":"10.13039\/100013132","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Extensive trauma, commonly seen in wounded military Service Members, often leads to a severe sterile inflammation termed systemic inflammatory response syndrome (SIRS), which can progress to multiple organ dysfunction syndrome (MODS) and death. MODS is a serious threat to wounded Service Members, historically causing 10% of all deaths in trauma admissions at a forward deployed combat hospital. The importance of this problem will be exacerbated in large-scale combat operations, in which evacuation will be delayed and care of complex injuries at lower echelons of care may be prolonged. The main goal of this study was to optimize an existing mouse model of lethal SIRS\/MODS as a therapeutic screening platform for the evaluation of immunomodulatory drugs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Materials and Methods<\/jats:title>\n                  <jats:p>Male C57BL\/6 mice were euthanized, and the bones and muscles were collected and blended into a paste termed tissue\u2013bone matrix (TBX). The TBX at 12.5%\u201320% relative to body weight of each recipient mouse was implanted into subcutaneous pouches created on the dorsum of anesthetized animals. Mice were observed for clinical scores for up to 48\u2009hours postimplantation and euthanized at the preset point of moribundity. To test effects of anesthetics on TBX-induced mortality, animals received isoflurane or ketamine\/xylazine (K\/X). In a separate set of studies, mice received TBX followed by intraperitoneal injection with 20\u2009mg\/kg or 40\u2009mg\/kg Eritoran or a placebo carrier. All Eritoran studies were performed in a blinded fashion.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We observed that K\/X anesthesia significantly increased the lethality of the implanted TBX in comparison to inhaled anesthetics. Although all the mice anesthetized with isoflurane and implanted with 12.5% TBX survived for 24\u2009hours, 60% of mice anesthetized with K\/X were moribund by 24\u2009hours postimplantation. To mimic more closely the timing of lethal SIRS\/MODS following polytrauma in human patients, we extended observation to 48\u2009hours. We performed TBX dose\u2013response studies and found that as low as 15%, 17.5%, and 20% TBX caused moribundity\/mortality in 50%, 80%, and 100% mice, respectively, over a 48-hour time period. With 17.5% TBX, we tested if moribundity\/mortality could be rescued by anti-inflammatory drug Eritoran, a toll-like receptor 4 antagonist. Neither 20\u2009mg\/kg nor 40\u2009mg\/kg doses of Eritoran were found to be effective in this model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We optimized a TBX mouse model of SIRS\/MODS for the purpose of evaluating novel therapeutic interventions to prevent trauma-related pathophysiologies in wounded Service Members. Negative effects of K\/X on lethality of TBX should be further evaluated, particularly in the light of widespread use of ketamine in treatment of pain. By mimicking muscle crush, bone fracture, and necrosis, the TBX model has pleiotropic effects on physiology and immunology that make it uniquely valuable as a screening tool for the evaluation of novel therapeutics against trauma-induced SIRS\/MODS.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/milmed\/usae233","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T16:52:03Z","timestamp":1724086323000},"page":"694-701","source":"Crossref","is-referenced-by-count":1,"title":["Optimization of a Lethal, Combat-Relevant Model of Sterile Inflammation in Mice for Drug Candidate Screening"],"prefix":"10.1093","volume":"189","author":[{"given":"Kariana E","family":"Rios","sequence":"first","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"},{"name":"Oak Ridge Institute for Science and Education , Oak Ridge, TN 37830, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yonas","family":"Alamneh","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lacie M","family":"Werner","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Leung","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radmila","family":"Pavlovic","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rania","family":"Abu-Taleb","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rex J.R.S","family":"Thanapaul","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"},{"name":"NRC Research Associateship Programs, National Academies of Sciences, Engineering, and Medicine , Washington, DC 20001, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunjoo","family":"Lee","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawn","family":"Hull","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Czintos","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"},{"name":"Oak Ridge Institute for Science and Education , Oak Ridge, TN 37830, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanwen","family":"Su","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derese","family":"Getnet","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vlado","family":"Antonic","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander G","family":"Bobrov","sequence":"additional","affiliation":[{"name":"Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research , Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"issue":"1","key":"2024082004163152000_R1","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1097\/TA.0b013e3181bdcf95","article-title":"Incidence and epidemiology of combat injuries sustained during \u201cThe Surge\u201d portion of operation Iraqi freedom by a U.S. Army brigade combat team","volume":"68","author":"Belmont","year":"2010","journal-title":"J Trauma Acute Care Surg"},{"key":"2024082004163152000_R2","doi-asserted-by":"publisher","DOI":"10.1186\/1749-7922-1-15","article-title":"Trauma: the role of the innate immune system","volume":"1","author":"Hietbrink","year":"2006","journal-title":"World J Emerg Surg"},{"issue":"9","key":"2024082004163152000_R3","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1016\/j.injury.2009.05.006","article-title":"Patterns of mortality and causes of death in polytrauma patients\u2014has anything changed?","volume":"40","author":"Pfeifer","year":"2009","journal-title":"Injury"},{"issue":"3","key":"2024082004163152000_R4","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1097\/sla.0000000000000837","article-title":"Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the resuscitation outcomes consortium","volume":"261","author":"Tisherman","year":"2015","journal-title":"Ann Surg"},{"issue":"1","key":"2024082004163152000_R5","doi-asserted-by":"publisher","DOI":"10.1186\/s40779-019-0202-0","article-title":"Late immune consequences of combat trauma: a review of trauma-related immune dysfunction and potential therapies","volume":"6","author":"Thompson","year":"2019","journal-title":"Mil Med Res"},{"issue":"1","key":"2024082004163152000_R6","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1001\/jamasurg.2015.3104","article-title":"The effect of a golden hour policy on the morbidity and mortality of combat casualties","volume":"151","author":"Kotwal","year":"2016","journal-title":"JAMA Surgery"},{"issue":"4 Suppl","key":"2024082004163152000_R7","doi-asserted-by":"publisher","DOI":"10.1097\/TA.0b013e31819d86ad","article-title":"An analysis of in-hospital deaths at a modern combat support hospital","volume":"66","author":"Martin","year":"2009","journal-title":"J Trauma Apr"},{"issue":"2","key":"2024082004163152000_R8","doi-asserted-by":"publisher","first-page":"190","DOI":"10.7205\/milmed.172.2.190","article-title":"Immune cytokine response in combat casualties: blast or explosive trauma with or without secondary sepsis","volume":"172","author":"Surbatovic","year":"2007","journal-title":"Mil Med"},{"key":"2024082004163152000_R9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01330","article-title":"Trauma-induced damage-associated molecular patterns-mediated remote organ injury and immunosuppression in the acutely ill patient","volume":"9","author":"Vourc\u2019h","year":"2018","journal-title":"Front Immunol"},{"issue":"1","key":"2024082004163152000_R10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1189\/jlb.0306164","article-title":"DAMPs, PAMPs and alarmins: all we need to know about danger","volume":"81","author":"Bianchi","year":"2007","journal-title":"J Leukoc Biol"},{"issue":"5","key":"2024082004163152000_R11","doi-asserted-by":"publisher","first-page":"L958","DOI":"10.1152\/ajplung.00359.2004","article-title":"HMGB1 contributes to the development of acute lung injury after hemorrhage","volume":"288","author":"Kim","year":"2005","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"1","key":"2024082004163152000_R12","doi-asserted-by":"publisher","first-page":"639","DOI":"10.2119\/molmed.2014.00076","article-title":"Toll-like receptor 4 (TLR4) antagonist eritoran tetrasodium attenuates liver ischemia and reperfusion injury through inhibition of high-mobility group box protein B1 (HMGB1) signaling","volume":"20","author":"McDonald","year":"2014","journal-title":"Mol Med"},{"issue":"1 Suppl","key":"2024082004163152000_R13","doi-asserted-by":"publisher","first-page":"I270","DOI":"10.1161\/circulationaha.105.000901","article-title":"Inhibition of toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury","volume":"114","author":"Shimamoto","year":"2006","journal-title":"Circulation"},{"issue":"5","key":"2024082004163152000_R14","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1016\/j.transproceed.2010.03.133","article-title":"Protective effects of toll-like receptor 4 inhibitor eritoran on renal ischemia-reperfusion injury","volume":"42","author":"Liu","year":"2010","journal-title":"Transplant Proc"},{"issue":"8","key":"2024082004163152000_R15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0014829","article-title":"Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice","volume":"6","author":"Reino","year":"2011","journal-title":"PLoS One"},{"issue":"4","key":"2024082004163152000_R16","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.2741\/4176","article-title":"The role of TLR4 in the pathogenesis of indirect acute lung injury","volume":"18","author":"Hu","year":"2013","journal-title":"Front Biosci (Landmark Ed)"},{"issue":"3","key":"2024082004163152000_R17","doi-asserted-by":"publisher","first-page":"693","DOI":"10.3892\/ijmm.2017.2873","article-title":"Monoclonal antibody against toll-like receptor 4 attenuates ventilator-induced lung injury in rats by inhibiting MyD88- and NF-\u03baB-dependent signaling","volume":"39","author":"Huang","year":"2017","journal-title":"Int J Mol Med"},{"issue":"3","key":"2024082004163152000_R18","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1124\/jpet.102.044487","article-title":"Inhibition of endotoxin response by e5564, a novel toll-like receptor 4-directed endotoxin antagonist","volume":"304","author":"Mullarkey","year":"2003","journal-title":"J Pharmacol Exp Ther"},{"issue":"11","key":"2024082004163152000_R19","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1001\/jama.2013.2194","article-title":"Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial","volume":"309","author":"Opal","year":"2013","journal-title":"JAMA"},{"issue":"7450","key":"2024082004163152000_R20","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/nature12118","article-title":"The TLR4 antagonist eritoran protects mice from lethal influenza infection","volume":"497","author":"Shirey","year":"2013","journal-title":"Nature"},{"issue":"2","key":"2024082004163152000_R21","doi-asserted-by":"publisher","first-page":"e00226","DOI":"10.1128\/mBio.00226-17","article-title":"The toll-like receptor 4 antagonist eritoran protects mice from lethal filovirus challenge","volume":"8","author":"Younan","year":"2017","journal-title":"mBio"},{"issue":"2","key":"2024082004163152000_R22","doi-asserted-by":"publisher","first-page":"e17","DOI":"10.1016\/j.jss.2013.03.023","article-title":"Eritoran attenuates tissue damage and inflammation in hemorrhagic shock\/trauma","volume":"184","author":"Korff","year":"2013","journal-title":"J Surg Res"},{"issue":"4","key":"2024082004163152000_R23","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1111\/j.1365-2982.2011.01675.x","article-title":"Novel model of peripheral tissue trauma-induced inflammation and gastrointestinal dysmotility","volume":"23","author":"Tsukamoto","year":"2011","journal-title":"Neurogastroenterol Motil"},{"issue":"3","key":"2024082004163152000_R24","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1097\/00005373-199709000-00008","article-title":"Fatal trauma: the modal distribution of time to death is a function of patient demographics and regional resources","volume":"43","author":"Meislin","year":"1997","journal-title":"J Trauma Acute Care Surg"},{"issue":"1","key":"2024082004163152000_R25","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.2741\/1858","article-title":"Hypothermia and sepsis","volume":"11","author":"Remick","year":"2006","journal-title":"Front Biosci"},{"issue":"5","key":"2024082004163152000_R26","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1177\/0300985813476062","article-title":"Effects of different anesthetics in the murine model of EHV-1 infection","volume":"50","author":"E\u00f6ry","year":"2013","journal-title":"Vet Pathol"},{"issue":"3","key":"2024082004163152000_R27","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e14368","article-title":"Administration of ketamine\/xylazine increases severity of influenza (A\/Puerto Rico\/8\/34) in mice","volume":"9","author":"Nash","year":"2023","journal-title":"Heliyon"},{"issue":"3","key":"2024082004163152000_R28","doi-asserted-by":"publisher","first-page":"641","DOI":"10.3892\/etm.2013.1213","article-title":"Combination of ketamine and xylazine exacerbates cardiac dysfunction in severely scalded rats during the shock stage","volume":"6","author":"Feng","year":"2013","journal-title":"Exp Ther Med"},{"issue":"6","key":"2024082004163152000_R29","doi-asserted-by":"publisher","first-page":"595","DOI":"10.30802\/aalas-jaalas-22-000061","article-title":"A review of long-acting parenteral analgesics for mice and rats","volume":"61","author":"Huss","year":"2022","journal-title":"J Am Assoc Lab Anim Sci"},{"issue":"12","key":"2024082004163152000_R30","doi-asserted-by":"publisher","first-page":"3215","DOI":"10.1097\/CCM.0b013e318265680a","article-title":"Respiratory toxicity of buprenorphine results from the blockage of P-glycoprotein-mediated efflux of norbuprenorphine at the blood-brain barrier in mice","volume":"40","author":"Alhaddad","year":"2012","journal-title":"Crit Care Med"},{"issue":"4","key":"2024082004163152000_R31","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1097\/shk.0b013e318048801a","article-title":"Toll-like receptor 2 participates in the response to lung injury in a murine model of pulmonary contusion","volume":"28","author":"Hoth","year":"2007","journal-title":"Shock"},{"issue":"6","key":"2024082004163152000_R32","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1097\/SHK.0b013e31816f257e","article-title":"Local exposure of bone components to injured soft tissue induces toll-like receptor 4-dependent systemic inflammation with acute lung injury","volume":"30","author":"Kobbe","year":"2008","journal-title":"Shock"},{"issue":"2","key":"2024082004163152000_R33","doi-asserted-by":"publisher","first-page":"e149","DOI":"10.1016\/j.jss.2010.11.914","article-title":"Models of lower extremity damage in mice: time course of organ damage and immune response","volume":"166","author":"Menzel","year":"2011","journal-title":"J Surg Res"}],"container-title":["Military Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/milmed\/article-pdf\/189\/Supplement_3\/694\/58855352\/usae233.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/milmed\/article-pdf\/189\/Supplement_3\/694\/58855352\/usae233.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T04:16:46Z","timestamp":1724127406000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/milmed\/article\/189\/Supplement_3\/694\/7735968"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,19]]},"references-count":33,"journal-issue":{"issue":"Supplement_3","published-online":{"date-parts":[[2024,8,19]]},"published-print":{"date-parts":[[2024,8,19]]}},"URL":"https:\/\/doi.org\/10.1093\/milmed\/usae233","relation":{},"ISSN":["0026-4075","1930-613X"],"issn-type":[{"value":"0026-4075","type":"print"},{"value":"1930-613X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,9]]},"published":{"date-parts":[[2024,8,19]]}}}