{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T23:55:04Z","timestamp":1774655704526,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016156","name":"US Army Medical Research and Development Command","doi-asserted-by":"crossref","award":["BA150310"],"award-info":[{"award-number":["BA150310"]}],"id":[{"id":"10.13039\/100016156","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100016156","name":"US Army Medical Research and Development Command","doi-asserted-by":"crossref","award":["W81XWH-19-2-0040\/BA180313"],"award-info":[{"award-number":["W81XWH-19-2-0040\/BA180313"]}],"id":[{"id":"10.13039\/100016156","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: A major challenge in developing effective immunological damage-control therapies for traumatic hemorrhage (TH) is the lack of animal models that accurately reproduce the immune and pathophysiological responses observed in humans. In this study, we established a clinically relevant rat model that combines blast injury with hemorrhagic shock in a simulated prolonged damage control resuscitation environment. Methods: Male Sprague Dawley rats were anesthetized and subjected to moderate blast overpressure, followed by controlled hemorrhage equivalent to 40% of the estimated total blood volume. Animals then received hypotensive resuscitation with Plasma-Lyte A at twice the shed blood volume. Plasma-Lyte A was used in our study to correct hypovolemia and electrolyte imbalances, thereby helping to standardize the traumatic hemorrhage model. Results: Four of six rats in the blast-plus-hemorrhage (B + H) group survived the 25 h observation period. During resuscitation, mean arterial pressure remained markedly below baseline for at least 4 h. The B + H insult triggered a rapid innate immune response, characterized by elevated circulating HMGB1, terminal complement activation, and increased myeloperoxidase levels. Complement deposition (C4d, C5a, and C5b-9) was evident in lung tissue, accompanied by multi-organ histopathological injury, including pronounced inflammatory cell infiltration, hemorrhage, and cellular degeneration, apoptosis, or necrosis. Metabolic disturbances, including acidosis, hyperkalemia, and dilutional anemia, were also observed. Conclusions: Overall, this model reproduced key features of inflammation-driven multi-organ dysfunction syndrome seen in human polytrauma, supporting its utility for studying TH-related immunopathology and therapeutic interventions during prolonged damage control resuscitation.<\/jats:p>","DOI":"10.3390\/cells15030250","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T15:56:12Z","timestamp":1769615772000},"page":"250","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development and Characterization of a Rat Model of Blast Polytrauma and Hemorrhagic Shock for Evaluating Innate Immunotherapies During Prolonged Damage Control Resuscitation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5261-810X","authenticated-orcid":false,"given":"Milomir","family":"Simovic","sequence":"first","affiliation":[{"name":"Department of Organ Function Support, US Army Institute of Surgical Research, Fort Sam Houston, San Antonio, TX 78234, USA"},{"name":"The Geneva Foundation, Tacoma, WA 98402, USA"},{"name":"Department of Surgery, University of Texas Health at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingwei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Organ Function Support, US Army Institute of Surgical Research, Fort Sam Houston, San Antonio, TX 78234, USA"},{"name":"The Geneva Foundation, Tacoma, WA 98402, USA"},{"name":"Department of Surgery, University of Texas Health at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2208-8632","authenticated-orcid":false,"given":"Zhangsheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Organ Function Support, US Army Institute of Surgical Research, Fort Sam Houston, San Antonio, TX 78234, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leopoldo C.","family":"Cancio","sequence":"additional","affiliation":[{"name":"Department of Organ Function Support, US Army Institute of Surgical Research, Fort Sam Houston, San Antonio, TX 78234, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yansong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Organ Function Support, US Army Institute of Surgical Research, Fort Sam Houston, San Antonio, TX 78234, USA"},{"name":"The Geneva Foundation, Tacoma, WA 98402, USA"},{"name":"Department of Surgery, University of Texas Health at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","first-page":"S13","article-title":"A Profile of Combat Injury","volume":"54","author":"Champion","year":"2003","journal-title":"J. Trauma"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1017\/S1049023X23006428","article-title":"Epidemiology of Trauma-Related Hemorrhage and Time to Definitive Care Across North America: Making the Case for Bleeding Control Education","volume":"38","author":"Jones","year":"2023","journal-title":"Prehosp. Disaster Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S135","DOI":"10.1016\/j.wem.2017.02.001","article-title":"Prolonged Field Care: Beyond the \u201cGolden Hour\u201d","volume":"28","author":"Keenan","year":"2017","journal-title":"Wilderness Environ. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1056\/NEJMra1609326","article-title":"Initial Care of the Severely Injured Patient","volume":"380","author":"King","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/s41590-018-0064-8","article-title":"Innate immune responses to trauma","volume":"19","author":"Lambris","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1016\/S0140-6736(14)60687-5","article-title":"The systemic immune response to trauma: An overview of pathophysiology and treatment","volume":"384","author":"Lord","year":"2014","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dobson, G.P., Morris, J.L., and Letson, H.L. (2022). Why are bleeding trauma patients still dying? Towards a systems hypothesis of trauma. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.990903"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Dobson, G.P., Morris, J.L., and Letson, H.L. (2022). Immune dysfunction following severe trauma: A systems failure from the central nervous system to mitochondria. Front. Med., 9.","DOI":"10.3389\/fmed.2022.968453"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Vourc\u2019h, M., Roquilly, A., and Asehnoune, K. (2018). Trauma-Induced Damage-Associated Molecular Patterns-Mediated Remote Organ Injury and Immunosuppression in the Acutely Ill Patient. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01330"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1002\/ams2.426","article-title":"Complement and coagulation cascades in trauma","volume":"6","author":"Satyam","year":"2019","journal-title":"Acute Med. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1111\/bph.15245","article-title":"Complement in trauma-Traumatised complement?","volume":"178","author":"Ignatius","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"260","DOI":"10.5492\/wjccm.v10.i5.260","article-title":"Neutrophil kinetics and function after major trauma: A systematic review","volume":"10","author":"Finlay","year":"2021","journal-title":"World J. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Chakraborty, S., Karasu, E., and Huber-Lang, M. (2018). Complement After Trauma: Suturing Innate and Adaptive Immunity. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02050"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ccc.2016.08.006","article-title":"Postinjury Inflammation and Organ Dysfunction","volume":"33","author":"Sauaia","year":"2017","journal-title":"Crit. Care Clin."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1097\/SHK.0000000000001628","article-title":"Neurointensive Care and Trauma Working Group of the Spanish Society of Intensive Care Medicine (SEMICYUC). Risk Factors Associated With Early and Late Posttraumatic Multiorgan Failure: An Analysis From RETRAUCI","volume":"55","year":"2021","journal-title":"Shock"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1097\/TA.0b013e318256e000","article-title":"Persistent inflammation and immunosuppression: A common syndrome and new horizon for surgical intensive care","volume":"72","author":"Gentile","year":"2012","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.injury.2004.12.037","article-title":"Pathophysiology of polytrauma","volume":"36","author":"Keel","year":"2005","journal-title":"Injury"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1097\/00003246-200107000-00002","article-title":"Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care","volume":"29","author":"Angus","year":"2001","journal-title":"Crit. Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Huang, Q., Gao, S., Yao, Y., Wang, Y., Li, J., Chen, J., Guo, C., Zhao, D., and Li, X. (2022). Innate immunity and immunotherapy for hemorrhagic shock. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.918380"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, Y., Yang, Z., Chavko, M., Liu, B., Aderemi, O.A., Simovic, M.O., Dubick, M.A., and Cancio, L.C. (2018). Complement inhibition ameliorates blast-induced acute lung injury in rats: Potential role of complement in intracellular HMGB1-mediated inflammation. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202594"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Simovic, M.O., Yang, Z., Jordan, B.S., Fraker, T.L., Cancio, T.S., Lucas, M.L., Cancio, L.C., and Li, Y. (2023). Immunopathological Alterations after Blast Injury and Hemorrhage in a Swine Model of Prolonged Damage Control Resuscitation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087494"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/milmed\/usy412","article-title":"Early Complement and Fibrinolytic Activation in a Rat Model of Blast-Induced Multi-Organ Damage","volume":"184","author":"Yang","year":"2019","journal-title":"Mil. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/bph.15970","article-title":"Immunopathology of terminal complement activation and complement C5 blockade creating a pro-survival and organ-protective phenotype in trauma","volume":"180","author":"Yang","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yang, Z., Le, T.D., Simovic, M.O., Liu, B., Fraker, T.L., Cancio, T.S., Cap, A.P., Wade, C.E., DalleLucca, J.J., and Li, Y. (2022). Traumatized triad of complementopathy, endotheliopathy, and coagulopathy\u2014Impact on clinical outcomes in severe polytrauma patients. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.991048"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yang, Z., Simovic, M.O., Edsall, P.R., Liu, B., Cancio, T.S., Batchinsky, A.I., Cancio, L.C., and Li, Y. (2022). HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma. Biomolecules, 12.","DOI":"10.3390\/biom12010101"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e000927","DOI":"10.1136\/tsaco-2022-000927","article-title":"Indices of complement activation and coagulation changes in trauma patients","volume":"7","author":"Yang","year":"2022","journal-title":"Trauma. Surg. Acute Care Open"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.jns.2012.02.002","article-title":"Blast-induced moderate neurotrauma (BINT) elicits early complement activation and tumor necrosis factor \u03b1 (TNF\u03b1) release in a rat brain","volume":"318","author":"Chavko","year":"2012","journal-title":"J. Neurol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1097\/SHK.0b013e31825a3522","article-title":"Effects of C1 inhibitor on tissue damage in a porcine model of controlled hemorrhage","volume":"38","author":"Li","year":"2012","journal-title":"Shock"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1097\/SHK.0b013e3182471795","article-title":"Early complementopathy after multiple injuries in humans","volume":"37","author":"Burk","year":"2012","journal-title":"Shock"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/2051-5960-1-52","article-title":"Protective effects of decay-accelerating factor on blast-induced neurotrauma in rats","volume":"1","author":"Li","year":"2013","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3233\/CH-151993","article-title":"Coagulation and Complement System in Critically Ill Patients","volume":"61","author":"Helling","year":"2015","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"962927","DOI":"10.1155\/2012\/962927","article-title":"Role of Complement in Multiorgan Failure","volume":"2012","author":"Rittirsch","year":"2012","journal-title":"Clin. Dev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1385\/IR:34:2:157","article-title":"The Role of Complement in Danger Sensing and Transmission","volume":"34","year":"2006","journal-title":"Immunol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1126\/science.1071059","article-title":"The Danger Model: A Renewed Sense of Self","volume":"296","author":"Matzinger","year":"2002","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.smim.2013.05.006","article-title":"The Role of Complement in Trauma and Fracture Healing","volume":"25","author":"Kovtun","year":"2013","journal-title":"Semin. Immunol."},{"key":"ref_36","first-page":"11","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."},{"key":"ref_37","first-page":"e000217","article-title":"Early complementopathy predicts the outcomes of patients with trauma","volume":"4","author":"Li","year":"2019","journal-title":"TSACO"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1097\/shk.0b013e3180342439","article-title":"Role of the alternative pathway in the early complement activation following major trauma","volume":"28","author":"Ganter","year":"2007","journal-title":"Shock"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"R174","DOI":"10.1186\/cc8152","article-title":"Early release of high mobility group box nuclear protein 1 after severe trauma in humans: Role of injury severity and tissue hypoperfusion","volume":"13","author":"Cohen","year":"2009","journal-title":"Crit. Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1097\/SLA.0b013e318295feba","article-title":"Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: A randomized trial","volume":"259","author":"Young","year":"2014","journal-title":"Ann. Surg."},{"key":"ref_41","first-page":"205","article-title":"A multicentre randomised controlled pilot study of fluid resuscitation with saline or Plasma-Lyte 148 in critically ill patients","volume":"18","author":"Verma","year":"2016","journal-title":"Crit. Care Resusc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.jcrc.2012.01.007","article-title":"Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis","volume":"27","author":"Chua","year":"2012","journal-title":"J. Crit. Care"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hazeldine, J., Naumann, D.N., Toman, E., Davies, D., Bishop, J.R.B., Su, Z., Hampson, P., Dinsdale, R.J., Crombie, N., and Duggal, N.A. (2017). Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: A prospective cohort study. PLoS Med., 14.","DOI":"10.1371\/journal.pmed.1002338"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Simovic, M.O., Falabella, M.J., Dalle Luca, J.J., and Li, Y. (2022). Decay-accelerating factor creates an organ-protective phenotype after hemorrhage in conscious rats. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113563"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1016\/j.injury.2022.04.009","article-title":"Pathophysiology in patients with polytrauma","volume":"53","author":"Pape","year":"2022","journal-title":"Injury"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.jen.2023.12.011","article-title":"Trauma Diamond of Death: Adding Calcium to the Lethal Triad","volume":"50","author":"Mills","year":"2024","journal-title":"J. Emerg. Nurs."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e364","DOI":"10.1097\/CCM.0000000000000231","article-title":"C4d deposits on the surface of RBCs in trauma patients and interferes with their function","volume":"42","author":"Muroya","year":"2014","journal-title":"Crit. Care Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1097\/SHK.0000000000001348","article-title":"Complement Deposition on the Surface of RBC After Trauma Serves a Biomarker of Moderate Trauma Severity: A Prospective Study","volume":"53","author":"Satyam","year":"2020","journal-title":"Shock"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/250\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T05:16:26Z","timestamp":1769750186000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/250"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,28]]},"references-count":48,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cells15030250"],"URL":"https:\/\/doi.org\/10.3390\/cells15030250","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,28]]}}}