{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:16:09Z","timestamp":1788066969285,"version":"build-2784847793"},"reference-count":47,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"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":["CO240046"],"award-info":[{"award-number":["CO240046"]}],"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":["CO250068"],"award-info":[{"award-number":["CO250068"]}],"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":["DM230026"],"award-info":[{"award-number":["DM230026"]}],"id":[{"id":"10.13039\/100016156","id-type":"DOI","asserted-by":"crossref"}]},{"award":["CO240046"],"award-info":[{"award-number":["CO240046"]}],"id":[{"id":"https:\/\/ror.org\/03cd02q50","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CO250068"],"award-info":[{"award-number":["CO250068"]}],"id":[{"id":"https:\/\/ror.org\/03cd02q50","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DM230026"],"award-info":[{"award-number":["DM230026"]}],"id":[{"id":"https:\/\/ror.org\/03cd02q50","id-type":"ROR","asserted-by":"publisher"}]},{"name":"The Metis Foundation","award":["DM230026"],"award-info":[{"award-number":["DM230026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Traumatic injury remains a critical global health challenge, with polytrauma frequently leading to multi-organ failure and mortality. A severe complication of polytrauma is acute kidney injury (AKI), which is driven by a massive systemic inflammatory response following the initial insult. This inflammation is exacerbated by the upregulation of phosphodiesterase 4 (PDE4) enzymes; therefore, PDE4 inhibition represents a rational therapeutic strategy. Roflumilast is an FDA-approved PDE4 inhibitor currently used for chronic obstructive pulmonary disease (COPD). This study evaluated the hypothesis that roflumilast can mitigate inflammation and prevent AKI in a polytrauma rat model. Anesthetized male Sprague\u2013Dawley rats were randomly assigned to either a vehicle control group (n = 9) or a roflumilast treatment group (0.2 mg\/kg, n = 10). All animals underwent a polytrauma protocol\u2014including soft tissue injury, fibula fracture, and pressure-controlled hemorrhage\u2014followed by whole blood resuscitation and a 72-h observation period. Rats treated with roflumilast demonstrated higher survival rates compared to injury controls (70% vs. 33%). Furthermore, roflumilast treatment significantly lowered blood urea nitrogen (BUN, p &lt; 0.05) and renal levels of Kidney Injury Molecule-1 (KIM-1, p &lt; 0.05). Roflumilast also significantly reduced levels of circulating High Mobility Group Box 1 (HMGB1) (p &lt; 0.05) and the proinflammatory cytokine macrophage inflammatory protein-1 alpha (MIP-1\u03b1) (p &lt; 0.05). These findings suggest that roflumilast is a promising therapeutic agent for mitigating trauma-induced AKI.<\/jats:p>","DOI":"10.3390\/ijms27177696","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:27:46Z","timestamp":1787920066000},"page":"7696","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphodiesterase 4 Inhibitor Roflumilast Ameliorates Polytrauma-Induced Acute Kidney Injury by Attenuating HMGB1 and Renal Inflammatory Pathways in Rats"],"prefix":"10.3390","volume":"27","author":[{"given":"Caroline Gusson","family":"Shimoura","sequence":"first","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research, 3698 Chambers Pass, Fort Sam Houston, TX 78234, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Dustin M.","family":"Kneifel","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research, 3698 Chambers Pass, Fort Sam Houston, TX 78234, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Heaven D.","family":"Sessions","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research, 3698 Chambers Pass, Fort Sam Houston, TX 78234, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Jeanette","family":"Rocha","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research, 3698 Chambers Pass, Fort Sam Houston, TX 78234, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Kassandra","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research, 3698 Chambers Pass, Fort Sam Houston, TX 78234, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8208-387X","authenticated-orcid":false,"given":"Emily M.","family":"Corbin","sequence":"additional","affiliation":[{"name":"Research Support Directorate, United States Army Institute of Surgical Research, Fort Sam Houston, TX 78234, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3819-9054","authenticated-orcid":false,"given":"Venkata","family":"Yellepeddi","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, UT 84132, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7196-3101","authenticated-orcid":false,"given":"Brian J.","family":"Kirkwood","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research, 3698 Chambers Pass, Fort Sam Houston, TX 78234, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Jose","family":"Salinas","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research, 3698 Chambers Pass, Fort Sam Houston, TX 78234, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Andrew D.","family":"Meyer","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research, 3698 Chambers Pass, Fort Sam Houston, TX 78234, USA"},{"name":"Long School of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Zhangsheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research, 3698 Chambers Pass, Fort Sam Houston, TX 78234, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","unstructured":"WHO (2026, June 19). Injuries and Violence. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/injuries-and-violence."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.injury.2009.07.010","article-title":"Current theories on the pathophysiology of multiple organ failure after trauma","volume":"41","author":"Tsukamoto","year":"2010","journal-title":"Injury"},{"key":"ref_3","first-page":"97","article-title":"Predicting multiple organ failure in patients with severe trauma","volume":"51","author":"Lausevic","year":"2008","journal-title":"Can. J. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.15585\/mmwr.mm6438a4","article-title":"Estimated Lifetime Medical and Work-Loss Costs of Fatal Injuries\u2014United States, 2013","volume":"64","author":"Florence","year":"2015","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1186\/s13690-024-01460-9","article-title":"Is polytrauma really just a simple accident? Recurrent characteristic of polytrauma","volume":"82","author":"Zhang","year":"2024","journal-title":"Arch. Public Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1097\/SLA.0b013e3181deb6bc","article-title":"Incidence, clinical predictors, genomics, and outcome of acute kidney injury among trauma patients","volume":"252","author":"Bihorac","year":"2010","journal-title":"Ann. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.afjem.2020.08.004","article-title":"Prevalence and risk factors of acute kidney injury in polytrauma patients at Muhimbili Orthopedic Institute, Tanzania","volume":"11","author":"Muhamedhussein","year":"2021","journal-title":"Afr. J. Emerg. Med."},{"key":"ref_9","first-page":"447","article-title":"Acute kidney injury in trauma patients","volume":"23","author":"Harrois","year":"2017","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s13054-018-2067-0","article-title":"Acute kidney injury is associated with a decrease in cortical renal perfusion during septic shock","volume":"22","author":"Harrois","year":"2018","journal-title":"Crit. Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1378\/chest.12-2016","article-title":"Rhabdomyolysis","volume":"144","author":"Zimmerman","year":"2013","journal-title":"Chest"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1097\/TA.0b013e31828586ec","article-title":"Acute kidney injury is associated with early cytokine changes after trauma","volume":"74","author":"Bihorac","year":"2013","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_13","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_14","first-page":"100257","article-title":"Small vessel disease: Connections between the kidney and the heart","volume":"26","author":"Meariman","year":"2023","journal-title":"Am. Heart J. Plus"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1001\/jamasurg.2019.0151","article-title":"Use of Combat Casualty Care Data to Assess the US Military Trauma System During the Afghanistan and Iraq Conflicts, 2001\u20132017","volume":"154","author":"Howard","year":"2019","journal-title":"JAMA Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s00134-019-05535-y","article-title":"Acute kidney injury in trauma patients admitted to the ICU: A systematic review and meta-analysis","volume":"45","author":"Sovik","year":"2019","journal-title":"Intensive Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wilson, N.M., Titus, D.J., Oliva, A.A., Furones, C., and Atkins, C.M. (2016). Traumatic Brain Injury Upregulates Phosphodiesterase Expression in the Hippocampus. Front. Syst. Neurosci., 10.","DOI":"10.3389\/fnsys.2016.00005"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj20021698","article-title":"PDE4 cAMP phosphodiesterases: Modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization","volume":"370","author":"Houslay","year":"2003","journal-title":"Biochem. J."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Raker, V.K., Becker, C., and Steinbrink, K. (2016). The cAMP Pathway as Therapeutic Target in Autoimmune and Inflammatory Diseases. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00123"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fan, T., Wang, W., Wang, Y., Zeng, M., Liu, Y., Zhu, S., and Yang, L. (2024). PDE4 inhibitors: Potential protective effects in inflammation and vascular diseases. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1407871"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Puertas-Umbert, L., Alonso, J., Hove-Madsen, L., Martinez-Gonzalez, J., and Rodriguez, C. (2023). PDE4 Phosphodiesterases in Cardiovascular Diseases: Key Pathophysiological Players and Potential Therapeutic Targets. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242317017"},{"key":"ref_22","first-page":"147","article-title":"Roflumilast: First phosphodiesterase 4 inhibitor approved for treatment of COPD","volume":"4","author":"Giembycz","year":"2010","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2147\/COPD.S89849","article-title":"Roflumilast: A review of its use in the treatment of COPD","volume":"11","author":"Wedzicha","year":"2016","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.21037\/jtd.2017.03.116","article-title":"Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases","volume":"9","author":"Kawamatawong","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_25","first-page":"e921319","article-title":"Roflumilast, a Phosphodiesterases-4 (PDE4) Inhibitor, Alleviates Sepsis-induced Acute Kidney Injury","volume":"26","author":"Xu","year":"2020","journal-title":"Med. Sci. Monit."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/fcp.12711","article-title":"Roflumilast improves resolution of sepsis-induced acute kidney injury by retarding late phase renal interstitial immune cells infiltration and leakage in urinary sediments","volume":"36","author":"Gupta","year":"2022","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_27","first-page":"32","article-title":"Prognostic Value of Lactate Levels in Trauma Patients\u2019 Outcomes in Emergency Department","volume":"13","author":"Sadrzadeh","year":"2025","journal-title":"Bull. Emerg. Trauma"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1080\/08941939.2021.1908462","article-title":"Roflumilast as a Potential Therapeutic Agent for Cecal Ligation and Puncture-Induced Septic Lung Injury","volume":"35","author":"Bayraktutan","year":"2022","journal-title":"J. Invest. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jss.2019.03.028","article-title":"Phosphodiesterase-4 Inhibitor Roflumilast Attenuates Pulmonary Air Emboli-Induced Lung Injury","volume":"241","author":"Peng","year":"2019","journal-title":"J. Surg. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1038\/labinvest.2017.59","article-title":"Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice","volume":"97","author":"Feng","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sousa, C.S., Lima, R., Cibr\u00e3o, J.R., Gomes, E.D., Fernandes, L.S., Pinho, T.S., Silva, D., Campos, J., Salgado, A.J., and Silva, N.A. (2023). Pre-Clinical Assessment of Roflumilast Therapy in a Thoracic Model of Spinal Cord Injury. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15051556"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111930","DOI":"10.1016\/j.cellsig.2025.111930","article-title":"Roflumilast inhibits neuronal ferroptosis via AMPK\/Nrf2\/HO-1 signaling and promotes motor function recovery after spinal cord injury in rats","volume":"134","author":"Han","year":"2025","journal-title":"Cell. Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"114217","DOI":"10.1016\/j.bbr.2022.114217","article-title":"Long-term treatment with roflumilast improves learning of fear extinction memory and anxiety-like response in a type-1 diabetes mellitus animal model","volume":"439","author":"Waltrick","year":"2023","journal-title":"Behav. Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kazmi, I., Al-Abbasi, F.A., Afzal, M., Nadeem, M.S., Altayb, H.N., and Gupta, G. (2022). Phosphodiesterase-4 Inhibitor Roflumilast-Mediated Protective Effect in Sepsis-Induced Late-Phase Event of Acute Kidney Injury: A Narrative Review. Pharmaceuticals, 15.","DOI":"10.3390\/ph15070899"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"144","DOI":"10.55460\/RBRA-WMWV","article-title":"Tactical Combat Casualty Care (TCCC) Guidelines for Medical Personnel: 05 November 2020","volume":"20","author":"Drew","year":"2020","journal-title":"J. Spec. Oper. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Staziaki, P.V., Qureshi, M.M., Maybury, A., Gangasani, N.R., LeBedis, C.A., Mercier, G.A., and Anderson, S.W. (2023). Hematocrit and lactate trends help predict outcomes in trauma independent of CT and other clinical parameters. Front. Radiol., 3.","DOI":"10.3389\/fradi.2023.1186277"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Webb, K.L., Gorman, E.K., Morkeberg, O.H., Klassen, S.A., Regimbal, R.J., Wiggins, C.C., Joyner, M.J., Hammer, S.M., and Senefeld, J.W. (2023). The relationship between hemoglobin and V\u02d9O2max: A systematic review and meta-analysis. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0292835"},{"key":"ref_38","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_39","doi-asserted-by":"crossref","first-page":"e677","DOI":"10.1097\/CCM.0000000000003839","article-title":"Circulating Histones Are Major Mediators of Multiple Organ Dysfunction Syndrome in Acute Critical Illnesses","volume":"47","author":"Cheng","year":"2019","journal-title":"Crit. Care Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1038\/nm.3368","article-title":"Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis","volume":"19","author":"Qiang","year":"2013","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hesselink, L., Hoepelman, R.J., Spijkerman, R., de Groot, M.C.H., van Wessem, K.J.P., Koenderman, L., Leenen, L.P.H., and Hietbrink, F. (2020). Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS) after Polytrauma: A Rare Syndrome with Major Consequences. J. Clin. Med., 9.","DOI":"10.3390\/jcm9010191"},{"key":"ref_42","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_43","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_44","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.ccc.2016.12.001","article-title":"Persistent Inflammation, Immunosuppression and Catabolism Syndrome","volume":"33","author":"Mira","year":"2017","journal-title":"Crit. Care Clin."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Young, M.D., Cancio, T.S., Thorpe, C.R., Willis, R.P., Snook, J.K., Jordan, B.S., Demons, S.T., Salinas, J., and Yang, Z. (2023). Circulatory HMGB1 is an early predictive and prognostic biomarker of ARDS and mortality in a swine model of polytrauma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1227751"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Yang, Z., Cancio, T.S., Willis, R.P., Young, M.D., Kneifel, D.M., Salinas, J., and Meyer, A.D. (2024). An early HMGB1 rise 12 hours before creatinine predicts acute kidney injury and multiple organ failure in a smoke inhalation and burn swine model. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1447597"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Yang, Z., Shimoura, C.G., Sessions, H.D., Kneifel, D.M., Rocha, J., Gonzalez, K., Willis, R.P., Corbin, E.M., Yellepeddi, V.K., and Kirkwood, B.J. (2026). CX-01 mitigates trauma-induced acute kidney injury and improves survival in a combat-relevant polytrauma rat model. Front. Pharmacol., 17.","DOI":"10.3389\/fphar.2026.1834668"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7696\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T04:22:41Z","timestamp":1788063761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7696"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":47,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177696"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177696","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}