{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T23:12:36Z","timestamp":1787958756384,"version":"build-2784847793"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Previous studies have shown that polytrauma may initiate a systemic inflammatory response that drives acute kidney injury (AKI), multiple organ failure (MOF), and high mortality. However, beyond supportive care, pharmacological treatments for trauma-induced AKI are lacking, which represents a serious unmet clinical need. Previous work from our group identified the inflammatory mediator high mobility group box 1 (HMGB1) as a promising therapeutic target to mitigate MOF and AKI. We have shown that HMGB1 levels correlate with organ failure, such as AKI, acute respiratory distress syndrome (ARDS), and MOF. In this study, we investigated CX-01, a modified heparin and HMGB1 inhibitor, to determine if it can reduce AKI and improve survival in a rat polytrauma model. Male Sprague-Dawley (SD) rats underwent polytrauma consisting of soft tissue injury, fibula fracture and pressure-controlled hemorrhage (MAP 55\u00a0mmHg) for 2\u00a0hours followed by whole blood resuscitation to maintain MAP at 90\u00a0mmHg for 30\u00a0min. Animals were randomly assigned to either a vehicle control group (vehicle, n = 9), or a therapeutic treatment group which received CX-01 (25\u00a0mg\/kg, n = 8) at specified intervals over a 72-h observation period. Vital signs, hemodynamics, blood chemistry, inflammation, and tissue damage were collected and analyzed. Treatment with CX-01 significantly increased survival over the 72-h study period (87.5% vs. 33.3%,\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05). The CX-01 treatment group showed reduced trauma-induced AKI, as evidenced by significantly improved glomerular filtration rate (GFR) (0.87 vs. 0.56,\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05) at 2.5\u00a0h post-injury compared to controls. Histological evaluations indicated that CX-01 treatment markedly reduced total kidney injury scores from 2.86 (0.29\u20134.14) to 0.86 (0.29\u20131.29). At 2.5\u00a0h post-injury, the treatment significantly attenuated trauma-induced lactate elevation. CX-01 therapy significantly decreased the release of HMGB1 and several inflammatory cytokines including MCP-1, RANTES, and GRO\/KC (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05 for all) at 2.5\u00a0h post-injury. Furthermore, CX-01 treatment did not alter the coagulation profile in these polytrauma animals when compared to vehicle control. These results demonstrate that CX-01 treatment might reduce trauma-induced AKI and improve survival in a clinically relevant rat model. Future studies should focus on validation of this approach in large animal models or advancing CX-01 toward clinical trials in trauma patients.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1834668","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:33:54Z","timestamp":1782970434000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["CX-01 mitigates trauma-induced acute kidney injury and improves survival in a combat-relevant polytrauma rat model"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhangsheng","family":"Yang","sequence":"first","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline Gusson","family":"Shimoura","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heaven D.","family":"Sessions","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin M.","family":"Kneifel","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanette","family":"Rocha","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kassandra","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Willis","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily M.","family":"Corbin","sequence":"additional","affiliation":[{"name":"Research Support Directorate, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkata","family":"Yellepeddi","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of Medicine, University of Utah","place":["Salt Lake City, UT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J.","family":"Kirkwood","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Salinas","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Meyer","sequence":"additional","affiliation":[{"name":"Expeditionary Medical Systems Department, United States Army Institute of Surgical Research","place":["San Antonio, TX, United States"]},{"name":"Long School of Medicine, the University of Texas Health Science Center","place":["San Antonio, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.3390\/ijms26051843","article-title":"Hemorrhagic shock and mitochondria: pathophysiology and therapeutic approaches","volume":"26","author":"Andrianova","year":"2025","journal-title":"Int. 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