{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:52:17Z","timestamp":1787003537587,"version":"build-2736575974"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["DM160152"],"award-info":[{"award-number":["DM160152"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS102815 and R01NS097875"],"award-info":[{"award-number":["R01NS102815 and R01NS097875"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007496","name":"Biomedical Laboratory Research and Development, VA Office of Research and Development","doi-asserted-by":"publisher","award":["BX003926"],"award-info":[{"award-number":["BX003926"]}],"id":[{"id":"10.13039\/100007496","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a lifesaving maneuver for the management of lethal torso hemorrhage. However, its prolonged use leads to distal organ ischemia\u2013reperfusion injury (IRI) and systemic inflammatory response syndrome (SIRS). The objective of this study is to investigate the blood-based biomarkers of IRI and SIRS and the efficacy of direct intestinal cooling in the prevention of IRI and SIRS. A rat lethal hemorrhage model was produced by bleeding 50% of the total blood volume. A balloon catheter was inserted into the aorta for the implementation of REBOA. A novel TransRectal Intra-Colon (TRIC) device was placed in the descending colon and activated from 10\u00a0min after the bleeding to maintain the intra-colon temperature at 37\u00a0\u00b0C (TRIC37\u00b0C group) or 12\u00a0\u00b0C (TRIC12\u00b0C group) for 270\u00a0min. The upper body temperature was maintained at as close to 37\u00a0\u00b0C as possible in both groups. Blood samples were collected before hemorrhage and after REBOA. The organ injury biomarkers and inflammatory cytokines were evaluated by ELISA method. Blood based organ injury biomarkers (endotoxin, creatinine, AST, FABP1\/L-FABP, cardiac troponin I, and FABP2\/I-FABP) were all drastically increased in TRIC37\u00b0C group after REBOA. TRIC12\u00b0C significantly downregulated these increased organ injury biomarkers. Plasma levels of pro-inflammatory cytokines TNF-\u03b1, IL-1b, and IL-17F were also drastically increased in TRIC37\u00b0C group after REBOA. TRIC12\u00b0C significantly downregulated the pro-inflammatory cytokines. In contrast, TRIC12\u00b0C significantly upregulated the levels of anti-inflammatory cytokines IL-4 and IL-10 after REBOA.\u00a0Amazingly, the mortality rate was 100% in TRIC37\u00b0C group whereas 0% in TRIC12\u00b0C group after REBOA. Directly cooling the intestine offered exceptional protection of the abdominal organs from IRI and SIRS, switched from a harmful pro-inflammatory to a reparative anti-inflammatory response, and mitigated mortality in the rat model of REBOA management of lethal hemorrhage.<\/jats:p>","DOI":"10.1038\/s41598-021-93064-4","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T06:02:45Z","timestamp":1625119365000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Focal intra-colon cooling reduces organ injury and systemic inflammation after REBOA management of lethal hemorrhage in rats"],"prefix":"10.1038","volume":"11","author":[{"given":"Awadhesh K.","family":"Arya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalita","family":"Subedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tieluo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingren","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"93064_CR1","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/j.jss.2013.05.099","volume":"184","author":"M Kisat","year":"2013","unstructured":"Kisat, M. et al. Epidemiology and outcomes of non-compressible torso hemorrhage. J. Surg. Res. 184, 414\u2013421 (2013).","journal-title":"J. Surg. Res."},{"key":"93064_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jvs.2006.02.057","volume":"44","author":"M Mehta","year":"2006","unstructured":"Mehta, M. et al. Establishing a protocol for endovascular treatment of ruptured abdominal aortic aneurysms: outcomes of a prospective analysis. J. Vasc. Surg. 44, 1\u20138 (2006).","journal-title":"J. Vasc. Surg."},{"key":"93064_CR3","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1016\/j.jvs.2016.05.045","volume":"64","author":"KHJ Ultee","year":"2016","unstructured":"Ultee, K. H. J. et al. Incidence of and risk factors for bowel ischemia after abdominal aortic aneurysm repair. J. Vasc. Surg. 64, 1384\u20131391 (2016).","journal-title":"J. Vasc. Surg."},{"issue":"354","key":"93064_CR4","first-page":"e5","volume":"56","author":"J Zhang","year":"2019","unstructured":"Zhang, J. et al. Resuscitative endovascular balloon occlusion of the aorta (REBOA) Not yet applicable for widespread out-of-hospital use: a case of nonsurvivable complication from prolonged REBOA inflation. Ann. Vasc. Surg. 56(354), e5-354.e9 (2019).","journal-title":"Ann. Vasc. Surg."},{"key":"93064_CR5","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1097\/TA.0b013e31823fe90c","volume":"71","author":"A Stannard","year":"2011","unstructured":"Stannard, A., Eliason, J. L. & Rasmussen, T. E. Resuscitative endovascular balloon occlusion of the aorta (REBOA) as an adjunct for hemorrhagic shock. J. Trauma Inj. Infect. Crit. Care 71, 1869\u20131872 (2011).","journal-title":"J. Trauma Inj. Infect. Crit. Care"},{"key":"93064_CR6","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1097\/TA.0000000000001711","volume":"84","author":"AJ Davidson","year":"2018","unstructured":"Davidson, A. J. et al. The pitfalls of resuscitative endovascular balloon occlusion of the aorta: risk factors and mitigation strategies. J. Trauma Acute Care Surg. 84, 192\u2013202 (2018).","journal-title":"J. Trauma Acute Care Surg."},{"key":"93064_CR7","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1097\/SHK.0000000000000085","volume":"41","author":"JJ Morrison","year":"2014","unstructured":"Morrison, J. J. et al. Use of resuscitative endovascular balloon occlusion of the aorta in a highly lethal model of noncompressible torso hemorrhage. Shock 41, 130\u2013137 (2014).","journal-title":"Shock"},{"key":"93064_CR8","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/jcbfm.1990.36","volume":"10","author":"Y Yamauchi","year":"1990","unstructured":"Yamauchi, Y., Kato, H. & Kogure, K. Brain damage in a new hemorrhagic shock model in the rat using long-term recovery. J. Cereb. Blood Flow Metab. 10, 207\u2013212 (1990).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"93064_CR9","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/B978-0-12-394309-5.00006-7","volume":"289","author":"T Kalogeris","year":"2012","unstructured":"Kalogeris, T., Baines, C. P., Krenz, M. & Korthuis, R. J. Cell biology of ischemia\/reperfusion injury. Int. Rev. Cell Mol. Biol. 289, 229\u2013317 (2012).","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"93064_CR10","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1111\/j.1553-2712.2001.tb00201.x","volume":"8","author":"EB Lerner","year":"2001","unstructured":"Lerner, E. B. & Moscati, R. M. The golden hour: scientific fact or medical \u2018urban legend\u2019?. Acad. Emerg. Med. 8, 758\u2013760 (2001).","journal-title":"Acad. Emerg. Med."},{"key":"93064_CR11","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1007\/s12975-012-0236-z","volume":"4","author":"T Kristian","year":"2013","unstructured":"Kristian, T. & Hu, B. Guidelines for using mouse global cerebral ischemia models. Transl. Stroke Res. 4, 343\u2013350 (2013).","journal-title":"Transl. Stroke Res."},{"key":"93064_CR12","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.surg.2006.03.015","volume":"140","author":"HB Alam","year":"2006","unstructured":"Alam, H. B. et al. Profound hypothermia is superior to ultraprofound hypothermia in improving survival in a swine model of lethal injuries. Surgery 140, 307\u2013314 (2006).","journal-title":"Surgery"},{"key":"93064_CR13","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1038\/sj.jcbfm.9600524","volume":"28","author":"X Wu","year":"2008","unstructured":"Wu, X. et al. Emergency preservation and resuscitation with profound hypothermia, oxygen, and glucose allows reliable neurological recovery after 3 h of cardiac arrest from rapid exsanguination in dogs. J. Cereb. Blood Flow Metab. 28, 302\u2013311 (2008).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"93064_CR14","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1097\/TA.0000000000000877","volume":"79","author":"TS Park","year":"2015","unstructured":"Park, T. S. et al. Resuscitative endovascular balloon occlusion of the aorta (REBOA): comparison with immediate transfusion following massive hemorrhage in swine. J. Trauma Acute Care Surg. 79, 930\u2013936 (2015).","journal-title":"J. Trauma Acute Care Surg."},{"key":"93064_CR15","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.1086\/315093","volume":"180","author":"SM Opal","year":"1999","unstructured":"Opal, S. M. et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS- binding protein in patients with severe sepsis and septic shock. J. Infect. Dis. 180, 1584\u20131589 (1999).","journal-title":"J. Infect. Dis."},{"key":"93064_CR16","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1097\/TA.0000000000002008","volume":"85","author":"TK Williams","year":"2018","unstructured":"Williams, T. K. et al. Endovascular variable aortic control (EVAC) versus resuscitative endovascular balloon occlusion of the aorta (REBOA) in a swine model of hemorrhage and ischemia reperfusion injury. J. Trauma Acute Care Surg. 85, 519\u2013526 (2018).","journal-title":"J. Trauma Acute Care Surg."},{"key":"93064_CR17","doi-asserted-by":"publisher","first-page":"490","DOI":"10.2174\/1871530319666181129112708","volume":"19","author":"T Magrone","year":"2019","unstructured":"Magrone, T. & Jirillo, E. Sepsis: from historical aspects to novel vistas. Pathogenic and therapeutic considerations. Endocr. Metab. Immune Disord. Drug Targets 19, 490\u2013502 (2019).","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"93064_CR18","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1378\/chest.125.4.1483","volume":"125","author":"PO Scumpia","year":"2004","unstructured":"Scumpia, P. O., Sarcia, P. J., Kelly, K. M., DeMarco, V. G. & Skimming, J. W. Hypothermia induces anti-inflammatory cytokines and inhibits nitric oxide and myeloperoxidase-mediated damage in the hearts of endotoxemic rats. Chest 125, 1483\u20131491 (2004).","journal-title":"Chest"},{"key":"93064_CR19","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1097\/PCC.0b013e3181b01042","volume":"11","author":"CR Stewart","year":"2010","unstructured":"Stewart, C. R., Landseadel, J. P., Gurka, M. J. & Fairchild, K. D. Hypothermia increases interleukin-6 and interleukin-10 in juvenile endotoxemic mice*. Pediatr. Crit. Care Med. 11, 109\u2013116 (2010).","journal-title":"Pediatr. Crit. Care Med."},{"key":"93064_CR20","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1007\/s12028-012-9688-y","volume":"16","author":"P Lyden","year":"2012","unstructured":"Lyden, P. et al. Determinants of effective cooling during endovascular hypothermia. Neurocrit. Care 16, 413\u2013420 (2012).","journal-title":"Neurocrit. Care"},{"key":"93064_CR21","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/0300-9572(96)00983-5","volume":"32","author":"EL Lloyd","year":"1996","unstructured":"Lloyd, E. L. Accidental hypothermia. Resuscitation 32, 111\u2013124 (1996).","journal-title":"Resuscitation"},{"key":"93064_CR22","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1097\/PEC.0b013e3182539098","volume":"28","author":"HM Corneli","year":"2012","unstructured":"Corneli, H. M. Accidental hypothermia.  Pediatr. Emerg. Care 28, 475\u2013480 (2012).","journal-title":"Pediatr. Emerg. Care"},{"key":"93064_CR23","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/icb.2012.85","volume":"91","author":"E Tomasello","year":"2013","unstructured":"Tomasello, E. & Bedoui, S. Intestinal innate immune cells in gut homeostasis and immunosurveillance. Immunol. Cell Biol. 91, 201\u2013203 (2013).","journal-title":"Immunol. Cell Biol."},{"key":"93064_CR24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13054-016-1458-3","volume":"20","author":"PR de Jong","year":"2016","unstructured":"de Jong, P. R., Gonz\u00e1lez-Navajas, J. M. & Jansen, N. J. G. The digestive tract as the origin of systemic inflammation. Crit. Care 20, 1\u201312 (2016).","journal-title":"Crit. Care"},{"key":"93064_CR25","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.ccc.2015.11.004","volume":"32","author":"NJ Klingensmith","year":"2016","unstructured":"Klingensmith, N. J. & Coopersmith, C. M. The gut as the motor of multiple organ dysfunction in critical illness. Crit. Care Clin. 32, 203\u2013212 (2016).","journal-title":"Crit. Care Clin."},{"key":"93064_CR26","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1159\/000499610","volume":"46","author":"A Petrenko","year":"2019","unstructured":"Petrenko, A. et al. Organ preservation into the 2020s: the era of dynamic intervention. Transfus. Med. Hemother. 46, 151\u2013172 (2019).","journal-title":"Transfus. Med. Hemother."},{"key":"93064_CR27","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1097\/00003246-199210000-00007","volume":"20","author":"MJ Rohrer","year":"1992","unstructured":"Rohrer, M. J. & Natale, A. M. Effect of hypothermia on the coagulation cascade. Crit. Care Med. 20, 1402\u20131405 (1992).","journal-title":"Crit. Care Med."},{"key":"93064_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fneur.2017.00092","volume":"8","author":"DV Agoston","year":"2017","unstructured":"Agoston, D. V. How to translate time? The temporal aspect of human and rodent biology. Front. Neurol. 8, 1\u20133 (2017).","journal-title":"Front. Neurol."},{"issue":"3","key":"93064_CR29","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/icb.2012.85","volume":"91","author":"E Tomasello","year":"2013","unstructured":"Tomasello, E. & Bedoui, S. Intestinal innate immune cells in gut homeostasis and immunosurveillance. Immunol. Cell Biol. 91(3), 201\u2013203 (2013).","journal-title":"Immunol. Cell Biol."},{"issue":"1","key":"93064_CR30","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1186\/s13054-016-1458-3","volume":"20","author":"PR de Jong","year":"2016","unstructured":"de Jong, P. R., Gonzalez-Navajas, J. M. & Jansen, N. J. The digestive tract as the origin of systemic inflammation. Crit. Care 20(1), 279 (2016).","journal-title":"Crit. Care"},{"issue":"4","key":"93064_CR31","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1097\/shk.0b013e31805569df","volume":"28","author":"JA Clark","year":"2007","unstructured":"Clark, J. A. & Coopersmith, C. M. Intestinal crosstalk: a new paradigm for understanding the gut as the \u201cmotor\u201d of critical illness. Shock 28(4), 384\u2013393 (2007).","journal-title":"Shock"},{"issue":"2","key":"93064_CR32","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1097\/SHK.0b013e3181eddcab","volume":"35","author":"R Gill","year":"2011","unstructured":"Gill, R. et al. B, Systemic inflammation and liver injury following hemorrhagic shock and peripheral tissue trauma involve functional TLR9 signaling on bone marrow-derived cells and parenchymal cells. Shock 35(2), 164\u2013170 (2011).","journal-title":"Shock"},{"issue":"2","key":"93064_CR33","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1001\/archsurg.1986.01400020082010","volume":"121","author":"CJ Carrico","year":"1986","unstructured":"Carrico, C. J., Meakins, J. L., Marshall, J. C., Fry, D. & Maier, R. V. Multiple-organ-failure syndrome. Arch. Surg. 121(2), 196\u2013208 (1986).","journal-title":"Arch. Surg."},{"issue":"Suppl 1","key":"93064_CR34","doi-asserted-by":"publisher","first-page":"E103","DOI":"10.1111\/j.1749-6632.2010.05713.x","volume":"1207","author":"EA Deitch","year":"2010","unstructured":"Deitch, E. A. Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction. Ann. N.Y. Acad. Sci. 1207(Suppl 1), E103\u2013E111 (2010).","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"93064_CR35","doi-asserted-by":"crossref","unstructured":"Liu, C., Yuan, D., Crawford, R., Sarkar, R. & Hu B. Directly cooling gut prevents mortality in the rat model of REBOA management of lethal hemorrhage. Shock (2021)","DOI":"10.1097\/SHK.0000000000001744"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93064-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93064-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93064-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T05:44:57Z","timestamp":1670046297000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93064-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,1]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["93064"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-93064-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,1]]},"assertion":[{"value":"29 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13696"}}