{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T04:29:58Z","timestamp":1786681798307,"version":"build-2736575974"},"reference-count":240,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Greater Copenhagen Health Science Partners, Copenhagen, Denmark"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Trauma with hemorrhagic shock causes about 2.3 million deaths yearly worldwide. Improved hemostatic management has shifted the relative distribution of mortality, leaving multiorgan failure (MOF) as a leading cause of death. Clinical observations suggest that the evolutionarily ancient and well-conserved sympathetic system and the microvascular endothelium are involved, and the experimental evidence is reviewed here. The analyzed clinical studies, human endothelial cell (EC) culture, and animal model-based experiments delineate how excess catecholamine levels increase endothelial cell reactive oxygen species production, causing glycocalyx damage and thrombomodulin cleavage. This leads to a prothrombotic EC surface, resulting in coagulation activation and thrombus formation that leaves tissues prone to hypoxia. Excess catecholamines also increase endothelial barrier permeability, leading to fluid extravasation, elevated tissue pressure, and hypoxia. The reviewed experimental data support, but do not yet prove, dysregulated sympathetic activation\u2019s critical contribution to the development of shock-induced endotheliopathy prone to tissue hypoxia and, ultimately, death from coagulopathy, loss of immune competence, and MOF, as observed clinically in shocked trauma patients. Due to the physiological differences between humans and model organisms, and EC culture growth conditions, some molecular mechanisms require further investigation through clinical studies and targeted experiments.<\/jats:p>","DOI":"10.3390\/ijms27167210","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T14:45:06Z","timestamp":1786545906000},"page":"7210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Shock Induced Endotheliopathy and High Trauma Mortality\u2014Fight-or-Flight Response Revisited"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2521-469X","authenticated-orcid":false,"given":"Nathan","family":"Weinstein","sequence":"first","affiliation":[{"name":"CAG Center for Endotheliomics, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8312-9157","authenticated-orcid":false,"given":"John B.","family":"Holcomb","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham, 1808 7th Avenue South, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9778-5964","authenticated-orcid":false,"given":"P\u00e4r I.","family":"Johansson","sequence":"additional","affiliation":[{"name":"CAG Center for Endotheliomics, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark"},{"name":"Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"ref_1","unstructured":"Dumovich, J., and Singh, P. 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