{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T23:48:42Z","timestamp":1778716122340,"version":"3.51.4"},"reference-count":56,"publisher":"Wiley","license":[{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["877"],"award-info":[{"award-number":["877"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2020,5,1]]},"abstract":"<jats:p>Tumor necrosis factor (TNF) is a well-known mediator of sepsis. In many cases, sepsis results in multiple organ injury including the lung with acute respiratory distress syndrome (ARDS). More than 20-year-old studies have suggested that TNF may be directly responsible for organ injury during sepsis. However, these old studies are inconclusive, because they relied on human rather than conspecific TNF, which was contaminated with endotoxin in most studies. In this study, we characterized the direct effects of intravenous murine endotoxin-free TNF on cardiovascular functions and organ injury in mice with a particular focus on the lungs. Because of the relevance of the acid sphingomyelinase in sepsis, ARDS, and caspase-independent cell death, we also included acid sphingomyelinase-deficient (ASM<jats:sup>-\/-<\/jats:sup>) mice. ASM<jats:sup>-\/-<\/jats:sup>and wild-type (WT) mice received 50\u2009<jats:italic>\u03bc<\/jats:italic>g endotoxin-free murine TNF intravenously alone or in combination with the pan-caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (zVAD) and were ventilated at low tidal volume while lung mechanics were followed. Blood pressure was stabilized by intra-arterial fluid support, and body temperature was kept at 37\u00b0C to delay lethal shock and to allow investigation of blood gases, lung histopathology, proinflammatory mediators, and microvascular permeability 6 hours after TNF application. Besides the lungs, also the kidneys and liver were examined. TNF elicited the release of inflammatory mediators and a high mortality rate, but failed to injure the lungs, kidneys, or liver of healthy mice significantly within 6 hours. Mortality in WT mice was most likely due to sepsis-like shock, as indicated by metabolic acidosis, high procalcitonin levels, and cardiovascular failure. ASM<jats:sup>-\/-<\/jats:sup>mice were protected from TNF-induced hypotension and reflex tachycardia and also from mortality. In WT mice, intravenous exogenous TNF does not cause organ injury but induces a systemic inflammatory response with cardiovascular failure, in which the ASM plays a role.<\/jats:p>","DOI":"10.1155\/2020\/3650508","type":"journal-article","created":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T23:30:53Z","timestamp":1588375853000},"page":"1-14","source":"Crossref","is-referenced-by-count":11,"title":["Reevaluation of Lung Injury in TNF-Induced Shock: The Role of the Acid Sphingomyelinase"],"prefix":"10.1155","volume":"2020","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9567-3328","authenticated-orcid":true,"given":"Lucy K.","family":"Reiss","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Medical Faculty of RWTH Aachen University, Wendlingweg, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ute","family":"Raffetseder","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Clinical Immunology, Medical Faculty of RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydia","family":"Gibbert","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Clinical Immunology, Medical Faculty of RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah K.","family":"Drescher","sequence":"additional","affiliation":[{"name":"Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konrad L.","family":"Streetz","sequence":"additional","affiliation":[{"name":"Department of Medicine III, Medical Faculty of RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agatha","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Christian-Albrechts University, Arnold-Heller-Str. 3, 24105 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Martin","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Medical Faculty of RWTH Aachen University, Wendlingweg, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2332-1280","authenticated-orcid":true,"given":"Stefan","family":"Uhlig","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Medical Faculty of RWTH Aachen University, Wendlingweg, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Adam","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Christian-Albrechts University, Arnold-Heller-Str. 3, 24105 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1177\/014860718801200608"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/138.6.1377"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60331"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.1097\/shk.0b013e3182a64682"},{"key":"5","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1987.294"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.169.3.823"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4804(88)90098-4"},{"key":"8","doi-asserted-by":"publisher","DOI":"10.1002\/9780470513521.ch14"},{"key":"9","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(89)90772-1"},{"key":"10","doi-asserted-by":"publisher","DOI":"10.1378\/chest.108.5.1303"},{"key":"11","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3182982add"},{"key":"12","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/144.1.179"},{"key":"13","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/137.6.1364"},{"issue":"4","key":"14","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1128\/IAI.57.4.1218-1226.1989","volume":"57","year":"1989","journal-title":"Infection and Immunity"},{"key":"15","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-7091-1511-4_11"},{"key":"16","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-2842fje"},{"key":"17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112323"},{"key":"18","doi-asserted-by":"publisher","DOI":"10.1084\/jem.186.11.1831"},{"key":"19","doi-asserted-by":"publisher","DOI":"10.1038\/nm977"},{"key":"20","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200705-752OC"},{"key":"21","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00095609"},{"key":"22","doi-asserted-by":"publisher","DOI":"10.1124\/mol.63.4.886"},{"key":"23","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90553-O"},{"key":"24","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.60.1.643"},{"key":"25","doi-asserted-by":"publisher","DOI":"10.1038\/ni914"},{"key":"26","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2011.00423"},{"key":"27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024527"},{"key":"28","year":"2012","journal-title":"RWTH Aachen Library"},{"key":"29","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2009-0210ST"},{"key":"30","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(00)00022-4"},{"key":"31","doi-asserted-by":"publisher","DOI":"10.1016\/S0344-0338(97)80025-8"},{"key":"32","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.67.1.68"},{"key":"33","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e3181a2adb7"},{"key":"34","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1993.264.4.H1161"},{"key":"35","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200207000-00014"},{"key":"36","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1988.64.4.1688"},{"key":"37","doi-asserted-by":"publisher","DOI":"10.1007\/bf01487039"},{"key":"38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1996.tb15356.x"},{"issue":"2","key":"39","first-page":"225","volume":"23","year":"2004","journal-title":"Journal of Experimental & Clinical Cancer Research"},{"key":"40","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091236"},{"key":"41","doi-asserted-by":"publisher","DOI":"10.1002\/9780470513521.ch9"},{"key":"42","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.51.6.579"},{"key":"43","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00284.2006"},{"key":"44","doi-asserted-by":"crossref","first-page":"943","DOI":"10.4049\/jimmunol.160.2.943","volume":"160","year":"1998","journal-title":"Journal of Immunology"},{"key":"45","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.286"},{"key":"46","doi-asserted-by":"publisher","DOI":"10.1097\/MCC.0000000000000472"},{"key":"47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300416"},{"key":"48","doi-asserted-by":"publisher","DOI":"10.1002\/ar.20646"},{"key":"49","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1988.6.2.344"},{"key":"50","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-14-74"},{"key":"51","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e31825b2db3"},{"key":"52","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4804(90)90260-9"},{"key":"53","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000194074.59584.42"},{"issue":"3","key":"54","first-page":"176","volume":"168","year":"1998","journal-title":"The Western Journal of Medicine"},{"issue":"10","key":"55","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1093\/clinchem\/47.10.1847","volume":"47","year":"2001","journal-title":"Clinical Chemistry"},{"key":"56","doi-asserted-by":"publisher","DOI":"10.1016\/s1071-9164(97)90045-2"}],"container-title":["Mediators of Inflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/mi\/2020\/3650508.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/mi\/2020\/3650508.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/mi\/2020\/3650508.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,30]],"date-time":"2023-09-30T15:03:23Z","timestamp":1696086203000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.hindawi.com\/journals\/mi\/2020\/3650508\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,1]]},"references-count":56,"alternative-id":["3650508","3650508"],"URL":"https:\/\/doi.org\/10.1155\/2020\/3650508","relation":{},"ISSN":["0962-9351","1466-1861"],"issn-type":[{"value":"0962-9351","type":"print"},{"value":"1466-1861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,1]]}}}