{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T01:46:08Z","timestamp":1793324768928,"version":"4.5.0"},"reference-count":41,"publisher":"American Society for Clinical Investigation","issue":"18","funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["2R01HL098032,1R01HL125886,5P01HL103455,T32 HL110849"],"award-info":[{"award-number":["2R01HL098032,1R01HL125886,5P01HL103455,T32 HL110849"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100016489","name":"Institute for Transfusion Medicine","doi-asserted-by":"crossref","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100016489","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100016251","name":"Hemophilia Center of Western Pennsylvania","doi-asserted-by":"crossref","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100016251","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,9,20]]},"abstract":"<jats:p>\n                    During the last half-century, numerous antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating septic shock. The observation in multiple studies that cell-free hemoglobin (CFH) levels are elevated during clinical sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human haptoglobin binds CFH with high affinity and, therefore, can potentially reduce iron availability and oxidative activity. CFH levels are elevated over approximately 24\u201348 hours in our antibiotic-treated canine model of\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    pneumonia that simulates the cardiovascular abnormalities of human septic shock. In this 96-hour model, resuscitative treatments, mechanical ventilation, sedation, and continuous care are translatable to management in human intensive care units. We found, in this\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>aureus<\/jats:italic>\n                    pneumonia model inducing septic shock, that commercial human haptoglobin concentrate infusions over 48-hours bind canine CFH, increase CFH clearance, and lower circulating iron. Over the 96-hour study, this treatment was associated with an improved metabolic profile (pH, lactate), less lung injury, reversal of shock, and increased survival. Haptoglobin binding compartmentalized CFH to the intravascular space. This observation, in combination with increasing CFHs clearance, reduced available iron as a potential source of bacterial nutrition while decreasing the ability for CFH and iron to cause extravascular oxidative tissue injury. In contrast, haptoglobin therapy had no measurable antiinflammatory effect on elevations in proinflammatory C-reactive protein and cytokine levels. Haptoglobin therapy enhances normal host defense mechanisms in contrast to previously studied antiinflammatory sepsis therapies, making it a biologically plausible novel approach to treat septic shock.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.123013","type":"journal-article","created":{"date-parts":[[2018,9,19]],"date-time":"2018-09-19T11:01:59Z","timestamp":1537354919000},"source":"Crossref","is-referenced-by-count":44,"title":["Haptoglobin improves shock, lung injury, and survival in canine pneumonia"],"prefix":"10.1172","volume":"3","author":[{"given":"Kenneth E.","family":"Remy","sequence":"first","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA."},{"name":"Department of Pediatrics, Division of Critical Care, Washington University in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Cort\u00e9s-Puch","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven B.","family":"Solomon","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin M.","family":"Pockros","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Feng","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan J.","family":"Lertora","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Program, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy R.","family":"Hantgan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physics, Wake Forest University, Winston-Salem, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Perlegas","sequence":"additional","affiliation":[{"name":"Department of Physics, Wake Forest University, Winston-Salem, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Shaw","family":"Warren","sequence":"additional","affiliation":[{"name":"Infectious Disease Unit, Massachusetts General Hospital, and Shriners Hospital for Crippled Children, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Gladwin","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel B.","family":"Kim-Shapiro","sequence":"additional","affiliation":[{"name":"Department of Physics, Wake Forest University, Winston-Salem, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvey G.","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Natanson","sequence":"additional","affiliation":[{"name":"Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2018,9,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0b013e32833157f4"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1202-799"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3182741a54"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1186\/cc13108"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1186\/cc11425"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59770"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0000000000000224"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/toxins6041244"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.02.011"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.07.068"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-10-462945"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/trf.12607"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-539353"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.008698"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-08-375303"},{"key":"B16","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2014.00415","article-title":"Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development","volume":"5","author":"Schaer","year":"2014","journal-title":"Front Physiol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-11-451229"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5195"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/trf.14488"},{"issue":"6","key":"B20","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1089\/ars.2004.6.941","article-title":"Redox biology of blood","volume":"6","author":"Alayash","year":"2004","journal-title":"Antioxid Redox Signal"},{"issue":"51","key":"B21","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3001118","article-title":"A central role for free heme in the pathogenesis of severe sepsis","volume":"2","author":"Larsen","year":"2010","journal-title":"Sci Transl Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.11.4160"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-10-245001"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/trf.14214"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/35051594"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-01-198309"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/01.TA.0000158244.69179.94"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-141-1-200407060-00014"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-008-1274-6"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200204-302OC"},{"issue":"3","key":"B31","first-page":"M482","article-title":"Administration of haptoglobin during cardiopulmonary bypass surgery","volume":"37","author":"Tanaka","year":"1991","journal-title":"ASAIO Trans"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.019955"},{"issue":"7","key":"B33","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.85375","article-title":"Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes","volume":"1","author":"Yang","year":"2016","journal-title":"JCI Insight"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/trf.13213"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2008.02.006"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/trf.12162"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.18.8423"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007446"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01313-06"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112559"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00589.2007"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/123013\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:41:37Z","timestamp":1779194497000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/123013"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,20]]},"references-count":41,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2018,9,20]]},"published-print":{"date-parts":[[2018,9,20]]}},"alternative-id":["10.1172\/jci.insight.123013"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.123013","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,20]]},"article-number":"e123013"}}