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Therefore, TNF may be a prominent mediator of endothelial cell and vascular wall dysfunction in sickle cell anemia, a hypothesis we addressed using NY1DD, S+S<jats:sup>Antilles<\/jats:sup>, and SS\u2010BERK sickle transgenic mice. Transfusion experiments revealed participation of abnormally activated blood monocytes exerting an endothelial activating effect, dependent upon Egr\u20101 in both vessel wall and blood cells, and upon NF\u03baB(p50) in a blood cell only. Involvement of TNF was identified by beneficial impact from TNF blockers, etanercept and infliximab, with less benefit from an IL\u20101 blocker, anakinra. In therapeutic studies, etanercept ameliorated multiple disturbances of the murine sickle condition: monocyte activation, blood biomarkers of inflammation, low platelet count and Hb, vascular stasis triggered by hypoxia\/reoxygenation (but not if triggered by hemin infusion), tissue production of neuro\u2010inflammatory mediators, endothelial activation (monitored by tissue factor and VCAM\u20101 expression), histopathologic liver injury, and three surrogate markers of pulmonary hypertension (perivascular inflammatory aggregates, arteriolar muscularization, and right ventricular mean systolic pressure). In aggregate, these studies identify a prominent\u2014and possibly dominant\u2014role for an abnormal monocyte\u2010TNF\u2010endothelial activation axis in the sickle context. Its presence, plus the many benefits of etanercept observed here, argue that pilot testing of TNF blockade should be considered for human sickle cell anemia, a challenging but achievable translational research goal.<\/jats:p>","DOI":"10.1002\/ajh.24856","type":"journal-article","created":{"date-parts":[[2017,7,12]],"date-time":"2017-07-12T02:22:09Z","timestamp":1499826129000},"page":"1119-1130","source":"Crossref","is-referenced-by-count":30,"title":["A monocyte\u2010TNF\u2010endothelial activation axis in sickle transgenic mice: Therapeutic benefit from TNF blockade"],"prefix":"10.1002","volume":"92","author":[{"given":"Anna","family":"Solovey","sequence":"first","affiliation":[{"name":"Division of Hematology\u2010Oncology\u2010Transplantation Department of Medicine, University of Minnesota Medical School Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arif","family":"Somani","sequence":"additional","affiliation":[{"name":"Division of Critical Care Department of Pediatrics, University of Minnesota Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Belcher","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology\u2010Transplantation Department of Medicine, University of Minnesota Medical School Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Milbauer","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology\u2010Transplantation Department of Medicine, University of Minnesota Medical School Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Vincent","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology\u2010Transplantation Department of Medicine, University of Minnesota Medical School Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafal","family":"Pawlinski","sequence":"additional","affiliation":[{"name":"Department of Medicine University of North Carolina at Chapel Hill Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl A.","family":"Nath","sequence":"additional","affiliation":[{"name":"Department of Medicine Mayo Clinic Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Robert J.","family":"Kelm","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Vermont College of Medicine Colchester Vermont"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Mackman","sequence":"additional","affiliation":[{"name":"Department of Medicine University of North Carolina at Chapel Hill Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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