Abstract
Elaboration of tumor necrosis factor (TNF) is a very early event in development of ischemia/reperfusion injury pathophysiology. 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+SAntilles, and SS-BERK sickle transgenic mice. Transfusion experiments revealed participation of abnormally activated blood monocytes exerting an endothelial activating effect, dependent upon Egr-1 in both vessel wall and blood cells, and upon NFκB(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-1 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-inflammatory mediators, endothelial activation (monitored by tissue factor and VCAM-1 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—and possibly dominant—role for an abnormal monocyte-TNF-endothelial 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.
Original language | English (US) |
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Pages (from-to) | 1119-1130 |
Number of pages | 12 |
Journal | American Journal of Hematology |
Volume | 92 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2017 |
Bibliographical note
Funding Information:We thank Jim Kiley, Fuad Abdullah, Sethu Nair, and Chunsheng Chen for technical assistance. We are grateful for editorial expertise provided by Tracy Daye-Groves and Michael Franklin. This work was supported by the National Institutes of Health: HL55552 to RPH; HL114567 to GV; and HL103773 to KG.
Publisher Copyright:
© 2017 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.