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CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions
Jung-Eun Jang, … , Steven L. Spitalnik, Paul S. Frenette
Jung-Eun Jang, … , Steven L. Spitalnik, Paul S. Frenette
Published March 7, 2011
Citation Information: J Clin Invest. 2011;121(4):1397-1401. https://doi.org/10.1172/JCI45336.
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Brief Report Hematology

CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions

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Abstract

Hemolytic transfusion reactions (HTRs) can produce serious and potentially life-threatening complications in sickle cell disease (SCD) patients; however, the mechanisms underlying these complications remain undetermined. We established a model of alloimmune, IgG-mediated HTRs in a well-characterized humanized murine model of SCD. HTRs induced acute vaso-occlusive crisis (VOC), resulting in shortened survival of SCD mice. Acute VOC was associated with elevated circulating inflammatory chemokine levels, including striking elevation of the levels of the neutrophil chemoattractant CXCL1. Recombinant CXCL1 administration was sufficient to induce acute VOC in SCD mice, characterized by leukocyte recruitment in venules, capture of circulating red blood cells, reduction of venular flow, and shortened survival. In contrast, blockade of the CXCL1 receptor, CXCR2, prevented HTR-elicited acute VOC and prolonged survival in SCD mice. These results indicate that CXCL1 is a key inflammatory mediator of acute VOC in SCD mice. Targeted inhibition of CXCL1 and/or CXCR2 may therefore represent a new therapeutic approach for acute VOC in SCD patients.

Authors

Jung-Eun Jang, Eldad A. Hod, Steven L. Spitalnik, Paul S. Frenette

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Figure 3

CXCR2 blockade prevents HTR-induced acute VOC in SCD mice.

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CXCR2 blockade prevents HTR-induced acute VOC in SCD mice.
At 30 minutes...
At 30 minutes before passive immunization with anti-hGPA antibodies for HTR induction, SCD mice (n = 5 or 6 per group) were injected intravenously with CXCR2 antagonist SB225002 (4.5 mg/kg) or DMSO vehicle control. (A) Survival of transfused fluorescently labeled rbcs 2 hours after HTR induction. (B) Blood flow. (C) Adherent wbcs. (D) Number of circulating sickle rbc–adherent wbc interactions. (E) Real-time intravital microscopy 91–120 minutes after HTR induction. Arrows denote sickle rbc–adherent wbc interactions. Scale bars: 20 μm. (F) Kaplan-Meier survival curves (P < 0.01, log-rank test). *P < 0.05, **P < 0.01 versus DMSO.
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