Continuous vaso-occlusive and inflammatory processes cause extensive end-organ damage in adults with sickle cell disease (SCD), and there is little evidence that long-term hydroxyurea therapy prevents this. In initial trials, P-selectin blockade with crizanlizumab reduced SCD vaso-occlusive crisis frequency, and interleukin (IL)-1β inhibition in SCD patients, using canakinumab, lowered inflammatory markers. We used murine SCD models to examine the effects of acute and chronic blockade of P-selectin and of IL-1β on vaso-occlusive events, their inflammatory profile and organ health. Both approaches improved impaired cutaneous microvascular perfusion in SCD mice by reducing TNF-α-induced vaso-occlusion. Acute P-selectin blockade markedly reduced TNF-α-induced neutrophil-platelet aggregate formation in SCD mice, and decreased leukocyte- rolling movements in the microvasculature, while acute IL-1β inhibition attenuated microvascular leukocyte adhesion. Six weeks of IL-1β-blocking immunotherapy improved the inflammatory profile of SCD mice, considerably reduced hepatic fibrosis and provided some relief from lung injury. In contrast, although P-selectin blockade reduced glomerular congestion, no significant benefit to overall organ pathology was observed. Unexpectedly, while combining the two immunotherapies reduced microvascular occlusion, their prolonged use caused acute liver injury. Notably, inhibition of IL-1β, but not of P-selectin, remarkably decreased hemosiderosis, in association with reduced tissue macrophage infiltration and the correction of biomarkers of dysregulated iron turnover. Our findings suggest that the attenuation of inflammation, as well as of vaso- occlusive processes, may be crucial for mitigating organ damage in SCD. Future trials should explore the ability of cytokine blockade to prevent multi-organ damage in patients with SCD, beyond evaluating vaso-occlusive crisis frequency.

中文翻译：

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靶向镰状细胞病小鼠的 P-选择素和白细胞介素-1β：对血管阻塞、肝损伤和器官铁沉积的影响。


持续的血管闭塞和炎症过程会导致镰状细胞病 （SCD） 成人患者广泛的终末器官损伤，几乎没有证据表明长期羟基脲治疗可以防止这种情况。在初步试验中，使用 crizanlizumab 阻断 P-选择素可降低 SCD 血管闭塞危象频率，并使用 canakinumab 抑制 SCD 患者的白细胞介素 （IL）-1β 降低炎症标志物。我们使用小鼠 SCD 模型来检查 P-选择素和 IL-1β 的急性和慢性阻断对血管闭塞事件、其炎症特征和器官健康的影响。两种方法都通过减少 TNF 诱导的血管闭塞来改善 SCD 小鼠α受损的皮肤微血管灌注。急性 P-选择素阻断显着减少 TNF α诱导的 SCD 小鼠中性粒细胞-血小板聚集体形成，并减少微血管系统中白细胞滚动的运动，而急性 IL-1β 抑制减弱了微血管白细胞粘附。为期 6 周的 IL-1β 阻断免疫疗法改善了 SCD 小鼠的炎症特征，大大减少了肝纤维化，并在一定程度上缓解了肺损伤。相比之下，尽管 P-选择素阻断减少了肾小球充血，但未观察到对整体器官病理的显着益处。出乎意料的是，虽然两种免疫疗法联合使用减少了微血管阻塞，但它们的长期使用却导致了急性肝损伤。值得注意的是，抑制 IL-1β 而不是 P-选择素，显着降低含铁血黄素沉着症，与减少组织巨噬细胞浸润和纠正铁失调的生物标志物有关。我们的研究结果表明，炎症的减弱以及血管闭塞过程对于减轻 SCD 中的器官损伤可能至关重要。 未来的试验应探索细胞因子阻断预防 SCD 患者多器官损伤的能力，而不仅仅是评估血管闭塞危象频率。