Patrolling Monocytes in Sickle Pain Crisis and following Transfusion

镰状疼痛危机和输血后单核细胞的巡逻 摘要 镰状细胞病（SCD）患者患有与血管损伤相关的血管内溶血， 功能障碍疼痛性血管闭塞危象（VOC），涉及镰状红细胞附着增加， 活化的白细胞对受损的血管内皮的损害也是SCD的标志。输血降低镰刀 （含血红蛋白（Hb S））RBC质量，尽管其用于VOC仍存在争议。在SCD，巡逻 单核细胞通常从脉管系统中清除受损细胞和碎片， 抗炎血红素加氧酶1（HO-1），一种血红素降解酶，具有抗细胞毒性和抗 炎症特性。我们发现SCD患者有一种新的巡逻单核细胞亚群， 表达非常高水平的HO-1（HO-1hi），其在最近患有糖尿病的患者中数量减少。 挥发性有机化合物发作。这个单核细胞亚群也负责摄取溶血损伤的内皮细胞 但不是HD RBC。在小鼠中，增加它们的数量降低了粘附的SCD RBC对 溶血损伤血管内皮。在这个建议中，我们将测试SCD巡逻的假设， 单核细胞粘附并清除受损的内皮和内皮附着的镰状红细胞，导致 HO-1上调和抑制VOC。我们假设当HO-1hi巡逻单核细胞受到限制时， 血管损伤和增加的镰状红细胞附着在内皮上， 增加VOC的风险。我们进一步证实，输血改善了HO-1hi巡逻单核细胞的存活， 使它们能够有效地清除血管系统中受损的内皮细胞，从而提供保护 针对VOC。为了验证我们的假设，我们将确定巡逻的单核细胞 保护SCD血管（目的1）;目的2，我们将剖析HO-1在巡逻抗VOC活性中的作用 最后，在目标3中，我们将检查巡逻单核细胞和HO-1hi亚群的关联 在i）急性VOC和ii）慢性输血期间。总之，我们相信这些研究将有助于 确定HO-1hi巡逻单核细胞在VOC病理生理学中的作用，及其作为治疗药物的潜力 目标是VOC。

Patrolling Monocytes in Sickle Pain Crisis and following Transfusion Abstract Patients with sickle cell disease (SCD) suffer from intravascular hemolysis associated with vascular injury and dysfunction. Painful vaso-occlusive crisis (VOC) involving increased attachment of sickle erythrocytes and activated leukocytes to damaged vascular endothelium is also a hallmark of SCD. Transfusion lowers sickle (hemoglobin (Hb S)-containing) RBCs mass, although its use for VOC remains controversial. In SCD, patrolling monocytes, which normally scavenge damaged cells and debris from the vasculature, express higher levels of anti-inflammatory heme oxygenase 1 (HO-1), a heme degrading enzyme with anti-cytotoxic and anti- inflammatory properties. We have found that patients with SCD have a novel subset of patrolling monocytes expressing very high levels of HO-1 (HO-1hi) which are decreased in numbers in patients who had a recent VOC episode. This monocyte subset was responsible for uptake of hemolysis-damaged endothelium as well as SCD, but not HD RBCs. In mice, increasing their numbers lowered adherent SCD RBC attachment to the hemolysis-damaged vascular endothelium. In this proposal, we will test the hypothesis that SCD patrolling monocytes scavenge and remove damaged endothelium and endothelial-attached sickle RBCs, resulting in HO-1 upregulation and dampening of VOC. We postulate that when HO-1hi patrolling monocytes are limiting, there is a buildup of vascular damage and increased sickle RBC attachment to the endothelium, which in turn increases the risk of VOC. We further posit that transfusions improve survival of HO-1hi patrolling monocytes, enabling them to effectively clear the vasculature from damaged endothelial cells, thereby affording protection against VOC. To test our hypotheses, we will determine the mechanisms by which patrolling monocytes protect SCD vasculature (aim 1); in aim 2, we will dissect the role of HO-1 in anti-VOC activity of patrolling monocytes, and finally in aim 3, we will examine the association of patrolling monocytes and HO-1hi subset during i) acute VOC and ii) with chronic transfusions. Altogether, we believe that these studies will help establish the role of HO-1hi patrolling monocytes in VOC pathophysiology, and their potential as a therapeutic target for VOC.