Human models of sickle cell vascular damage

描述(申请人提供)：该项目将测试抗炎药阻止镰状细胞性贫血患者皮肤、深层组织和骨髓直接测量的血流量减少的能力。我们假设，阻断镰状红细胞、白细胞、血小板和血管内皮细胞之间黏附相互作用的治疗干预将减少间歇性低氧引起的血管闭塞、血红蛋白脱饱和度和血管损伤介质的释放。虽然镰状细胞性贫血(SCA)被认为是显著的红细胞(RBC)镰状的急性发作，但镰刀相关的血管闭塞即使在非危象期也会持续发生。这些过程的累积效应是终末器官损害。最近来自动物模型的数据强调了白细胞与血管内皮细胞的黏附在镰刀状血管闭塞的发生中的重要性。因此，干扰白细胞、镰刀状红细胞和血管内皮细胞之间黏附相互作用形成的治疗方法可能会减少终末器官损伤。红细胞病态是由低氧引发的。对SCD儿童的睡眠研究表明，每晚会发生10到40次减饱和，血氧饱和度下降到75%到85%。我们直接测量了镰状细胞病受试者对氮气诱导的低氧反应的血流量减少。这些降幅是正常对照组的6倍(P&lt；.001)。我们将在人类中开发这一血管闭塞模型，并将研究扩展到测量低氧诱导的炎症介质的变化、血管损伤的标记物和深部组织血流的测量。这些参数将根据氮气诱导的低氧以及睡眠中自然发生的低氧事件进行测量。然后，我们将使用抗炎药来阻断血流的变化，并在详细描述氮气挑战和睡眠低氧模型后增加血管损伤的标志物。如果这些药物成功，我们将在人类身上获得炎症在血管闭塞中发挥作用的直接证据。此外，该模型可能用于测试镰状细胞病的候选治疗方法。虽然不在本提案的范围内，但我们预计，如果在更大的临床试验中进行测试，在这些人类模型中检测到的血管损伤标志物减少和血管损伤标志物的变化将减少危象的发生频率并减轻终末器官损伤的程度。

DESCRIPTION (provided by applicant): This project will test the ability of anti-inflammatory agents to block decrease in blood flow directly measured in the skin, deep tissue and bone marrow of subjects with sickle cell anemia. We hypothesize that therapeutic interventions that interrupt adhesive interactions between sickle erythrocytes, leukocytes, platelets and vascular endothelium will lessen the vaso occlusion, hemoglobin desaturations, and release of mediators of vascular damage induced by intermittent hypoxia. While sickle cell anemia (SCA) is thought of as acute episodes of marked red blood cell (RBC) sickling, sickle-related vaso occlusion occurs continually even dudng non-crisis periods. The cumulative effect of these processes is end-organ damage. Recent data from animal models underscore the importance of leukocyte adhesion to the vascular endothelium in the genesis of sickle vasoocclusion. It is therefore likely that therapies that interfere with the formation of the adhesive interactions between leukocytes, sickle red cells and vascular endothelium will decrease end-organ damage. RBC sickling is triggered by hypoxia. Sleep studies in SCD children demonstrate that 10 to 40 episodes of desaturation occur each night with oxygen saturation dropping to 75 to 85 percent. We directly measured decreases in blood flow in response to nitrogen-induced hypoxia in subjects with sickle cell disease. These decreases are six-times greater than normal controls (p<.001). We will develop this model of vaso occlusion in humans and extend the studies to include measurement of hypoxia-induced changes in inflammatory mediators, markers of vascular damage, and measures of deep tissue blood flow. These parameters will be measured in response to nitrogen-induced hypoxia as well as hypoxic episodes naturally occurring during sleep. We will then use anti-inflammatory agents to block the changes in blood flow and increase in markers of vascular damage after detailed characterization of the N2 challenge and sleep hypoxia models. If these agents are successful, we will have direct evidence in humans that inflammation plays a role in vaso occlusion. Furthermore, this model may serve to test candidate treatments for sickle cell disease. While not within the scope of the present proposal, we anticipate that therapeutic interventions that abrogate hypoxia-induced blood flow decreases and changes in markers of vascular damage detected in these human models will decrease frequency of crisis and lessen the degree of end-organ damage if tested in larger clinical trials.