Human models of sickle cell vascular damage

项目描述（由申请人提供）：本项目将测试抗炎药对镰状细胞性贫血患者皮肤、深部组织和骨髓中直接测量的血流减少的能力。我们假设，中断镰状红细胞、白细胞、血小板和血管内皮之间的粘附相互作用的治疗干预将减轻间歇性缺氧引起的血管阻塞、血红蛋白去饱和和血管损伤介质的释放。虽然镰状细胞性贫血（SCA）被认为是急性发作的显著红细胞（RBC）镰状细胞，镰状相关的血管闭塞持续发生，甚至在非危机时期。这些过程的累积效应是终末器官损伤。最近来自动物模型的数据强调了白细胞粘附到血管内皮在镰状血管闭塞发生中的重要性。因此，干扰白细胞、镰状红细胞和血管内皮之间黏附相互作用形成的疗法可能会减少终末器官损伤。红细胞镰状细胞是由缺氧引起的。对SCD儿童的睡眠研究表明，每晚发生10到40次血氧饱和度下降到75%到85%。我们直接测量镰状细胞病患者因氮诱导的缺氧而导致的血流量减少。这些下降是正常对照的6倍（p< 0.001）。我们将在人体中发展这种血管闭塞模型，并将研究扩展到包括测量缺氧引起的炎症介质变化、血管损伤标志物和深层组织血流量的测量。这些参数将根据氮诱导的缺氧以及睡眠期间自然发生的缺氧发作来测量。在详细描述N2刺激和睡眠缺氧模型后，我们将使用抗炎药来阻止血流的变化和血管损伤标志物的增加。如果这些药物成功，我们将有直接的证据表明炎症在血管闭塞中起作用。此外，该模型可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，如果在更大规模的临床试验中进行测试，消除缺氧诱导的血流量减少和在这些人体模型中检测到的血管损伤标志物的变化的治疗干预措施将减少危机的频率并减轻终器官损伤的程度。

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.