Human models of sickle cell vascular damage

描述（由申请方提供）：本项目将测试抗炎药阻断镰状细胞贫血受试者皮肤、深部组织和骨髓中直接测量的血流量减少的能力。 我们假设，中断镰状红细胞，白细胞，血小板和血管内皮细胞之间的粘附相互作用的治疗干预，将减少血管闭塞，血红蛋白去饱和，并释放介质的血管损伤引起的间歇性缺氧。 镰状细胞性贫血（SCA）被认为是红细胞（RBC）镰状化的急性发作，但即使在非危象期，镰状细胞相关的血管闭塞也会持续发生。 这些过程的累积效应是终末器官损伤。 最近的数据从动物模型强调的重要性，白细胞粘附到血管内皮的镰状血管闭塞的成因。 因此，干扰白细胞、镰状红细胞和血管内皮之间粘附相互作用的形成的疗法可能会减少终末器官损伤。 红细胞镰状化是由缺氧引起的。 对SCD儿童的睡眠研究表明，每晚发生10至40次去饱和，氧饱和度下降到75%至85%。 我们直接测量了镰状细胞病受试者对氮诱导缺氧的血流量减少。 这些下降是正常对照组的6倍（p<0.001）。 我们将开发这种人体血管闭塞模型，并将研究扩展到包括测量缺氧诱导的炎症介质变化、血管损伤标志物和深部组织血流测量。 这些参数将在响应氮诱导的缺氧以及睡眠期间自然发生的缺氧事件时进行测量。 然后，我们将使用抗炎剂来阻断血流的变化，并在详细表征N2激发和睡眠缺氧模型后增加血管损伤标志物。 如果这些药物是成功的，我们将有直接的证据表明，炎症在人类血管闭塞中发挥作用。 此外，该模型可用于测试镰状细胞病的候选治疗。 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，消除缺氧诱导的血流减少和在这些人类模型中检测到的血管损伤标志物变化的治疗干预将降低危机的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.