MECHANISMS OF BLOOD VOLUME ABNORMALITIES IN CFS

慢性疲劳综合征（CFS）有越来越多的文献描述神经-心血管异常与CFS复发相关的阵发性低血压。Streeten和Bell增加了红细胞（RBC）质量减少的观察结果，这一发现得到了迈阿密研究小组的证实。这一观察结果与Natelson小组的CFS每搏输出量减少的观察结果一致。直立不耐受和红细胞质量减少的作用以及这些观察结果在CFS病理生理学中的相互关系尚不清楚。此外，立位不耐受与静脉收缩力受损、肾素-血管紧张素醛固酮系统异常、肾上腺皮质功能以及自主神经功能的关系尚未阐明。CFS中观察到的红细胞质量减少特别令人困惑，因为促红细胞生成素（EPO）水平正常或较低。 红细胞生成的主要驱动力是EPO，其响应于低氧血症由肾脏释放，并且在低RBC质量的情况下通常会相当升高。我们假设，在低RBC质量的情况下，低至正常的EPO水平可能由一种以上的机制引起：1）通过将足够的血液供应分流到肾脏，感觉不到对升高的EPO的需要; 2）存在小管水平的感觉缺陷，其使适当的反应变钝;和/或3）EPO产生被可溶性介质直接抑制。在本协议中，我们将测试这些机制的相互作用。我们预测一个混合的机制，包括感觉缺陷和EPO抑制。我们将进行肾血流量、肾血管阻力和肾功能的研究，以及比较肾血流动力学与外周血流动力学的研究，以检测血流量和肾与外周交感神经张力的充分性。进一步的研究将评估肾素-血管紧张素-醛固酮系统和肾上腺皮质功能对肾血流动力学的影响。还将比较仰卧位和直立位之间的血流动力学特征。最后，将研究血浆或RBC容量扩张前后的心血管健康，以进一步描述血容量减少和/或RBC质量减少对这些参数的作用。通过炎性细胞因子TNF-α、IL-1 β、TGF-β或IL-6直接抑制EPO是在RBC质量减少的情况下正常至低EPO水平的另一合理解释。这些细胞因子已在体外和体内被证明抑制EPO产生，并且已显示在大量CFS受试者中升高。 检查炎性细胞因子在EPO抑制中的作用的研究将包括细胞因子肽的血浆测量以及来自单核细胞的编码这些细胞因子的信息的mRNA测量。将进行CFS血清与对照血清对Hep 3B细胞系中EPO产生的体外研究，以确定CFS中观察到的细胞因子水平升高是否足以减少缺氧诱导的EPO产生。

Chronic Fatigue Syndrome (CFS) has an increasing literature describing neuro-cardiovascular abnormalities with associated episodic hypotension associated with CFS relapse. Streeten and Bell have added the observation of a reduced red blood cell (RBC) mass, a finding confirmed by the Miami research group. This observation is consistent with that of Natelson's group of a reduced stroke volume in CFS. The role of both orthostatic intolerance and reduced RBC mass and the relationship of these observations to each other in the pathophysiology of CFS is poorly understood. Moreover, the relationship of orthostatic intolerance to impaired venous contractility, abnormalities of the renin-angiotensinaldosterone system, adrenocortical function as well as autonomic function has not been elucidated. The observation of a reduced RBC mass in CFS is particularly puzzling because erythropoietin (EPO) levels are normal to low. A major drive of erythropoiesis is EPO, which is released in response to hypoxemia by the kidney, and would normally be quite elevated in the setting of low RBC mass. We postulate that the low to normal EPO levels in the face of low RBC mass can result from more than one mechanism: l) By shunting adequate blood supply to the kidney, the need for elevated EPO is not sensed; 2) A sensory defect at the level of the tubules exists which blunts the appropriate response; and/or 3) EPO production is directly suppressed by soluble mediators. In this protocol, we will test the interaction of these mechanisms. We predict a mixed mechanism including a sensory defect and EPO suppression. We will perform studies of renal blood flow, renal vascular resistance, and renal function as well as studies to compare renal hemodynamics to peripheral hemodynamics to test both adequacy of blood flow and renal vs. peripheral sympathetic tone. Additional studies will evaluate the influence of the renin-angiotensin-aldosterone system and adrenalcortical function on renal hemodynamics. The hemodynamic profiles between the supine and upright position will also be compared. Finally, cardiovascular fitness pre- and post- plasma or RBC volume expansion will be studied to further delineate the role of hypovolemia and/or RBC mass reduction on these parameters. Direct suppression of EPO via the inflammatory cytokines TNF-alpha, IL- lbeta, TGF-beta or IL-6 is another reasonable explanation of normal to low EPO levels in the face of a reduced RBC mass. These cytokines have been demonstrated in vitro and in vivo to inhibit EPO production and have been shown to be elevated in significant numbers of CFS subjects. Studies to examine the role of inflammatory cytokines in EPO inhibition will include plasma measures of cytokine peptide as well as mRNA measures of the message encoding these cytokines from the mononuclear cells. Jn vitro studies of CFS sera vs. control sera on EPO production in Hep3B cell lines will be performed to determine if the level of elevated of cytokines seen in CFS is sufficient to reduce hypoxia induced EPO production.