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了与CFS复发相关的与发作性低血压相关的神经心血管异常。Streeten和Bell增加了红细胞(RBC)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的研究小组关于CFS患者卒中体积减少的观点一致。立位耐受和红细胞质量减少在CFS的病理生理学中的作用以及它们之间的相互关系还知之甚少。此外，立位耐力障碍与静脉收缩功能受损、肾素-血管紧张素醛固酮系统异常、肾上腺皮质功能和自主神经功能的关系尚未阐明。在CFS中观察到的红细胞质量减少特别令人费解，因为促红细胞生成素(EPO)水平从正常到低。红细胞生成的一个主要驱动力是促红细胞生成素，它是肾脏对低氧血症的反应而释放的，在低红细胞质量的情况下通常会相当高。我们推测，面对低RBC质量时，EPO水平低到正常可能是多种机制的结果：L)通过分流足够的血液供应到肾脏，没有感觉到需要升高的EPO；2)在小管水平存在感觉缺陷，削弱了适当的反应；和/或3)EPO的产生直接受到可溶性介质的抑制。在本协议中，我们将测试这些机制的交互作用。我们预测一种混合机制，包括感觉缺陷和EPO抑制。我们将进行肾血流、肾血管阻力和肾功能的研究，以及比较肾血流动力学和外周血流动力学的研究，以测试血流充分性和肾与外周交感神经张力的充分性。其他研究将评估肾素-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的血流动力学曲线。最后，将研究血浆或红细胞体积扩张前后的心血管适合性，以进一步阐明血容量减少和/或红细胞质量减少对这些参数的作用。通过炎性细胞因子肿瘤坏死因子-α、白细胞介素1-β、转化生长因子-β或白细胞介素6直接抑制促红细胞生成素是红细胞质量减少时促红细胞生成素水平正常至低的另一个合理解释。这些细胞因子已经在体外和体内被证明抑制EPO的产生，并且在相当数量的CFS受试者中被证明是升高的。检测炎症细胞因子在EPO抑制中的作用的研究将包括血浆细胞因子多肽的测量以及单核细胞编码这些细胞因子的信息的信使核糖核酸的测量。JN将进行CFS血清和对照血清对Hep3B细胞株EPO产生的体外研究，以确定CFS中细胞因子水平的升高是否足以减少低氧诱导的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.