A characteristic aspect of the robust, systemic inflammatory state in sickle cell disease is dysfunction of endothelial nitric oxide synthase (eNOS). We identify 10 aberrant endothelial cell inputs, present in the specific sickle context, that are known to have the ability to cause eNOS dysfunction. These are: endothelial arginase depletion, asymmetric dimethylarginine, complement activation, endothelial glycocalyx degradation, free fatty acids, inflammatory mediators, microparticles, oxidized low density lipoproteins, reactive oxygen species, and Toll-like receptor 4 signaling ligands. The effect of true eNOS dysfunction on clinical testing using flow-mediated dilation can be simulated by two known examples of endothelial dysfunction mimicry (hemoglobin consumption of NO; and oxidation of smooth muscle cell soluble guanylate cyclase). This lends ambiguity to interpretation of such clinical testing. The presence of these multiple perturbing factors argues that a therapeutic approach targeting only a single injurious endothelial input (or either example of mimicry) would not be sufficiently efficacious. This would seem to argue for identifying therapeutics that directly protect eNOS function or application of multiple therapeutic approaches.

中文翻译：

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镰状细胞病中内皮 NOS (eNOS) 功能障碍的多种诱导剂

镰状细胞病中强烈的全身炎症状态的一个特征是内皮一氧化氮合酶 (eNOS) 功能障碍。我们确定了 10 种异常内皮细胞输入，存在于特定的镰状环境中，已知它们具有导致 eNOS 功能障碍的能力。它们是：内皮精氨酸酶耗竭、不对称二甲基精氨酸、补体激活、内皮糖萼降解、游离脂肪酸、炎症介质、微粒、氧化低密度脂蛋白、活性氧和 Toll 样受体 4 信号配体。真正的 eNOS 功能障碍对使用流动介导的扩张的临床测试的影响可以通过两个已知的内皮功能障碍模拟示例（NO 的血红蛋白消耗；和平滑肌细胞可溶性鸟苷酸环化酶的氧化）来模拟。这使得对此类临床测试的解释变得模糊不清。这些多重干扰因素的存在表明，仅针对单个损伤性内皮输入（或模拟的任一示例）的治疗方法将不够有效。这似乎有利于确定直接保护 eNOS 功能的治疗方法或多种治疗方法的应用。