Mollapour E, Porter J B, Kaczmarski R, Linch D C, Roberts P J
Departments of Haematology, University College London Medical School, London, UK.
Blood. 1998 May 1;91(9):3423-9.
Intermittent painful crises due to vasoocclusion are the major clinical manifestation of sickle cell disease (SCD), but subclinical episodes may also occur. There is sparse evidence for the involvement of neutrophils in the pathophysiology of SCD, but production of cytokines by the damaged endothelium might influence neutrophil function and modulate responses to subsequent cytokine exposure. In addition, the activation of neutrophils in the microcirculation could itself exacerbate vasoocclusion. To test whether neutrophil inflammatory responses were altered in SCD, neutrophil phospholipase A2 and NADPH oxidase activity in response to in vitro priming by granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) were measured both during and between painful crises. Resting levels of neutrophil phospholipase A2 activity in steady-state SCD (4.0% +/- 0. 5% of total cell radioactivity) were raised relative to control values (2.0% +/- 0.2%, n = 10, P = .008). There was no defect of agonist-stimulated phospholipase A2 or NADPH oxidase activity in steady-state SCD; however, the ability of phospholipase A2 to respond to priming with GM-CSF was attenuated to 63% +/- 17% of control values (n = 10, P = .04). Similarly, neutrophil NADPH oxidase activity after priming with GM-CSF and TNF-alpha was, respectively, 65% +/- 11% (n = 7, P = .03) and 57% +/- 7% of control (n = 10, P = .007) in steady-state disease, and was further reduced during painful vasoocclusive crises to 34% +/- 9% and 25% +/- 3% of control for GM-CSF and TNF-alpha, respectively. These data were not explained by poor splenic function or any racial factor, as normal cytokine responses were seen in splenectomized patients in remission from Hodgkin's disease and in healthy Afro-Caribbean subjects. Abnormal neutrophil cytokine priming responses were not observed in either patients with rheumatoid arthritis or iron-deficiency anemia. Our findings are indicative of an ongoing inflammatory state in SCD between painful crises involving neutrophil activation and an abnormality of cytokine-regulated neutrophil function, which may compromise the host defenses against certain microorganisms.
血管阻塞引起的间歇性疼痛危象是镰状细胞病（SCD）的主要临床表现，但也可能发生亚临床发作。关于中性粒细胞参与SCD病理生理学的证据很少，但受损内皮细胞产生的细胞因子可能会影响中性粒细胞功能并调节对随后细胞因子暴露的反应。此外，微循环中中性粒细胞的激活本身可能会加剧血管阻塞。为了测试SCD中中性粒细胞炎症反应是否改变，在疼痛危象期间和之间测量了粒细胞-巨噬细胞集落刺激因子（GM-CSF）和肿瘤坏死因子-α（TNF-α）体外预刺激后中性粒细胞磷脂酶A2和NADPH氧化酶的活性。稳态SCD中中性粒细胞磷脂酶A2活性的静息水平（占总细胞放射性的4.0%±0.5%）相对于对照值（2.0%±0.2%，n = 10，P = 0.008）升高。稳态SCD中激动剂刺激的磷脂酶A2或NADPH氧化酶活性没有缺陷；然而，磷脂酶A2对GM-CSF预刺激的反应能力减弱至对照值的63%±17%（n = 10，P = 0.04）。同样，在稳态疾病中，GM-CSF和TNF-α预刺激后中性粒细胞NADPH氧化酶活性分别为对照值的65%±11%（n = 7，P = 0.03）和57%±7%（n = 10，P = 0.007），在疼痛性血管阻塞危象期间进一步降低至GM-CSF和TNF-α对照值的34%±9%和25%±3%。这些数据不能用脾功能低下或任何种族因素来解释，因为在霍奇金病缓解期的脾切除患者和健康的非洲加勒比受试者中观察到了正常的细胞因子反应。类风湿性关节炎患者或缺铁性贫血患者均未观察到异常的中性粒细胞细胞因子预刺激反应。我们的研究结果表明，在疼痛危象之间，SCD中存在持续的炎症状态，涉及中性粒细胞激活和细胞因子调节的中性粒细胞功能异常，这可能会损害宿主对某些微生物的防御能力。
