Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil.
Haematologica. 2011 Apr;96(4):526-33. doi: 10.3324/haematol.2010.032912. Epub 2010 Dec 20.
Pharmacological approaches to inhibit increased leukocyte adhesive interactions in sickle cell disease may represent important strategies for the prevention of vaso-occlusion in patients with this disorder. We investigated, in vitro, the adhesion molecules involved in endothelial-sickle cell disease neutrophil interactions and the effect of simvastatin on sickle cell disease neutrophil adhesion to tumor necrosis factor-α-activated endothelial monolayers (human umbilical vein endothelial cells), and neutrophil chemotaxis.
Sickle cell disease patients in steady state and not on hydroxyurea were included in the study. Endothelial cells treated, or not, with tumor necrosis factor-α and simvastatin were used for neutrophil adhesion assays. Neutrophils treated with simvastatin were submitted to interleukin 8-stimulated chemotaxis assays.
Sickle cell disease neutrophils showed greater adhesion to endothelial cells than control neutrophils. Adhesion of control neutrophils to endothelial cells was mediated by Mac-1 under basal conditions and by the Mac-1 and LFA-1 integrins under inflammatory conditions. In contrast, adhesion of sickle cell disease neutrophils to endothelium, under both basal and tumor necrosis factor-α-stimulated conditions, was mediated by Mac-1 and LFA-1 integrins and also by VLA-4. Under stimulated inflammatory conditions, simvastatin significantly reduced sickle cell disease neutrophil adhesion, and this effect was reversed by inhibition of nitric oxide synthase. Furthermore, intercellular adhesion molecule-1 expression was significantly abrogated on tumor necrosis factor-α-stimulated endothelium incubated with simvastatin, and statin treatment inhibited the interleukin-8-stimulated migration of both control and sickle cell disease neutrophils.
The integrins Mac-1, LFA-1 and, interestingly, VLA-4 mediate the adhesion of sickle cell disease leukocytes to activated endothelial cell layers, in vitro. Our data indicate that simvastatin may be able to reduce endothelial activation and consequent leukocyte adhesion in this in vitro model; future experiments and clinical trials may determine whether simvastatin therapy could be employed in patients with sickle cell disease, with beneficial effects on vaso-occlusion.
抑制镰状细胞病中白细胞黏附相互作用的药理学方法可能是预防该疾病患者血管阻塞的重要策略。我们在体外研究了参与内皮细胞-镰状细胞病中性粒细胞相互作用的黏附分子，以及辛伐他汀对肿瘤坏死因子-α激活的内皮单层（人脐静脉内皮细胞）上镰状细胞病中性粒细胞黏附的影响，以及中性粒细胞趋化性。
纳入稳定期且未接受羟基脲治疗的镰状细胞病患者进行研究。用肿瘤坏死因子-α和辛伐他汀处理或未处理的内皮细胞用于中性粒细胞黏附测定。用辛伐他汀处理的中性粒细胞进行白细胞介素 8 刺激的趋化性测定。
镰状细胞病中性粒细胞与对照中性粒细胞相比，对内皮细胞的黏附作用更强。对照中性粒细胞在内皮细胞上的黏附作用在基础条件下由 Mac-1 介导，在炎症条件下由 Mac-1 和 LFA-1 整合素介导。相比之下，镰状细胞病中性粒细胞在基础和肿瘤坏死因子-α刺激条件下与内皮细胞的黏附作用由 Mac-1 和 LFA-1 整合素以及 VLA-4 介导。在刺激炎症条件下，辛伐他汀可显著降低镰状细胞病中性粒细胞的黏附作用，而一氧化氮合酶的抑制可逆转这种作用。此外，与肿瘤坏死因子-α刺激的内皮细胞孵育的辛伐他汀显著降低了细胞间黏附分子-1 的表达，他汀类药物治疗抑制了对照和镰状细胞病中性粒细胞的白细胞介素-8 刺激的迁移。
体外实验中，整合素 Mac-1、LFA-1 以及有趣的 VLA-4 介导了镰状细胞病白细胞与激活的内皮细胞层的黏附。我们的数据表明，辛伐他汀可能能够减少该体外模型中内皮细胞的激活和随后的白细胞黏附；未来的实验和临床试验可能确定辛伐他汀治疗是否可用于镰状细胞病患者，从而对血管阻塞产生有益影响。
