Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy
Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy
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DOI：
10.1189/jlb.0708445
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发表时间：
2009-02-01
影响因子：
5.5
通讯作者：
Costa, F. F.
中科院分区：
文献类型：
--
作者：
Lanaro, C.;Franco-Penteado, C. F.;Costa, F. F.
炎症、细胞与血管内皮细胞的黏附和内皮细胞损伤导致镰状细胞性贫血(SCA)血管闭塞。虽然炎性细胞因子和生物标记物的改变是相关的，但报告一直相互矛盾，这些分子在疾病中的决定性作用仍有待确定。此外，羟基脲疗法(HU)对炎症介质释放的影响尚不清楚。本研究旨在测定健康对照组、稳定期SCA患者和接受HU治疗的SCA患者的血浆炎症介质水平和白细胞基因表达。SCA患者血浆中的肿瘤坏死因子-α、IL-8和PGE(2)水平显著高于对照组。HU治疗与增强的肿瘤坏死因子-α显著逆转有关，有趣的是，还与血浆抗炎IL-10升高有关。SCA单个核细胞(MC)的干扰素-γ、IL-10、环氧合酶-2(COX-2)和诱导型一氧化氮合酶(INOS)基因表达无明显变化，而肿瘤坏死因子-α、IL-8和保护酶HO-1的基因表达显著升高。虽然COX-2mRNA表达降低，但HU治疗与SCA-MC炎症基因表达无明显相关。SCA患者中性粒细胞IL-8、干扰素-γ、诱导型一氧化氮合酶和HO-1的基因表达显著高于对照组。HU组iNOS表达降低，IL-10基因表达增强。综上所述，数据表明，SCA中存在许多促炎和抗炎介质的基因表达和产物的变化，更重要的是，在接受HU治疗的患者中。对这些途径的了解可能有助于进一步了解这种疾病的病理生理学。J.Leukoc。比奥尔。85：235-242；2009。
Inflammation, cell adhesion to vascular endothelium, and endothelial injury contribute to sickle cell anemia (SCA) vaso-occlusion. Although alterations in inflammatory cytokines and biomarkers have been related, reports have been conflicting, and a conclusive role for these molecules in the disease remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not understood. This study aimed to determine plasma levels and leukocyte gene expressions of inflammatory mediators in healthy controls, steady-state SCA patients, and SCA patients on HU therapy. TNF-alpha, IL-8, and PGE(2) levels were significantly higher in the plasma of SCA individuals when compared with control individuals. HU therapy was associated with a significant reversal of augmented TNF-alpha and, interestingly, increased plasma anti-inflammatory IL-10. IFN-gamma, IL-10, cyclooxygenase 2 (COX-2), and inducible NO synthase (iNOS) gene expressions were unaltered in SCA mononuclear cells (MC); however, gene expressions of TNF-alpha, IL-8, and the protective enzyme heme oxygenase-1 (HO-1) were significantly higher. HU therapy was not associated with significantly altered SCA MC inflammatory gene expression, although COX-2 mRNA expression was decreased. In SCA neutrophils, gene expressions of IL-8, IFN-gamma, iNOS, and HO-1 were significantly higher than those of control subjects. Patients on HU demonstrated lower iNOS and higher IL-10 neutrophil gene expressions. Taken together, data suggest that alterations in the gene expressions and productions of a number of pro- and anti-inflammatory mediators are present in SCA and importantly, in those patients on HU therapy. Knowledge of these pathways may contribute to further the understanding of the pathophysiology of this disease. J. Leukoc. Biol. 85: 235-242; 2009.