Anti-Inflammatory Effect of Hydroxyurea Therapy in Sickle Cell Disease.

Abstract

There is growing evidence that inflammatory stresses within the microvasculature may play a significant role in the vaso-occlusion that is characteristic of sickle cell disease. Inflammation, leukocyte adhesion to vascular endothelium, and subsequent endothelial injury appear to contribute to the pathogenesis of SCD. Whilst alterations in a number of inflammatory, anti-inflammatory cytokines and inflammatory biomarkers have been previously related, reports have been conflicting and a conclusive role for cytokines in SCD remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not well understood. This study was undertaken to determine plasma levels of IL-8, IL-10, TNF-a and PGE2 in healthy controls, SCD patients in steady-state and in SCD patients on HU therapy (SCDHU; 20–30 mg/kg/day; 3-month minimum treatment duration) using specific ELISA assays (R&D Research). TNF-a levels were significantly higher in SCD individuals when compared to controls (2.95 ± 0.44 pg/ml, n=17; vs 1.43 ± 0.20 pg/ml, n=8, p=0.006). HU therapy, however, was observed to significantly reverse augmented TNF-a levels (SCDHU; 1.61 ± 0.18 pg/ml, n=15, p=0.007). Plasma IL-8 levels were significantly elevated in SCD individuals (16.58 ± 2.52 pg/ml, n=29, p<0.001) compared to healthy controls (5.67 ± 0.62 pg/ml, n=16); however HU therapy did not significantly alter augmented IL-8 in SCD (14.59 ± 1.57 pg/ml, n=22). Interestingly, detectable levels of the anti-inflammatory cytokine, IL-10 (>3.8 pg/ml), were found in 3 (15%) of 20 SCD patients, and 1 (11%) of 9 controls, whilst 7 (50%) of 14 HU-treated patients demonstrated detectable IL-10 levels. Levels of plasma PGE2, an inflammatory biomarker, were significantly increased in SCD patients compared to control individuals (128.35 ± 12.25 pg/ml, n=26; vs 88.45 ± 5.95 pg/ml, n=14, p=0.01) and similar levels were detected in patients treated with HU (143.6 ± 16.75 pg/ml, n=17, p=0.004, compared to control). Data demonstrate that the inflammatory cytokines, TNFa and IL-8, and the inflammatory biomarker, PGE2, are augmented in a population of SCD patients studied during steady-state, contributing to clarify conflicting data. Furthermore, HU therapy reversed augmented TNFa levels, and appears to have an augmenting effect on the anti-inflammatory cytokine, IL-10, suggesting an anti-inflammatory action of HU therapy that may be important for the prevention of vaso-occlusion.