Cytokines and Soluble Adhesion Molecules in Sickle Cell Anemia Patients during Hydroxyurea Therapy

Sickle cell anemia is characterized by chronic hemolysis coupled with extensive vascular inflammation. This inflammatory state also mechanistically promotes a high risk of lethal, invasive pneumococcal infection. Current treatments to reduce vaso-occlusive complications include chronic hydroxyurea therapy to induce fetal hemoglobin. Because hydroxyurea also reduces leukocytosis, an understanding of the impact of this treatment on pneumococcal pathogenesis is needed. Using a sickle cell mouse model of pneumococcal pneumonia and sepsis, administration of hydroxyurea was found to significantly improve survival. Hydroxyurea treatment decreased neutrophil extravasation into the infected lung coincident with significantly reduced levels of E-selectin in serum and on pulmonary epithelia. The protective effect of hydroxyurea was abrogated in mice deficient in E-selectin. The decrease in Eselectin levels was also evident in human sickle cell patients receiving hydroxyurea therapy. These data indicate that in addition to induction of fetal hemoglobin, hydroxyurea attenuates leukocyteendothelial interactions in sickle cell anemia, resulting in protection against lethal pneumococcal sepsis. IntroductionSickle cell anemia (SCA) is characterized by chronic hemolytic anemia and vascular inflammation. Hydroxyurea therapy decreases vasoocclusive complications of SCA and reduces mortality, 1,2 but the mechanism of this benefit has been debated. Elevated white blood cell counts have been found to correlate with greater mortality in sickle cell disease (SCD), 3 and early studies suggested hydroxyurea reduced leukocytosis. 4,5 Subsequent studies found no statistical association between reduction of leukocytosis and mortality in SCA patients receiving hydroxyurea, implicating increased levels of hemoglobin F (HbF) as the main predictor of mortality. 6 A recent placebo-controlled clinical trial of hydroxyurea in pediatric SCA patients confirmed a highly significant decrease in total white blood cell and absolute neutrophil counts after hydroxyurea treatment as well as increases in hemoglobin and HbF levels. 7 A significant decrease in acute chest syndrome, which is oftentimes initiated by lung infection, also was observed in this study. 7 Bacteremia was recorded 6 times in the placebo group but only 3 times in the hydroxyurea-treated patients, 7 a trend that was not significant because of the low incidence. Although induction of HbF is generally accepted to be a major benefit of hydroxyurea therapy in SCA, the relative contribution of other factors, including decreased white blood cell counts, to positive outcomes remains a possibility that has yet to be explored.Modulation of leukocytosis by hydroxyurea raises the question of infection risk in SCA. Children with SCA have a 400-fold greater risk of fulminant, lethal pneumococcal sepsis than their healthy peers or patients with other hemolytic anemias, 8-10 a finding recapitulated in the sickle cell mouse model. 11 Despite administration of penicillin prophylaxis, pneumococcal polysac...

Section: Discussionsupporting

confidence: 52%

Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

Lebensburger¹,

Howard²,

Hu³

et al. 2012

“…In addition to a link with pulmonary hypertension, we and others have observed a link between LDH and a generalized state of endothelial activation, reflected by elevated blood plasma levels of soluble adhesion molecules, especially vascular cell adhesion molecule (VCAM-1). [2][3][4][5][6][7][8][9][10] Both pathologic endothelial activation and pulmonary hypertension are associated with more severe hemolytic anemia, reflected by low hemoglobin levels and high reticulocyte counts. 1,2,8 These data begin to suggest that LDH elevation may be a marker of hemolysis-associated endothelial dysfunction and pulmonary hypertension.…”

Section: Introductionmentioning

confidence: 99%

Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease

Kato

McGowan

Machado

et al. 2006

569

346

Pulmonary hypertension is prevalent in adult patients with sickle cell disease and is strongly associated with early mortality and markers of hemolysis, in particular, serum lactate dehydrogenase (LDH). Intravascular hemolysis leads to impaired bioavailability of nitric oxide (NO), mediated by NO scavenging by plasma oxyhemoglobin and by arginine degradation by plasma arginase. We hypothesized that serum LDH may represent a convenient biomarker of intravascular hemolysis and NO bioavailability, characterizing a clinical subphenotype of hemolysisassociated vasculopathy. In a cohort of 213 patients with sickle cell disease, we found statistically significant associations of steady-state LDH with low levels of hemoglobin and haptoglobin and high levels of reticulocytes, bilirubin, plasma hemoglobin, aspartate aminotransferase, arginase, and soluble adhesion molecules. LDH isoenzyme fractionation confirmed predominance of LD1 and LD2, the principal isoforms within erythrocytes. In a subgroup, LDH levels closely correlated with plasma cell-free hemoglobin, accelerated NO consumption by plasma, and impaired vasodilatory responses to an NO donor. Remarkably, this simple biomarker was associated with a clinical subphenotype of pulmonary hypertension, leg ulceration, priapism, and risk of death in patients with sickle cell disease. We propose that LDH elevation identifies patients with a syndrome of hemolysisassociated NO resistance, endothelial dysfunction, and end-organ vasculopathy. IntroductionPulmonary hypertension is an increasingly recognized complication of sickle cell disease and other chronic hereditary and acquired hemolytic anemias. Doppler echocardiography screening reveals a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or greater in 33% of adults with sickle cell disease, indicative of pulmonary hypertension. 1 Pulmonary hypertension in these patients is associated with a 10-fold increased risk for early mortality. Elevated pulmonary artery pressures in patients with sickle cell disease have been associated with low hemoglobin concentration, high levels of serum lactate dehydrogenase (LDH), elevated systolic systemic blood pressure, history of priapism, renal insufficiency, and markers of iron overload. Of the several independent epidemiologic factors associated with pulmonary hypertension, an elevated level of serum LDH has drawn particular interest and controversy. In addition to a link with pulmonary hypertension, we and others have observed a link between LDH and a generalized state of endothelial activation, reflected by elevated blood plasma levels of soluble adhesion molecules, especially vascular cell adhesion molecule (VCAM-1). 2-10 Both pathologic endothelial activation and pulmonary hypertension are associated with more severe hemolytic anemia, reflected by low hemoglobin levels and high reticulocyte counts. 1,2,8 These data begin to suggest that LDH elevation may be a marker of hemolysis-associated endothelial dysfunction and pulmonary hypertension.LDH has long been considered a useful c...

“…12 Further, elevated blood levels of inflammatory and anti-inflammatory cytokines (ie, interleukin 1 ␤ [IL-1␤], IL-4, IL-6, tumor necrosis factor ␣ [TNF␣]), increased adhesion molecule expression (ie, intercellular adhesion molecule [ICAM], vascular cell adhesion molecule [VCAM], integrins, and P-selectin), and increased inflammatory biomarkers such as Creactive protein and isoprostanes have been described and appear to contribute to the development of chronic organ injury. 6,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Gene expression signatures have been used successfully to characterize tumor phenotype and to predict disease recurrence and mortality in B-cell lymphoma and breast cancer. 29,30 This comprehensive analysis of transcription profiles provides a novel means to enhance knowledge of the pathogenesis and treatment of different diseases.…”

Section: Introductionmentioning

confidence: 99%

Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease

Jison

Munson²,

Barb³

et al. 2004

201

149

In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide consumption, and free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state sickle cell disease (