transforming-growth-factor-beta and Anemia--Sickle-Cell

Investigate the role of homocysteine (Hcy), Th17-related cytokines, and adhesion molecules in the inflammatory state seen in the sickle cell anemia (SCA).. We studied the Hcy, interleukin (IL)-17, and transforming growth factor β (TGF-β) cytokine levels of 62 SCA patients, as well as the expression levels of inflammatory and endothelial activation markers.. We found significant associations between Hcy levels and increased expression of IL-17 and TGF-β among SCA patients, and a positive significant correlation between Hcy and soluble vascular cellular adhesion molecules (sVCAM). SCA individuals had raised IL-17 levels when compared with controls.. These results suggest a possible role of Hyc in the induction of TGF-β and IL-17. Other authors proposed that Hcy may contribute to the initiation and progression of vascular disease by monocyte activation, resulting in the secretion of cytokines that amplify the inflammatory response. The role of Hcy in cytokine production and oxidative stress in the endothelium may explain the increase of sVCAM expression and, the vascular activation currently described among the SCA individuals with the highest Hcy serum levels. The chronic inflammation was observed in hyperhomocysteinemic mice, with an increased expression of VCAM-1 and plasma levels of tumor necrosis factor-alpha, showing an association of this inflammatory molecule and vascular changes.. Our findings suggest that the increased levels of IL-17,Hcy and sVCAM contributes contributes to the vascular inflammation and activation presented by SCA patients, which probably have an important role in vaso-occlusion. On the basis of the presented data, IL-17 and Hcy might be considered as important components in the pathogenesis of SCA.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Animals; Child; Female; Homocysteine; Humans; Inflammation Mediators; Interleukin-17; Male; Mice; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Cardiovascular involvement in sickle cell disease (SCD) has a great impact on patients' morbidity and mortality. Recently, interleukin-18 (IL-18) and transforming growth factor beta (TGF-β) were suggested as potential biomarkers for sickle cell cardiomyopathy. Global longitudinal strain (GLS) is a reliable early parameter for estimation of deformed myocardium. This study evaluated the role of TGF-β and IL-18 as risk indicators of altered strain in patients with SCD.. Forty children with SCD (age >5 years) and 40 healthy children as controls, matched in age and sex, were enrolled in the study. All participants were subjected to clinical examination, complete blood count, serum ferritin, TGF-β, IL-18, and assessment of cardiac function by echocardiography.. TGF-β, IL-18, and lactic acid dehydrogenase (LDH) were significantly higher among cases (mean age: 10.6 ± 3.5 years) when compared to controls (p < .001), at cutoff values 41.7 ng/mL, 128.9 pg/mL, and 340 unit, respectively. The LS of free wall of RV (FW-RV) was significantly lower among cases when compared to controls (-23.55% ± 5.55% vs. -28.73% ± 2.43%, p < .001). Free wall longitudinal strain of the right ventricle (FWLS-RV) was significantly correlated to IL-18 and LDH (p < .001), while GLS-RV was significantly correlated to TGF-β. The GLS-LV was correlated to frequency of vaso-occlusive crises (VOCs) per year (p < .001). Diastolic function, E/A of LV, and RV were negatively correlated to the hemoglobin and serum ferritin levels.. The TGF-β, IL-18, and LDH along with frequent VOCs are correlated to altered LS, especially the right ventricle, and could serve as risk indicators for subclinical cardiomyopathy in children with SCD.

Topics: Adolescent; Anemia, Sickle Cell; Cardiomyopathies; Child; Child, Preschool; Ferritins; Heart Ventricles; Humans; Interleukin-18; Transforming Growth Factor beta; Ventricular Dysfunction, Right; Ventricular Function, Right

Respiratory manifestations related to the intake of non-steroidal anti-inflammatory drugs (NSAIDs) during the treatment of the painful vaso-occlusive crisis of sickle cell disease are either a type I hypersensitivity mechanism of the Gell and Coombs classification, or a pharmacological mechanism of NSAIDs. The use of NSAIDs is essential in the Abidjan school because of the absence of therapeutic alternatives in the management of the inflammatory crisis of this disease. The induction of tolerance to NSAIDs initiated by the authors has had clear clinical success. The basic biological reasons for this tolerance were evaluated in this study. A group of 11 sickle cell patients aged 12 to 39 years in whom post-NSAID respiratory manifestations disappeared for at least 6 months following a short tolerance induction protocol with ibuprofen, was assayed by ELISA for TNFα, INF (Th1 cytokines), IL-4 (Th2 cytokine), IL-10, TGF-β (immunosuppressive cytokines) and total IgE, before induction or pre-induction (D-1) and at day one (D1), D2- 3, one month (M1), and M6 after induction. A repolarization of the Th1/Th2 balance was noted during the post induction period. The high concentration of IL-4 observed at D-1 gradually decreased in favor of the cytokines TNFα, INF. The decrease in cytokine IL-4 with the level of total IgE was accompanied by the increase of IL-10 and TGF-β demonstrating the regulatory role of these cytokines in the control of allergic diseases. In conclusion, the induction of immuno-tolerance to NSAIDs through a short protocol is well supported by immune regulation. The medium-term effects are real, unlike the results of allergen desensitization or specific immunotherapy. However, this protocol could be used in certain circumstances such as in the case of intolerance to trimethoprim-sulfamethoxazole, used as the treatment of choice for the prevention of opportunistic diseases in people living with human immunodeficiency virus.

Topics: Anemia, Sickle Cell; Anti-Inflammatory Agents, Non-Steroidal; Cote d'Ivoire; Cytokines; Humans; Immune Tolerance; Immunoglobulin E; Interleukin-10; Interleukin-4; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Renal dysfunction affects 5-18% of patients with sickle cell disease (SCD). To date, no studies have described urinary levels of transforming growth factor β-1 (TGF-β1), a marker of fibrosis, and neutrophil gelatinase-associated lipocalin (NGAL), a marker of acute/chronic kidney disease, as biomarkers in identifying patients at risk of developing renal disease in SCD. We hypothesized that SCD subjects will have increased urinary excretion of TGF-β1 and NGAL compared with healthy controls (CTR). We examined 51 SCD subjects: 42 HbSS, 8 HbSC, and 1 HbSD. Sixteen out of 42 patients with HbSS were on hydroxyurea (HU). Urinary excretion of TGF-β1 was 26.4 ± 1.5 pg/mgCr in SCD subjects vs 15.0 ± 2.4 pg/mgCr in CTR (p<0.00001). SCD patients with hemoglobin < 9 g/dl had higher urinary TGF-β1 than patients with milder anemia (p=0.002). Urinary TGF-β1 trended lower in HbSS patients treated with HU (23.61 ± 2.6 pg/mgCr), vs patients not on HU (27.69 ± 1.8 pg/mgCr; p=0.055). There was no correlation between urinary TGF-β1 and microalbuminuria or estimated glomerular function. There was no difference in urinary NGAL in SCD patients vs CTR. We suggest that urinary TGF-β1 may serve as a marker of early renal injury in SCD.

Topics: Acute-Phase Proteins; Adolescent; Age Factors; Albuminuria; Anemia, Sickle Cell; Biomarkers; Child; Child, Preschool; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Lipocalin-2; Lipocalins; Male; Proto-Oncogene Proteins; Transforming Growth Factor beta; Young Adult

Cutaneous leg ulcers are common in sickle cell anaemia and their risk might be genetically determined. Sickle cell anaemia patients were studied to examine the relationship of leg ulcers with haemolysis and with single nucleotide polymorphisms (SNPs) in candidate genes that could affect sickle vasoocclusion. Leg ulcer patients had lower haemoglobin levels and higher levels of lactate dehydrogenase, bilirubin, aspartate transaminase and reticulocytes than did control patients with sickle cell anaemia but without leg ulcers. Age-adjusted comparisons showed that sickle cell anaemia-alpha thalassaemia was more frequent among controls than cases. These results strongly suggested that the likelihood of having leg ulcers was related to the intensity of haemolysis. 215 SNPs in more than 100 candidate genes were studied. Associations were found with SNPs in Klotho, TEK and several genes in the TGF-beta/BMP signalling pathway by genotypic association analyses. KL directly or indirectly promotes endothelial nitric oxide (NO) production and the TEK receptor tyrosine kinase is involved in angiogenesis. The TGF-beta/BMP signalling pathway modulates wound healing and angiogenesis, among its other functions. Haemolysis-driven phenotypes, such as leg ulcers, could be improved by agents that reduce sickle erythrocyte density or increase NO bioavailability.

Topics: Adult; Anemia, Sickle Cell; Bone Morphogenetic Proteins; Female; Genotype; Glucuronidase; Hemolysis; Humans; Klotho Proteins; Leg Ulcer; Male; Phenotype; Polymorphism, Single Nucleotide; Receptor, TIE-2; Thalassemia; Transforming Growth Factor beta

Infection and bacteremia are common in sickle cell disease. We hypothesized that, consistent with evidence for the genetic modulation of other disease complications, the risk of developing bacteremia might also be genetically modulated. Accordingly, we studied the association of single nucleotide polymorphisms (SNPs) in candidate genes with the risk of bacteremia in sickle cell anemia. We found significant associations with SNPs in IGF1R and genes of the TGF-beta /BMP pathway (BMP6, TGFBR3, BMPR1A, SMAD6 and SMAD3). We suggest that both IGF1R and the TGF-beta /BMP pathway could play important roles in immune function in sickle cell anemia and their polymorphisms may help identify a "bacteremia-prone" phenotype.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Bacteremia; Bone Morphogenetic Protein 6; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Linkage Disequilibrium; Male; Polymorphism, Genetic; Proteoglycans; Receptor, IGF Type 1; Receptors, Transforming Growth Factor beta; Smad3 Protein; Smad6 Protein; Transforming Growth Factor beta

A hemoglobin F (HbF) level between eight and nine percent divides sickle cell anemia (SS) patients into two populations, according to the kinetics of circulating burst forming units-erythroid (BFU-E), long term culture-initialing cells (LTC-IC), and cytokine plasma concentrations. The SS patients with HbF levels lower than 8-9% are more anemic (LFSS patients) than those with HbF levels higher than 8-9% who have less severe anemia (HFSS patients). We report here that the level of erythropoiesis [evaluated by the levels of soluble transferin receptors (sTfR)] is not identical in these two patient populations, supporting the idea that a different set of regulatory mechanisms might be required to maintain the two levels of increased hematopoiesis. The plasma sTfR concentration was increased in all SS samples compared with controls (P < 0.002) and sTfR levels were negatively correlated with peripheral HbF%. (r = -0.574, P < 0.002). Furthermore, sTfR levels were higher in LFSS than in HFSS patients. Erythropoietin (Epo) levels were increased in the plasma of LFSS individuals (range = 34-215 ml U/ml), while the values in HFSS patients were in the normal range (3-20 ml U/ml). Furthermore, we identify here stem cell factor (SCF) and transforming growth factor-beta (TGF-beta) as regulatory factors specifically affected by the presence of SS genotype and its level of severity. The plasma concentrations of SCF and TGF-beta were increased compared with normal controls and high levels of SCF (up to 7,000 pg/ml) were detected in LFSS patients. The latter also showed increased proportion of SCF+ CD34 enriched circulating cells (49%). Low SCF in HFSS patients is associated with elevated TGF-beta, suggesting a regulatory role of the latter on either SCF release or c-kit expression in progenitor cells. Occasional elevation of granulocyte macrophage-colony stimulating factor (G-CSF), interleukin (IL)-7, and macrophage inflammatory protein (MIP)-1alpha in plasma of SS patients is not specific because no relation to HbF could be demonstrated. All plasma tested for leukemia inhibitory factor (LIF) were negative. Data presented here, complementing previously published information, supports a model in which HFSS patients achieve a balance between inhibitory (TGF-beta) and stimulatory (SCF, IL-3) factors, resulting in moderate erythropoietic response. In contrast, in LFSS patients, low levels of TGF-beta and the increased release of GM-CSF and SCF maintain the intense erythropoies

Topics: Adult; Anemia, Sickle Cell; Antigens, CD34; Cytokines; Erythrocytes; Erythropoiesis; Erythropoietin; Fetal Hemoglobin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-3; Interleukin-7; Kinetics; Middle Aged; Receptors, Transferrin; Solubility; Stem Cell Factor; Transforming Growth Factor beta