Hydroxycarbamide stimulates the production of proinflammatory cytokines by endothelial cells: relevance to sickle cell disease

Laurance, Sandrine; Pellay, François-Xavier; Dossou-Yovo, Omer Placide; Verger, Emmanuelle; Krishnamoorthy, Rajagopal; Lapouméroulie, Claudine; Benecke, Arndt; Élion, Jacques

doi:10.1097/fpc.0b013e32833854d6

Cited by 16 publications

(27 citation statements)

References 33 publications

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“…In our study, hepatic CCL20 expression could not be explained exclusively by the presence of CRLM, its level being higher in patients with SOS than in patients with CRLM alone. Immunohistochemistry showed CCL20 expression in macrophages but not in endothelial cells (30). In monocytes/macrophages, CCL20 is a hypoxia-inducible gene as illustrated by ischemic/hypoxic transcriptome studies (31,32), in which it constitutes an important mechanism to promote recruitment of specific leukocyte subsets at pathologic sites.…”

Section: Discussionmentioning

confidence: 99%

“…Several drugs such as oxaliplatin and other platinum compounds lead to the production of reactive oxygen species and glutathione depletion in SEC, resulting in SEC injury in vitro (30). Oxidative stress also contributes to SEC injury through monocrotaline induced depletion of cellular glutathione and the augmentation of reactive oxygen species production in vitro and in vivo (39).…”

Section: Discussionmentioning

confidence: 99%

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Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Rubbia‐Brandt

Tauzin

Brézault

et al. 2011

Molecular Cancer Therapeutics

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Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Rubbia‐Brandt

Tauzin

Brézault

et al. 2011

Molecular Cancer Therapeutics

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“…The exhaustive list of HC-target genes modulated in TrHBMEC under basal and pro-inflammatory conditions has been established previously. 24 Adhesion events are crucial for vasoocclusion. We therefore focused on 1,275 genes related to adhesion (Online Supplementary Table S1).…”

Section: Microarray Analysis Of Adhesion-related Gene Expression In Tmentioning

confidence: 99%

“…24 Data were generated using the Human Genome Survey (HGS) arrays (version 1 and 2) which measure gene expression levels of 29,918 validated human genes. Logarithmic fold-changes were calculated as previously described in an "everyone-againsteveryone" scheme.…”

Section: Microarray Experimentsmentioning

confidence: 99%

“…24 The aim of the present study was to focus our analysis of the micro-array data on the expression of genes related to adhesion events and to extend our investigation to other human VEC types in order to appreciate how HC and/or cytokines (CY) may modify the adhesogenic patterns of vascular endothelia in different sites. Thus, in addition to TrHBMEC, we studied and compared the effect of HC and/or CY treatments on primary VEC from the lung microcirculation (HPMEC) and from the umbilical vein (HUVEC), the most widely utilized macrocirculation model.…”

Section: Introductionmentioning

confidence: 99%

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Differential modulation of adhesion molecule expression by hydroxycarbamide in human endothelial cells from the micro- and macrocirculation: potential implications in sickle cell disease vasoocclusive events

Laurance¹,

Lansiaux²,

Pellay³

et al. 2011

Haematologica

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BackgroundAll the cellular partners of the vascular system and especially endothelial cells are involved in the pathophysiology of the vasoocclusive crises associated with sickle cell disease. In sickle cell disease, circulating cells adhere abnormally to endothelial cells in a chronic pro-inflammatory context. Hydroxycarbamide is the only drug with demonstrated efficacy to reduce the frequency of vasoocclusive crises. Here, we investigated the effects of hydroxycarbamide and/or cytokines on the expression of genes related to adhesion events in endothelial cells from three different vascular sites. Design and MethodsEndothelial cells representative of the macro-(HUVEC) or microcirculation (TrHBMEC and HPMEC) were grown in the presence or absence of hydroxycarbamide and/or cytokines (TNFα and IFNγ). Expression of genes encoding adhesion proteins was analyzed by RQ-PCR, ELISA, flow cytometry, in situ ELISA for extracellular matrix proteins, and Western blot. ResultsIn cells from the microcirculation, expression of TSP-1, vWF, and PECAM-1 genes was decreased by hydroxycarbamide and/or cytokine treatment at the mRNA level. In the macrocirculation their expression was unaffected or increased. Hydroxycarbamide significantly decreased vWF incorporated in the TrHBMEC extracellular matrix. CD36 mRNA was strongly down-regulated by cytokines in HPMEC, the only cell type in which it is expressed. Hydroxycarbamide decreased soluble PECAM-1 in HUVEC supernatants. ConclusionsOur results highlight the heterogeneity of vascular endothelial cell responses to hydroxycarbamide and/or cytokines depending upon their origin. They also suggest that hydroxycarbamide has an anti-adhesogenic effect on endothelial cells, but by mechanisms which could vary according to their macro-or microcirculation and organ origin.Key words: sickle cell disease, adhesion, hydroxycarbamide, vascular endothelial cells. disease vasoocclusive events. Haematologica 2011;96(4):534-542. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Laurance S, Lansiaux P, Pellay F-X, Hauchecorne M, Benecke A, Elion J, and Lapoumeroulie C. Differential modulation of adhesion molecule expression by hydroxycarbamide in human endothelial cells from the micro-and macrocirculation: potential implications in sickle cell

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Chemokines in pregnant women with sickle cell disease

Hazin-Costa

Araújo²,

Guerra

et al. 2019

Cytokine

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Hydroxycarbamide stimulates the production of proinflammatory cytokines by endothelial cells: relevance to sickle cell disease

Abstract: Our study confirms that VECs are significant targets of HC in the context of SCD and identifies its earlier unsuspected action on another major component of SCD pathophysiology, that is, the 'inflammation pathway'.

Cited by 16 publications

References 33 publications

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Differential modulation of adhesion molecule expression by hydroxycarbamide in human endothelial cells from the micro- and macrocirculation: potential implications in sickle cell disease vasoocclusive events

Chemokines in pregnant women with sickle cell disease

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