Distinct Deleterious Effects of Cyclosporine and Tacrolimus and Combined Tacrolimus–Sirolimus on Endothelial Cells: Protective Effect of Defibrotide

Carmona, Alba; Díaz‐Ricart, Maribel; Palomo, Marta; Molina, P.; Pino, Marcos; Rovira, Montserrat; Escolar, Ginés; Carreras, Enric

doi:10.1016/j.bbmt.2013.07.001

Cited by 67 publications

(69 citation statements)

References 39 publications

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“…11 Results from several studies carried out over the last 15 years, 2 trials aimed to evaluate the effect of DF on SOS, 12,13 and our in vitro studies 5,7,14 led to its approval for the treatment of severe SOS and the orphan designation for the prevention of graft-versus-host disease (GVHD) in European countries by the European Medicines Agency in 2013.…”

Section: Key Pointsmentioning

confidence: 99%

“…[8][9][10] However, 2 distinct properties of DF (endothelial protection and restoration of the thrombotic-fibrinolytic balance) were key to test its effect on the sinusoidal obstruction syndrome (SOS), a life-threatening complication associated with HCT. 11 Results from several studies carried out over the last 15 years, 2 trials aimed to evaluate the effect of DF on SOS, 12,13 and our in vitro studies 5,7,14 led to its approval for the treatment of severe SOS and the orphan designation for the prevention of graft-versus-host disease (GVHD) in European countries by the European Medicines Agency in 2013.…”

Section: Introductionmentioning

confidence: 99%

“…4 In this regard, our group has demonstrated the protective effect of DF on the endothelium, by preventing the endothelial damage associated with hematopoietic cell transplantation (HCT) conditions, 5,6 and with the deleterious effect of immunosuppresants. 7 In our in vitro endothelial activation model, DF has exhibited reproducible effects on endothelial cells (ECs) from different origins. DF demonstrates antiinflammatory, antithrombotic, and antiapoptotic properties.…”

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confidence: 99%

“…7 To evaluate whether DF exerts its function after binding to the cell membrane or if it requires its internalization, we exposed DF-treated ECs to the immunosuppressant For personal use only. on May 10, 2018. by guest www.bloodjournal.org From CSA in the absence and presence of Wortmannin.…”

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What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance

Palomo

Mir

Rovira

et al. 2016

Blood

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Key Points• Specific interaction of DF with EC membranes is followed by its internalization mainly through macropinocytic mechanisms.• DF attachment to the cell membrane is sufficient to perform its antiinflammatory and antioxidant effects on the endothelium.Defibrotide (DF) has received European Medicines Agency authorization to treat sinusoidal obstruction syndrome, an early complication after hematopoietic cell transplantation. DF has a recognized role as an endothelial protective agent, although its precise mechanism of action remains to be elucidated. The aim of the present study was to investigate the interaction of DF with endothelial cells (ECs). A human hepatic EC line was exposed to different DF concentrations, previously labeled. Using inhibitory assays and flow cytometry techniques along with confocal microscopy, we explored: DF-EC interaction, endocytic pathways, and internalization kinetics. Moreover, we evaluated the potential role of adenosine receptors in DF-EC interaction and if DF effects on endothelium were dependent of its internalization.Confocal microscopy showed interaction of DF with EC membranes followed by internalization, though DF did not reach the cell nucleus even after 24 hours. Flow cytometry revealed concentration, temperature, and time dependent uptake of DF in 2 EC models but not in other cell types. Moreover, inhibitory assays indicated that entrance of DF into ECs occurs primarily through macropinocytosis. Our experimental approach did not show any evidence of the involvement of adenosine receptors in DF-EC interaction. The antiinflammatory and antioxidant properties of DF seem to be caused by the interaction of the drug with the cell membrane. Our findings contribute to a better understanding of the precise mechanisms of action of DF as a therapeutic and potential preventive agent on the endothelial damage underlying different pathologic situations. (Blood. 2016;127(13):1719-1727 Introduction Defibrotide (DF) is a mixture of 90% single-stranded phosphodiester oligonucleotides (length, 9-80 mer; average molecular mass, 16.5 6 2.5 KDa) and 10% double-stranded phosphodiester oligonucleotides, derived from the controlled depolymerization of porcine intestinal mucosal DNA.1-3 Several functions, specially related to hemostasis, have been ascribed to DF. 4 In this regard, our group has demonstrated the protective effect of DF on the endothelium, by preventing the endothelial damage associated with hematopoietic cell transplantation (HCT) conditions, 5,6 and with the deleterious effect of immunosuppresants. 7 In our in vitro endothelial activation model, DF has exhibited reproducible effects on endothelial cells (ECs) from different origins. DF demonstrates antiinflammatory, antithrombotic, and antiapoptotic properties. However, although its effects are increasingly better understood, its precise mechanism of action remains to be elucidated.There is limited knowledge about DF pharmacokinetics, pharmacodynamics, and mechanisms of action. [8][9][10] However, 2 distinct properties of ...

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Section: Key Pointsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance

Palomo

Mir

Rovira

et al. 2016

Blood

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“…20 Carmona and associates found that cyclosporine alone and the combination of tacrolimus and sirolimus had an increased proinflammatory effect on endothelial cells; however, only cyclosporine showed additional prothrombotic effects. 21 The incidence of de novo TMA was recently shown to be 3% in renal allografts without evidence of AHR; however, all of the study patients were receiving tacrolimus and none were using Abbreviations: ACR, acute cellular rejection; TMA, thrombotic microangiopathy mammalian target of rapamycin inhibitors. 12 In another study of patients receiving a combination of sirolimus and cyclosporine with steroid avoidance, the incidence of de novo TMA was 3.6% in biopsies without evidence of AHR.…”

Section: Discussionmentioning

confidence: 95%

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Özdemir

Atılgan²,

Akçay³

et al. 2018

Exp Clin Transplant

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Objectives: Thrombotic microangiopathy is a form of renal capillary injury possibly associated with calcineurin inhibitor toxicity, acute humoral rejection, infections, and recurrent diseases. Here, we examined its incidence in patients diagnosed with acute and chronic active humoral rejection, polyomavirus nephropathy, acute cellular rejection, and immunoglobulin A recurrence. Materials and Methods: In total, 272 renal allograft recipients who met the inclusion criteria were reevaluated for presence of renal thrombotic microangiopathy. Thrombotic microangiopathy diagnosis was established by clinical, laboratory, and histologic features. C4d expression in peritubular capillaries was determined. Clinical data were collected from medical records. Results: Of 272 patients (mean age of 42.8 ± 12.7 years), only 74 patients (27.2%) had de novo thrombotic microangiopathy, which was found in 30/90 patients (33.3%) with acute humoral rejection, 9/51 (17.6%) with acute cellular rejection, 22/53 (41.5%) with chronic active humoral rejection, 10/55 (18.2%) with polyomavirus nephropathy, and 3/23 (13%) with immunoglobulin A nephropathy. Significant differences were shown between therapy type and thrombotic microangiopathy development (P = .02). Patients who received cyclosporine (38.5%) tended to show higher incidence of thrombotic microangiopathy than patients who received tacrolimus (20.7%) or sirolimus (7.7%). Patients with C4d-positive acute humoral (97.6% vs 2.4%) and chronic active humoral rejection (68.2% vs 31.8%) had greater incidence of thrombotic microangiopathy versus those who were C4d-negative. Graft loss was significantly higher in C4d-positive than in C4d-negative thrombotic microangiopathy groups (P < .001). Overall 1-, 3-, and 5-year graft survival was 94%, 85%, and 85% versus 83%, 51%, and 51% in thrombotic microangiopathy-negative versus thrombotic microangiopathy-positive patients (P < .001). Conclusions: Acute humoral rejection and chronic active humoral rejection were the most common and therefore most important causes of de novo thrombotic microangiopathy in renal transplant patients. Its presence in the renal allograft biopsy should arouse suspicion for underlying acute or chronic active humoral rejection. Key words: Acute cellular rejection, Acute humoral rejection, C4d expression, Chronic active humoral rejection, IgA nephropathy, Polyomavirus nephropathy, Renal allograft biopsy IntroductionThrombotic microangiopathy (TMA) describes a pathologic lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis. The clinical features of TMA result from the obstruction of the microcirculation and ultimately depend on the distribution of involved vascular beds. Microangiopathic hemolysis is the hallmark feature of this obstructed microcirculation. Thrombotic microangiopathy is a pathologic diagnosis, but its presence is commonly inferred from observations of thrombocytopenia and microangiopathic hemolysis in the appropriate clinical setting. [1][2]...

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