Publicació científica

S'han trobat 114 publicacions amb els criteris indicats.
Castro P, Palomo M, Moreno-Castaño AB, Fernández S, Torramadé-Moix S, Pascual G, Martinez-Sanchez J, Richardson E, Téllez A, Nicolas JM, Carreras E, Richardson PG, Badimon JJ, Escolar G, Diaz-Ricart M

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Cardiovasc Drugs Ther 7 Jun 2021, . Epub 7 Jun 2021
Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.
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Fernández S, Palomo M, Molina P, Díaz-Ricart M, Escolar G, Tellez A, Seguí F, Ventosa H, Torramade-Moix S, Rovira M, Carreras E, Nicolás JM, Castro P

Progressive endothelial cell damage in correlation with sepsis severity. Defibrotide as a contender.

J Thromb Haemost 19 Abr 2021, .
Background: The vascular endothelium plays a key role in sepsis pathophysiology and the associated organ dysfunction. Methods: We evaluated endothelial function in an experimental in-vitro model of sepsis, using endothelial cells grown in the presence of serum from patients with septic syndromes (sepsis, severe sepsis, and septic shock), non-infectious systemic inflammatory response syndrome (NI-SIRS) and healthy volunteers. Experiments were performed in the absence and presence of defibrotide (DF) (100µg/mL) to evaluate its potential protective effect. Results: After exposure to patients' sera, there was a progressive endothelial cell activation in correlation with sepsis severity, with a proinflammatory and prothrombotic phenotype, exhibiting significantly increased expression of adhesion receptors at the surface (ICAM-1, p< 0.05 and VCAM-1, p< 0.05); higher production and release to the extracellular matrix (ECM) of Von Willebrand factor (p< 0.001); augmented thrombogenicity of the ECM towards platelets (p< 0.001); and increased phosphorylation of intracellular p38MAPK. DF prevented these changes in all groups. Conclusions: Markers of endothelial damage increased progressively in association with the severity of septic syndromes. The endothelium is therefore an important therapeutic target to prevent complications of sepsis. DF shows promising potential to modulate the endothelial damage associated with sepsis and may constitute a pharmacological tool to decrease its sequelae including multiorgan failure.
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Blasco M, Martínez-Roca A, Rodríguez-Lobato LG, Garcia-Herrera A, Rosiñol L, Castro P, Fernández S, Quintana LF, Cibeira MT, Bladé J, Fernández de Larrea C, Tovar N, Jimenez R, Poch E, Guillen E, Campistol JM, Carreras E, Diaz-Ricart M, Palomo M

Complement as the enabler of carfilzomib-induced thrombotic microangiopathy.

Br. J. Haematol. 29 Mai 2020, . Epub 29 Mai 2020
Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.
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Martinez-Sanchez J, Palomo M, Torramade-Moix S, Moreno-Castaño AB, Rovira M, Gutiérrez-García G, Fernández-Avilés F, Escolar G, Penack O, Rosiñol L, Carreras E, Diaz-Ricart M

The induction strategies administered in the treatment of multiple myeloma exhibit a deleterious effect on the endothelium.

Bone Marrow Transplant. 13 Mai 2020, . Epub 13 Mai 2020
Multiple myeloma induction treatment includes proteasome inhibitors (PI) and immunomodulatory agents at present. The incidence of engraftment syndrome, a transplant complication potentially related to endothelium, has increased in the last years. Our aim was to investigate whether bortezomib (Velcade, V), thalidomide (T), and dexamethasone (D) affect the endothelium, and explore defibrotide (DF) as protective agent. Endothelial cells (ECs) in culture were exposed to the compounds separately or in combination, without (VTD) and with DF (VTD + DF). Changes in markers of: (i) inflammation (ICAM-1 expression and leukocyte adhesion), (ii) VWF production, (iii) cell permeability (VE-cadherin expression and cell monolayer integrity), and (iv) oxidative stress (ROS production and eNOS expression) were measured. ICAM-1 and VWF expression increased significantly in VTD but were similar to controls in VTD + DF. Separately, bortezomib was the main deleterious agent whereas dexamethasone showed no harmful effect. Leukocyte adhesion showed similar trends. VE-cadherin expression was lower in VTD and normalized in VTD + DF. EC permeability increased only with bortezomib. No changes were observed in oxidative stress markers. Our results demonstrate that bortezomib damages the endothelium, and DF prevents this effect. A better knowledge of the induction drugs impact will allow the design of measures to protect the endothelium.
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de Udaeta MP, Diaz-Ricart M, Carreras E

Is sickle cell disease-related neurotoxicity a systemic endotheliopathy?

Hematol Oncol Stem Cell Ther 13 Mar 2020, . Epub 13 Mar 2020
The aim of the present article is to review the role of endothelial damage and dysfunction in the vaso-occlusive episodes associated with sickle cell disease (SCD). This inherited hematological disorder leads to irreversible damage of multiple organs through a wide variety of mechanisms, such as sickling of red cells, oxidative state due to ischemic-reperfusion episodes, inflammation, hypercoagulation state, and platelet activation, among others. In SCD, the endothelium arises as the key entity where most of these processes, which eventually lead to increased morbidly and mortality, interact. This review begins with the already accepted idea that organ-specific vasculopathy precedes clinical manifestation, and briefly explains one of the main triggers of vaso-occlusive episodes, the complex interplay between blood cells and the dysfunctional endothelium. Endothelial protective strategies emerge as a potential tool for the prevention of organ-specific disease in SCD. Actually, this knowledge is currently used for the development of potential pharmacologic interventions to improve the lives of SCD patients.
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Palomo M, Vera M, Martin S, Torramadé-Moix S, Martinez-Sanchez J, Belen Moreno A, Carreras E, Escolar G, Cases A, Díaz-Ricart M

Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide.

J. Cell. Mol. Med. 28 Nov 2019, . Epub 28 Nov 2019
Endothelial dysfunction is an earlier contributor to the development of atherosclerosis in chronic kidney disease (CKD), in which the role of epigenetic triggers cannot be ruled out. Endothelial protective strategies, such as defibrotide (DF), may be useful in this scenario. We evaluated changes induced by CKD on endothelial cell proteome and explored the effect of DF and the mechanisms involved. Human umbilical cord vein endothelial cells were exposed to sera from healthy donors (n = 20) and patients with end-stage renal disease on haemodialysis (n = 20). Differential protein expression was investigated by using a proteomic approach, Western blot and immunofluorescence. HDAC1 and HDAC2 overexpression was detected. Increased HDAC1 expression occurred at both cytoplasm and nucleus. These effects were dose-dependently inhibited by DF. Both the HDACs inhibitor trichostatin A and DF prevented the up-regulation of the endothelial dysfunction markers induced by the uraemic milieu: intercellular adhesion molecule-1, surface Toll-like receptor-4, von Willebrand Factor and reactive oxygen species. Moreover, DF down-regulated HDACs expression through the PI3/AKT signalling pathway. HDACs appear as key modulators of the CKD-induced endothelial dysfunction as specific blockade by trichostatin A or by DF prevents endothelial dysfunction responses to the CKD insult. Moreover, DF exerts its endothelial protective effect by inhibiting HDAC up-regulation likely through PI3K/AKT.
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Palomo M, Blasco M, Molina P, Lozano M, Praga M, Torramade-Moix S, Martinez-Sanchez J, Cid J, Escolar G, Carreras E, Paules C, Crispi F, Quintana LF, Poch E, Rodas L, Goma E, Morelle J, Espinosa M, Morales E, Avila A, Cabello V, Ariceta G, Chocron S, Manrique J, Barros X, Martin N, Huerta A, Fraga-Rodriguez GM, Cao M, Martin M, Romera AM, Moreso F, Manonelles A, Gratacos E, Pereira A, Campistol JM, Diaz-Ricart M

Complement Activation and Thrombotic Microangiopathies.

Clin J Am Soc Nephrol 6 Nov 2019, . Epub 6 Nov 2019
Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response.
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Martinez-Sanchez J, Hamelmann H, Palomo M, Mir E, Moreno-Castaño AB, Torramade S, Rovira M, Escolar G, Cordes S, Kalupa M, Mertlitz S, Riesner K, Carreras E, Penack O, Diaz-Ricart M

Acute Graft-vs.-Host Disease-Associated Endothelial Activation

Front Immunol 2019, 10 2339. Epub 9 Oct 2019
Angiogenesis and endothelial activation and dysfunction have been associated with acute graft-vs.-host disease (aGVHD), pointing to the endothelium as a potential target for pharmacological intervention. Defibrotide (DF) is a drug with an endothelium-protective effect that has been approved for the treatment of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Clinical data suggest that DF also reduces the incidence of aGVHD; however, the mechanisms of DF-mediated aGVHD regulation have not been examined. To investigate possible DF-mediated prophylactic and therapeutic mechanisms in aGVHD, we performed
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Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, Dignan F, Gibson B, Guengoer T, Gruhn B, Lankester A, Locatelli F, Pagliuca A, Peters C, Richardson PG, Schulz AS, Sedlacek P, Stein J, Sykora KW, Toporski J, Trigoso E, Vetteranta K, Wachowiak J, Wallhult E, Wynn R, Yaniv I, Yesilipek A, Mohty M, Bader P

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation.

Bone Marrow Transplant. Feb 2018, 53 (2) 138-145. Epub 31 Jul 2017
The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate >80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation.
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Mir E, Palomo M, Rovira M, Pereira A, Escolar G, Penack O, Holler E, Carreras E, Diaz-Ricart M

Endothelial damage is aggravated in acute GvHD and could predict its development.

Bone Marrow Transplant. Set 2017, 52 (9) 1317-1325. Epub 26 Jun 2017
The aim of the present study was to explore whether there is enhanced endothelial dysfunction in patients developing acute GvHD (aGvHD) after allogeneic hematopoietic cell transplantation (allo-HCT) and to identify biomarkers with predictive and/or diagnostic value. In in vitro experiments, endothelial cells (ECs) were exposed to serum from patients with (aGvHD, n=31) and without (NoGvHD, n=13) aGvHD, to evaluate changes in surface adhesion receptors, the reactivity of the extracellular matrix by measuring the presence of Von Willebrand factor (VWF) and platelet adhesion, and the activation of intracellular signaling proteins. Plasma levels of VWF, ADAMTS-13, TNF receptor 1 (TNFR1), soluble vascular cell adhesion molecule 1 and soluble intercellular adhesion molecule 1 were also measured. In vitro results showed a more marked proinflammatory and prothrombotic phenotype in ECs in association with aGvHD. Regarding circulating biomarkers, levels of VWF and TNFR1 above an optimal cutoff score, taken independently or combined, at day 7 after allo-HCT, would be able to positively predict that around 90% of patients will develop aGvHD. Our results demonstrate that endothelial damage is aggravated in those allo-HCT recipients developing aGvHD, and that VWF and TNFR1 are promising predictive aGvHD biomarkers. These findings could contribute to improve the understanding of the pathophysiology of aGvHD.
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