defibrotide and Inflammation

Use of haematopoietic cell transplantation (HCT) in the treatment of haematologic and neoplastic diseases may lead to life-threatening complications that cause substantial morbidity and mortality if untreated. In addition to patient- and disease-related factors, toxicity associated with HCT puts patients at risk for complications that share a similar pathophysiology involving endothelial cells (ECs). Normally, the endothelium plays a role in maintaining homeostasis, including regulation of coagulation, vascular tone, permeability and inflammatory processes. When activated, ECs acquire cellular features that may lead to phenotypic changes that induce procoagulant, pro-inflammatory and pro-apoptotic mediators leading to EC dysfunction and damage. Elevated levels of coagulation factors, cytokines and adhesion molecules are indicative of endothelial dysfunction, and endothelial damage may lead to clinical signs and symptoms of pathological post-HCT conditions, including veno-occlusive disease/sinusoidal obstruction syndrome, graft-versus-host disease, transplant-associated thrombotic microangiopathy and idiopathic pneumonia syndrome/diffuse alveolar haemorrhage. The endothelium represents a rational target for preventing and treating HCT complications arising from EC dysfunction and damage. Additionally, markers of endothelial damage may be useful in improving diagnosis of HCT-related complications and monitoring treatment effect. Continued research to effectively manage EC activation, injury and dysfunction may be important in improving patient outcomes after HCT.

Topics: Adult; Capillary Permeability; Child; Endothelial Cells; Endothelium, Vascular; Forecasting; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Idiopathic Interstitial Pneumonias; Immunotherapy, Adoptive; Inflammation; Multiple Organ Failure; Polydeoxyribonucleotides; Thrombophilia; Thrombotic Microangiopathies; Transplantation Conditioning

Endothelial cells are unique multifunctional cells with basal and inducible metabolic and synthetic functions. Various stimuli can induce physiological or pathological changes in endothelial cell biology. Hematopoietic stem cell transplantation (HSCT) requires high-dose irradiation and/or chemotherapy and is associated with increased risk of bacterial infections and immune reactions. These factors can affect endothelial cells. This review provides an overview of the effects of HSCT on endothelial cells, based on findings observed in cultured cells as well as in patients. We first describe to what extent irradiation and chemotherapy constitute direct and indirect triggers for endothelial cell activation and injury. Then, we highlight the role of the endothelium in several complications of HSCT, including capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy, graft-versus-host disease, and diffuse alveolar hemorrhages. We also analyze in detail available data on sinusoidal obstruction syndrome, previously known as veno-occlusive disease of the liver, where liver sinusoidal endothelial cells are first injured and eventually lead to sinusoid occlusion and liver cell damage. Finally, we open the question of the possible contribution of endothelial damage to cardiovascular events occurring long after HSCT.

Topics: Angiogenic Proteins; Animals; Anticoagulants; Bone Marrow Transplantation; Capillary Leak Syndrome; Cardiovascular Diseases; Cell Adhesion Molecules; Cell-Derived Microparticles; Endothelium, Vascular; Fever; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Inflammation; Nitric Oxide; Polydeoxyribonucleotides; Pulmonary Veno-Occlusive Disease; Radiation Injuries; Syndrome; Thrombotic Microangiopathies; Transplantation Conditioning

Defibrotide is a polydeoxyribonucleotide sodium salt extracted from mammalian organs. Its mean molecular weight is 15,000-30,000 daltons. Defibrotide contains aptamers, i.e., single-stranded polynucleotides with a well-defined base sequence and composition (5'-GGTTGG-ATT-GGTTGG-3' and 5'-GGTTGG-ATC-GGTTGG-3') that bind thrombin. For the time being, these aptamers are the only ones that have been identified in defibrotide, but there may also be other aptamers that bind proteins other than thrombin. Defibrotide has no anticoagulant activity, but in some other aspects it probably parallels heparin. Heparin is a sulfated polysaccharide sodium salt with a mean molecular weight ranging from 5,000 to 40,000 daltons extracted from mammalian organs. It contains disaccharide sequences of well-defined structure and frequency. Heparin binds an array of proteins, enzymes, and growth factors and shows inhibitory or stimulatory or protective activity. Defibrotide has a spectrum of interesting pharmacological properties that make this drug very useful for the treatment of arterial and venous thrombotic diseases. In fact, defibrotide has profibrinolytic, antithrombotic-thrombolytic, anti-ischemic, and antiatherosclerotic activity and protective activity in shock. What have all the above activities to do with a single drug? The explanation is that atherosclerosis, myocardial, renal, and liver ischemia, hemorrhagic and septic shock, and shock induced by occlusion of splanchnic artery and thrombosis are different facets of the same entity: the polyhedric inflammatory process.

Topics: Fibrinolytic Agents; Humans; Inflammation; Polydeoxyribonucleotides

Topics: Biomarkers; Fibrinolytic Agents; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Inflammation; Polydeoxyribonucleotides; Receptors, Tumor Necrosis Factor, Type I; Vascular Cell Adhesion Molecule-1

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.

Topics: Anti-Inflammatory Agents; Antioxidants; Cell Membrane; Cells, Cultured; Dose-Response Relationship, Drug; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Nitric Oxide Synthase Type III; Pinocytosis; Polydeoxyribonucleotides; Temperature; Time Factors