Protectant Activity of Defibrotide in Cardioplegia Followed by IschernialReperfusion Injury in the Isolated Rat Heart

Rossoni, Giuseppe; Pompilio, Giulio; Biglioli, Paolo; Alamanni, Francesco; Tartara, Paolo; Rona, P; Porqueddu, Massimo; Berti, F.

doi:10.1111/j.1540-8175.1985.tb01302.x

Cited by 2 publications

(2 citation statements)

References 15 publications

(1 reference statement)

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“…33 In addition, an increasing number of preclinical and clinical reports show its efficacy in treating ischemia-reperfusion injury, atherosclerosis, and recurrent thrombotic thrombocytopenic purpura. [34][35][36] Defibrotide is known to act directly on endothelial cells without the requirement for further ELISA for the production of IFN-␥ and IL-4 in the supernatants of stimulated effector cells (7 days, irradiated HMECs, 50 U/mL IL-2). PBMCs were left unseparated or were negatively selected for CD8 ϩ T cells as given for the experiments in Figure 6.…”

Section: Discussionmentioning

confidence: 99%

Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide

Eißner

Multhoff

Gerbitz

et al. 2002

Blood

122

120

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Fludarabine is a nonmyeloablative immunosuppressant increasingly used as a component of alternative conditioning regimens before allogeneic bone marrow transplantation. It is expected to reduce conditioning-related toxicity and proinflammatory activation of the host tissues. However, in our in vitro study, we provide evidence that 2-fluoroadenine 9-␤-D-arabinofuranoside (F-Ara) as the active metabolized form of fludarabine damages human microvascular endothelial cells (HMECs) and dermal and alveolar epithelial cell lines after 48 hours of culture when it is used in pharmacologically relevant concentrations (range, 10 g/mL-1 g/mL). In addition, flow cytometric analyses revealed a significant up-regulation of intercellular adhesion molecule 1 and major histocompatibility complex (MHC) class I molecules by F-Ara, suggesting a proinflammatory activation of HMECs. Cytotoxicity assays demonstrated that target HMECs pretreated with F-Ara (10 g/ mL) showed increased lysis by allogeneic MHC class I-restricted cytotoxic T lymphocytes from healthy human donors. We conclude that, beside its immunosuppressive activities, F-Ara can be harmful for target tissues of transplantation-related complications and can even stimulate allogeneic immune responses. We identified the pharmaceutical compound defibrotide as protective against F-Arainduced apoptosis and alloactivation, importantly, without affecting the antileukemic effect of F-Ara. This observation argues for a potential clinical usage of defibrotide in pretransplantation conditioning. (Blood. 2002;100:334-340)

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Section: Discussionmentioning

confidence: 99%

Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide

Eißner

Multhoff

Gerbitz

et al. 2002

Blood

122

120

View full text Add to dashboard Cite

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“…Results are expressed as mean Ϯ S.E.M., n ϭ 5 for each treatment group. fusion model either neutralize TNF-␣ (Calabresi et al, 2003b), enhance prostacyclin production (Rossoni et al, 1999), or act as prostacyclin analogs (Berti et al, 1993). sHDLs seem to be less effective than plasma HDLs, suggesting that some components of plasma HDL, not included into sHDL, may participate in the cardioprotective action.…”

Section: Tablementioning

confidence: 99%

Synthetic High-Density Lipoproteins Exert Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

Rossoni¹,

Gomaraschi²,

Berti³

et al. 2003

J Pharmacol Exp Ther

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Human high-density lipoproteins (HDLs) protect the heart against ischemia/reperfusion injury. In the present study, the cardioprotective effects of synthetic high-density lipoproteins (sHDLs) made of phosphatidylcholine and apolipoprotein A-I were investigated in isolated rat hearts, which underwent a 20-min low-flow ischemia followed by a 30-min reperfusion. The administration of sHDL during the 10 min immediately before ischemia caused a rapid, dose-dependent improvement of postischemic cardiac function: at the maximum dose (2.0 mg of sHDL protein/ml), left ventricular developed pressure (LVDP) recovered to 71.0 Ϯ 3.2 versus 40.5 Ϯ 3.8 mm Hg in salinetreated hearts, and coronary perfusion pressure (CPP) increased to 100.3 Ϯ 6.2 versus 132.0 Ϯ 9.0 mm Hg. The preservation of postischemic cardiac function was associated with a dose-dependent reduction of creatine kinase release into the coronary effluent. sHDLs administered in the first 10 min postischemia also exerted a significant, dose-dependent improvement of postischemic LVDP, CPP, and creatine kinase release, but the cardioprotective effect was less than when sHDLs were given preischemia. The preservation of postischemic cardiac function by sHDL was mediated through a reduction of cardiac tumor necrosis factor-␣ content and an enhanced cardiac production of prostaglandin E 2 and I 2 . The present experimental data indicate that sHDLs may provide a novel therapeutic approach to clinical conditions in which myocardial ischemia/ reperfusion occurs, such as acute coronary syndromes, cardiac surgery, or revascularization procedures.Cardiovascular diseases that are initiated by tissue ischemia remain the chief cause of death in the industrialized world. The high morbidity and mortality of these diseases have focused the attention of physicians on restoring coronary blood flow to resuscitate the ischemic or hypoxic myocardium. Timely reperfusion indeed facilitates cardiomyocyte salvage and decreases cardiac morbidity and mortality.

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Protectant Activity of Defibrotide in Cardioplegia Followed by IschernialReperfusion Injury in the Isolated Rat Heart

Cited by 2 publications

References 15 publications

Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide

Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide

Synthetic High-Density Lipoproteins Exert Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

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