Possible role of defibrotide in endothelial cell protection.
Defibrotide is a single-stranded DNA fraction obtained from mammalian lung and is able to increase prostacyclin production by endothelial cells. It has profibrinolytic and antithrombotic properties, and we have successfully used it as an anti-ischaemic drug in many in-vivo experimental models. In fact, we showed that defibrotide treatment significantly protected rat heart, kidney and liver from ischaemia and postischaemic reperfusion injury. In rats treated with defibrotide, the functionality and metabolic activity of ischaemic organs were significantly protected from impairment as compared to controls treated only with the vehicle of the drug. In the present work we evaluated all our results, together with those of others, in order to hypothesize the mechanism of action of the drug. We postulated that the prominent function of defibrotide is to inhibit platelet and leukocyte adhesion to endothelial cells: this may depend on reduced cell activation possibly following drug interaction with adenosine receptors. Defibrotide could also favour endothelial-cell function through binding with haemoglobin: such binding permits oxygen release and preservation of endothelium-derived relaxing factor. Moreover, prostacyclin production by endothelial cells is responsible for many drug activities and also limits superoxide radical generation.
Corsi
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M
Institute of General Pathology, University of Milan, Italy.
Parise
M
M
Gaja
G
G
Ferrero
M E
ME
D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis; D016027:Heart Transplantation; D007511:Ischemia / Q000188:drug therapy; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D016030:Kidney Transplantation; D007962:Leukocytes / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009243:NAD / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000187:drug effects; D011089:Polydeoxyribonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control*
D000227:Adenine Nucleotides; D011089:Polydeoxyribonucleotides; D018047:Receptors, Purinergic P1; D009243:NAD; C036901:defibrotide; D011464:Epoprostenol