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Biomedical subjects

M E Ferrero

Publications and source records attributed to M E Ferrero.

At least 37 records · Page 2Linked to original sources
PubMed1996

Drug-induced in vitro inhibition of neutrophil-endothelial cell adhesion.

1. Leukocyte-endothelial cell interactions play an important role during ischaemia-reperfusion events. Adhesion molecules are specifically implicated in this interaction process. 2. Since defibrotide has been shown to be an efficient drug in reducing damage due to ischaemia-reperfusion in many experimental models, we analysed the effect of defibrotide in vitro on leukocyte adhesion to endothelial cells in basal conditions and after their stimulation. 3. In basal conditions, defibrotide (1000 micrograms ml-1) partially inhibited leukocyte adhesion to endothelial cells by 17.3% +/- 3.6 (P < 0.05), and after endothelial cell stimulation (TNF-alpha, 500 u ml-1) or after leukocyte stimulation (fMLP, 10(-7) M), it inhibited leukocyte adhesion by 26.5% +/- 3.4 and 32.4% +/- 1.8, respectively (P < 0.05). 4. In adhesion blockage experiments, the use of the monoclonal antibody anti-CD31 (5 micrograms ml-1) did not demonstrate a significant inhibitory effect whereas use of the monoclonal antibody anti-LFA-1 (5 micrograms ml-1) significantly interfered with the effect of defibrotide. 5. This result was confirmed in NIH/3T3-ICAM-1 transfected cells. 6. We conclude that defibrotide is able to interfere with leukocyte adhesion to endothelial cells mainly in activated conditions and that the ICAM-1/LFA-1 adhesion system is involved in the defibrotide mechanism of action.

Cell Adhesion↗
PubMed1995

The platelet endothelial cell adhesion molecule-1 (PECAM1) contributes to endothelial barrier function.

In this study we have analyzed the role of the platelet-endothelial cell adhesion molecule-1 (PECAM1) in vascular barrier function. PECAM1 is an immunoglobulin gene superfamily member expressed by endothelial cells at the cell boundaries. Macromolecule permeability assays performed on cell monolayers that express native or transfected PECAM1, indicated that the molecule participates in the establishment and maintenance of vascular barrier function in vitro. This hypothesis was confirmed by the finding that in vivo injection of the specific monoclonal antibody directed against the murine vascular PECAM1 led to a detectable leakage of hepatic and renal blood vessels.

Animals↗
PubMed1995

Influence of inhalational, neuroleptic and local anaesthesia on lymphocyte subset distribution.

We previously demonstrated that anaesthetics affect leukocyte response by inhibiting lymphocyte capping and metabolism and the phagocytic activity of neutrophils in some experimental models. In the present study, we investigated the effects of the clinical use of three different types of anaesthesia on lymphocyte subset distribution and activity: inhalational anaesthesia (isoflurane), a neuroleptoanalgesia, or local anaesthesia was used in patients submitted to the same operation (hysterectomy). At time 0 (before administering the anaesthesia) and at 10 min and 48 h from the start of the operation, heparinized blood was obtained from each of the 30 patients studied; three lymphocyte subpopulations were isolated (CD4+, CD8+ and CD19+). Cell number was identified for each lymphocyte subset, and (as an indication of cellular function) the intracellular contents of ATP and cAMP were evaluated by luminescence methods. The relevant results for each of the 3 anaesthetic methods were as follows: i) treatment with isoflurane induced a significant reduction in the number and function of CD4+ cells at 10 min, which was reversed at 48 h; a functional but not reversible decrease of CD19+ cells was obtained, ii) treatment with neuroleptic drugs induced a significant progressive functional impairment of CD4+ and CD19+ cells, and iii) local anaesthesia caused a significant functional impairment of CD8+ cells at 48 h and a significant functional impairment of CD19+ cells at 10 min and 48 h.

Adult↗
PubMed1994

Increased cAMP levels in human hair follicles due to local treatment with trichoriboside.

Local therapy with trichoriboside and trichosaccharide, which have been found to be beneficial for scalp hair maintenance in adult males affected by androgenic alopecia, was found to increase cAMP levels in human scalp hair follicles. The increase was significant in men affected by androgenic alopecia, whereas it was not significant in unaffected control men. Trichoriboside showed a greater activity than trichosaccharide, and such activity was accompanied by a significant concomitant reduction of ATP in the hair.

Adenosine Triphosphate↗
PubMed1993

Antiischaemic effect of defibrotide treatment in rat kidney.

The authors previously demonstrated the protective activity of defibrotide (a profibrinolytic and antithrombotic drug) on endothelial cells. In the present work they examine the efficacy of defibrotide in protecting rat kidney from ischaemic/reperfusion injury by studying the modifications of intrarenal adenine nucleotide levels. Right renal ischaemia of 60 min and reperfusion of 30 min were induced in adult male Wistar rats. Defibrotide was administered as a bolus through a catheter inserted into the left femoral vein 5 min before the beginning of ischaemia at the dose of 32 mg/kg and continuously infused during ischaemia/reperfusion through the same vein at the final dose of 32 mg/kg in 5 ml of saline at the rate of 3 ml/h. Rats treated with vehicle of the drug were used as controls. At the end of postischaemic reperfusion, the ischaemic and left kidneys were rapidly removed and frozen in liquid nitrogen. Tissue extracts were prepared, and their ATP, ADP, AMP, cAMP, NAD+, and NADH contents were determined by using luminescence methods. In controls, ATP intrarenal levels were significantly higher in the left kidney than in the ischaemic organ of the same rat (3405 +/- 320 vs. 378 +/- 36 nmol/g fresh tissue and mean +/- s.e.m. of 10 experiments). Defibrotide treatment significantly protected ischaemic kidneys from the drop in ATP intrarenal content (1465 +/- 147 vs. 3124 +/- 303 nmol/g fresh tissue measured in the left kidney).

Adenosine Diphosphate↗
PubMed1993

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.

Adenine Nucleotides↗
PubMed1992

Cyclosporine-induced insulin release in rats is related to an increase in plasma lipid levels.

We studied the modifications of plasma lipid levels induced by cyclosporine (CsA), streptozocin (STZ) or both drugs in rats. Male Wistar rats (RT1y) were administered i.p. with CsA or STZ or both at the dosage of 15 mg/kg daily for 8 days and were sacrificed on day 9. Total lipid, triglyceride and total cholesterol plasma levels were measured. The plasma total lipid content was significantly increased in CsA-treated and in CsA + STZ-treated rats with respect to controls (662 +/- 29 and 632 +/- 32, respectively, vs 472 +/- 27 mg/dl). The triglyceride content was significantly higher in CsA-treated and in CsA + STZ-treated animals than in controls (137 +/- 8.7 and 188 +/- 14.1, respectively, vs 79 +/- 7.7 mg/dl). The total cholesterol level was not significantly different in CsA- and STZ-treated rats with respect to controls. CsA-treated and STZ-treated rats concomitantly revealed a significant impairment of glucose tolerance. In fact, 150 min after orogastric administration of 350 mg glucose, glycaemia was significantly more elevated in treated animals than in controls. We conclude that the increase in lipid levels induced by CsA treatment could be related to drug-induced damage to the pancreas islets, as shown by the early insulin release and fatty tissue degeneration.

Animals↗
PubMed1991

Protection of rat heart from damage due to ischemia-reperfusion during procurement and grafting by defibrotide.

We studied the efficacy of defibrotide, a prostacyclin-stimulating agent, in preventing ischemia reperfusion injury in Wistar rat heart by using three experimental models: (1) hearts from donors were perfused with the drug (32 mg/kg/hr) during 15, 30, 45, and 60 min of cold ischemia following 5, 10, and 15 min of warm ischemia; (2) hearts from donors treated with the drug were cold-stored for 12 or 24 hr; and (3) procured hearts perfused with the drug were isografted, after 30 or 60 min of warm ischemia, in recipient rats treated daily with defibrotide. Hearts perfused with saline and/or vehicle of the drug were used as controls. At the end of established ischemia times, and after 30 min, and 2, 4, 7 and 14 days from transplantation, hearts were rapidly cooled in liquid nitrogen. ATP, ADP, AMP, cAMP contents, and NAD+/NADH ratios were evaluated in prepared tissue extracts. Cardiac ATP and ADP levels and NAD+/NADH ratios were significantly higher in defibrotide-treated organs than in controls. Isografted defibrotide-treated hearts were also significantly preserved, with respect to controls, from the loss of ATP levels until rejection occurred. Our results demonstrate the protective activity of the drug against the myocardial metabolic damage due to ischemia-reperfusion.

Adenosine Diphosphate↗
PubMed1991

Are increased ATP blood levels responsible for PGI2 release from endothelium?

Defibrotide, a polydeoxyribonucleotide with profibrinolytic and antithrombotic properties obtained from mammalian lungs was shown capable of favoring the release of prostacyclin from endothelial cells. We previously evidenced that the use of defibrotide i.p. (32 mg/kg for 30 min) or orally (50 mg/kg for 1 h) induced a significant increase in 2,3-diphosphoglycerate (2,3-DPG) content of blood cells in rats. We tested the in-vivo capacity of defibrotide to modify over 90 min the blood content of ATP, cAMP and 2,3-DPG. Male Wistar rats were anaesthetized with pentobarbital (20 mg/kg) i.p.; the left carotid artery was cannulated with a polyethylene tube, from which 0.4 ml of blood was drawn at 0, 5, 10, 15, 20, 30, 40, 50, 60 and 90 min. At 0 min, defibrotide was administered i.p. or i.v. (through the femoral vein) at the dose of 1 ml containing 80 mg of drug or orally at the dose of 1 ml containing 160 mg of drug. The control rats employed received either the vehicle of the drug or physiologic saline. Our results demonstrated a significant drug-related increase with time (maximal levels were revealed about 20 min after i.v., i.p., or oral defibrotide treatment) of blood ATP content and a significant decrease in cAMP content as compared with the controls. Our data confirm the relation between increased drug-induced prostacyclin production and that of ATP of in blood.

2,3-Diphosphoglycerate↗
PubMed1991

Prostacyclin release from endothelial cells, induced by defibrotide treatment, favours the function of grafted rat hearts and kidneys.

Defibrotide, a single-stranded DNA fraction obtained from mammalian lungs and able to increase prostacyclin production by endothelial cells, has been shown to be efficient in protecting rat organs (heart, kidney and liver) from ischaemic damage. We studied the efficacy of the drug in preserving the function of rat heart and kidney submitted to isotransplantation. Defibrotide was administered to donor Wistar rats at the dose of 32 mg/kg in 1.5 ml of saline. Heart and kidney were isolated and cold-preserved in buffered phosphate medium and continuously infused with defibrotide (32 mg/h) through the innominate or renal artery. Recipient Wistar rats were treated with defibrotide before and after transplantation at the dose of 32 mg/kg/day. Controls were treated with the vehicle of the drug. The function of isografted organs was evaluated at 12 and 24 h and at 2, 4 and 7 days from grafting. Heart function was evaluated by studying creatinine phosphokinase (CPK) and lactic dehydrogenase (LDH) activities of myocardial tissue. Renal function was evaluated by studying serum creatinine and urea levels of kidney-grafted rats. CPK and LDH activities were found to be significantly higher in defibrotide-treated rats than in controls. Creatinine and urea levels remained significantly lower in defibrotide-treated rats than in the controls. The results of the present work indicate that defibrotide treatment is useful to maintain the functionality of grafted hearts and kidneys.

Animals↗