Biomedical subjects

E Lupia

Publications and source records attributed to E Lupia.

22 records · Page 2Linked to original sources

PubMed1994

Role of platelet activating factor in acute pancreatitis induced by lipopolysaccharides in rabbits.

In the present study we demonstrated that a single injection of endotoxin (lipopolysaccharides, E. Coli 0111-B4) into the superior pancreaticoduodenal artery of rabbits induced a dose-dependent acute necrotizing pancreatitis. The lesions observed by light microscopy were significant for 10 micrograms lipopolysaccharides and were maximal for 20 micrograms. After 24 h the main findings were edema, acinar cell vacuolisation, polymorphonuclear neutrophil infiltration and tissue necrosis. The pancreatic lesions developed strictly in the area supplied by the artery injected with lipopolysaccharides, without significant intestinal involvement. Since platelet-activating factor (1-O-hexadecyl-2-acetyl-sn-glycero-3- phosphocholine, PAF; 50-500 ng), a phospholipid mediator of endotoxin-induced inflammation and shock, was previously shown to cause an acute necrotizing pancreatitis in rabbits, the role of PAF in the development of acute pancreatitis induced by lipopolysaccharides was studied by evaluating: (1) the synergism between doses of lipopolysaccharides (5-10 micrograms), which produced a mild tissue injury, and doses of PAF (10 ng) not producing, per se, any significant injury, and (2) the effect of three structurally unrelated PAF receptor antagonists. The results obtained demonstrated that 10 ng of PAF significantly potentiated pancreatic tissue damage induced by 10 micrograms of lipopolysaccharides.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1994

Tumor necrosis factor alpha-induced angiogenesis depends on in situ platelet-activating factor biosynthesis.

Tumor necrosis factor (TNF) alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Therefore, it was suggested that the angiogenic properties of this agent might be consequent to the production of secondary mediators. Since TNF-alpha stimulates the synthesis of platelet-activating factor (PAF) by monocytes and endothelial cells, we investigated the possible involvement of PAF in the angiogenic effect of TNF-alpha. Angiogenesis was studied in a murine model in which Matrigel was used as a vehicle for the delivery of mediators. In this model the angiogenesis induced by TNF-alpha was shown to be inhibited by WEB 2170, a specific PAF receptor antagonist. Moreover, in mice injected with TNF-alpha, PAF was detected within the Matrigel, 6 and 24 h after TNF-alpha injection. The synthesis of PAF within the Matrigel was concomitant with the early migration of endothelial cells and infiltration of monocytes. No infiltration of lymphocytes or polymorphonuclear leukocytes was observed. Synthetic PAF as well as PAF extracted and purified from mice challenged with TNF-alpha induced a rapid angiogenic response, inhibited by WEB 2170. These results suggest that the angiogenic effect of TNF-alpha is, at least in part, mediated by PAF synthesized from monocytes and/or endothelial cells infiltrating the Matrigel plug.

Animals↗

PubMed1993

Streptokinase induces intravascular release of platelet-activating factor in patients with acute myocardial infarction and stimulates its synthesis by cultured human endothelial cells.

BACKGROUND: Reocclusion of a successfully recanalized infarct-related artery may account for failure of thrombolytic therapy. Evidence suggests that the intravascular activation of platelets may limit the response to this treatment. The aim of the present study was to investigate whether platelet-activating factor (PAF), an ether lipid mediator with multiple potent biological activities, is synthesized during therapy with thrombolytic agents. Two sets of experiments were performed: (1) we extracted and quantified PAF in blood of patients with acute myocardial infarction treated or untreated with streptokinase (SK), and (2) since the endothelium/platelet interaction is thought to be at the basis of vascular reocclusion, we studied whether cultured human endothelial cells synthesize PAF after stimulation with SK or plasmin. METHODS AND RESULTS: PAF was extracted from blood samples immediately after acidification to destroy the acid-labile PAF-acetylhydrolase in 25 patients with acute myocardial infarction treated (group A, n = 14) and untreated (group B, n = 11) with intravenous infusion of SK. PAF was detected in 10 of 14 patients of group A and none of group B. PAF began to be detectable 60 to 90 minutes after SK infusion and disappeared from the circulation within 120 to 180 minutes. Percent variation of platelet count over basal values correlated negatively with the amount of PAF present in the circulation at 90 minutes (r = -.719; P < .001) and at 120 minutes (r = -.652; P < .001). Cultured human umbilical cord vein-derived endothelial cells (ECs) synthesized PAF in a dose-dependent manner in response to SK and plasmin, with a synthesis that peaked at 15 minutes and persisted up to 30 minutes for SK and 2 hours for plasmin. PAF extracted from blood samples or from ECs was quantified by bioassay performed after purification by thin-layer chromatography and high-performance liquid chromatography (HPLC). PAF-bioactive material was characterized as PAF with physicochemical and enzymatic treatments, HPLC-tandem mass spectrometry, and specific PAF-receptor antagonists. CONCLUSIONS: The observation that PAF was detectable in the blood of patients of group A only after treatment with SK and was not detectable in patients with a comparable infarct not treated with SK (group B) suggested that SK stimulates the synthesis of this mediator either directly or via plasmin generation. Indeed, cultured human ECs synthesize PAF after stimulation with both SK and plasmin. PAF production by ECs may promote platelet activation and interaction of these cells as well as of circulating leukocytes with endothelium. These events may limit the beneficial effects of thrombolytic therapy.

Cells, Cultured↗

PubMed1993

Role of platelet-activating factor in hypotension and platelet activation induced by infusion of thrombolytic agents in rabbits.

Infusion of the thrombolytic agents streptokinase (SK, 666 units/kg per minute for 60 minutes) and tissue-type plasminogen activator (t-PA, 10 micrograms/kg per minute for 15 minutes) in rabbits induced a significant hypotension and decrease in platelet count that were completely prevented by treatment with platelet-activating factor (PAF) receptor antagonists SDZ 63-675 and WEB 2170. PAF synthesis by vascular tissue was suggested by its extraction from blood-free heart and aorta of rabbits treated in vivo with SK or t-PA but not of control rabbits. In contrast, PAF was not detected in peripheral blood. Ex vivo studies on platelet aggregation response to ADP and PAF performed on platelet-rich plasma obtained before and after SK and t-PA infusion demonstrated an early hyperaggregable phase, abrogated by PAF receptor antagonists and followed by reduced sensitivity of platelets to PAF. The ED50 values for the aggregation of washed rabbit platelets induced by PAF but not thrombin were significantly increased at 60 and 120 minutes after SK and t-PA infusion, suggesting a specific desensitization of platelets to PAF. In contrast to PAF receptor antagonists, aspirin did not significantly modify the hypotension and the platelet hyperaggregability induced by SK or t-PA or the platelet hypoaggregability induced by t-PA. Thrombocytopenia induced by t-PA, but not by SK, was partially prevented by aspirin. The effect of SK, t-PA, and plasmin on the aggregation of washed platelets from untreated rabbits and from humans was also studied. Whereas SK and t-PA were inactive, plasmin induced dose-dependent platelet aggregation that was inhibited by platelet pretreatment with PAF receptor antagonists. In conclusion, the effect of PAF receptor antagonists observed in the present experimental model suggests that the hypotension and activation of platelets induced by SK and t-PA infusion are mediated by PAF.

Animals↗