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Biomedical subjects

P Borgeat

Publications and source records attributed to P Borgeat.

At least 127 records · Page 7Linked to original sources
PubMed1985

Intraperitoneal injection of zymosan in mice induces pain, inflammation and the synthesis of peptidoleukotrienes and prostaglandin E2.

Intraperitoneal injection of zymosan in mice induced rapid extravasation and accumulation of plasma protein in the peritoneal cavity. Neutrophils began to appear in the peritoneal cavity after a lag period of approximately 3 hours. The injected mice exhibited a pain response (writhing) during the first 30 minutes after injection, but writhing ceased before protein or cell accumulation had reached maximum levels. The injection of zymosan induced synthesis of PGE2 (measured by RIA) which reached maximum levels at 30 minutes, then declined slowly. Peptido-leukotriene levels (detected by bioassay, RIA and HPLC) increased rapidly after injection, reached a peak within an hour of injection and declined to undetectable levels within 4 hours. The early peptido-LT was predominantly LTC4, while later, LTE4 was the major component. LTD4 levels remained low throughout and no LTB4 was detected at any time. Indomethacin treatment elevated levels of peptido-LTs, reduced PGE2 levels and inhibited writhing. Phenidone reduced peptido-LT levels. In vitro studies demonstrated that zymosan stimulates LTC4 synthesis by peritoneal cells whereas LTE4, LTD4, LTB4 or monoHETES were not detectable (using HPLC methods). The source of enzymes responsible for the in vivo metabolism of LTC4 to LTD4 and LTE4 could not be identified.

Animals↗
PubMed1985

Leukocytic functions in burn-injured patients.

Anergy associated with an increase in suppressor helper T cell (Tc) ratio and a decrease in natural killer (NK) is one main cause of death following thermal injury (Tl). Recently, in vitro studies have shown that LTB4 can induce human Tc to exert suppressor cell activity, and incubation of lymphocytes with LTB4 for 24 hours significantly suppressed NK cell activity. Thus, we undertook an investigation of both AA metabolism and immunologic response in 20 patients who suffered 40-90% total body surface area (TBSA) burns. Cyclooxygenase (CO:RIA) and lipoxygenase (LO;HPLC det.) metabolites and superoxide (O2 X-) production were measured in stimulated polymorphonuclear cells (PMNL) (A 23187 +/- AA for icosanoid release; phorbol myristate acetate for O2 X-production). Lyso-paf-acether (P-LPA) was measured in plasma samples. Ca2+-dependent K+permeability in PMNL was measured by the cell K+ release induced by A 23187. Tc and Tc subsets were determined using monoclonal antibodies (OKT3+, OKT4+ and OKT8+). A biphasic sequential release of the different substances (leukocytic icosanoids and O2 X-) was monitored: increase (approximately 36-48 h after Tl) and decrease (greater than or equal to 72 h after Tl). The increase in AA stimulation was more transient than that of O2 X -. The decline in the release of AA metabolites and O2 X-production was associated with the anergic phase (decrease OKT4+/OKT8+ ratio) and with the clinical outcome of the patients. The decrease in LTB4 and other LO metabolites could explain the impairment of neutrophil chemotaxis. Ca2+-dependent K+ permeability increased early up to 2 or 3 times normal. In order to go further with the mechanism of inhibition of LTB4 and O X-release, the effect of Tl plasma was assayed on normal leukocytes: a 10 min incubation with such plasma was sufficient to abolish LTB4 secretion. A less important inhibition was observed with O2 X-release (-32%) and Ca2+-dependent K+ permeability (-30%). Plasma inhibition seems to be due to a thermolabile factor(s) [protein(s): "suppressive factor(s) of membrane activation "SFMA] which is (are) under active investigation using gel-filtration chromatography and fast protein liquid chromatography (FPLC). Among the SFMAs, certain acute phase proteins could play a key role: i.e., incubation (10 min) of normal PMNL with ceruloplasmin (1 mg/ml) abolished LO products and O X 2-release.

Adolescent↗
PubMed1985

Correlation between the myotropic activity of leukotriene A4 on guinea-pig lung, trachea and ileum and its biotransformation in situ.

Leukotrienes A4 and D4 displayed equivalent myotropic activity on guinea pig lung parenchyma strips. However, on the trachea, the activity of LTD4 was much higher than that of LTA4. The potencies of these two leukotrienes were also different on strips of longitudinal muscles of the ileum where LTD4 was very active whereas LTA4 was inactive. Since the activities of both leukotrienes were blocked by FPL-55712, our results suggested that the transformation of LTA4 by the smooth muscle preparations was a prerequisite to its biological activity. LTA4 was then incubated for 10 min with homogenates of guinea pig lung parenchyma, trachea and longitudinal muscles of ileum, and the metabolites were analysed by bioassay using strips of guinea pig ileum and lung parenchyma in a cascade superfusion system and also by reversed phase high performance liquid chromatography (RP-HPLC). Homogenates of lung parenchyma rapidly transformed LTA4 to LTB4, LTC4, LTD4 and LTE4. Incubation of LTA4 with homogenates of trachea or of the longitudinal muscles of ileum showed the formation of LTB4 and its isomers but no significant amount of peptido-leukotrienes were detected. These findings reveal that LTA4 undergoes distinctly different metabolic transformations in these tissues which correspond to the biological activities of the products recovered. These results strongly suggest that the myotropic activity and potency of LTA4 is related to the tissue levels of enzymes which catalyse its biotransformation.

Animals↗
PubMed1985

Role of cyclooxygenase products in the lung action of leukotrienes A4, B4, C4, D4 and E4.

Leukotrienes (LT) LTA4, LTB4, LTC4, LTD4 and LTE4 induced marked contractions of guinea pig lung parenchymal strips mounted in organ baths. These contractions were inhibited differentially (40-50% for LTA4, LTC4, LTD4 and LTE4, and 90% for LTB4) by indomethacin (20 micrograms.ml-1; 55.9 microM). Two novel inhibitors of thromboxane synthetase (OKY-1581 and OKY-046) reduced the myotropic activity of the lung strips and the release of prostaglandins and thromboxanes from the perfused guinea pig lungs stimulated by LTB4 and LTD4. The release of cyclooxygenase products prostaglandin F2 alpha, thromboxane B2 and 12-hydroxyheptadecatrienoic acid by guinea pig lungs following stimulation with LTB4 and LTD4 was also measured by gas chromatography-mass spectrometry. The role of prostaglandins and thromboxanes in the lung actions of leukotrienes was confirmed using a cascade superfusion system and classical organ baths. Although prostaglandins and thromboxanes contribute to the contractile effect of LTB4 on the guinea pig lung whereas they may play a lesser role in the action of the peptidoleukotrienes (approx. 40-50%), stimulation of their release by the peptidoleukotrienes is many times more effective than by LTB4.

Animals↗
PubMed1985

Metabolism of leukotrienes by adult and fetal human lungs.

The metabolism of leukotriene (LT) A4, B4, C4, D4, and E4 was studied using both bioassay and reversed phase high performance liquid chromatography (RP-HPLC) methods. The incubation of 20,000 g supernatants of homogenates of human adult lung with LTA4 and LTC4 for various periods of time produced substances of higher biologic activity than the controls (without incubation) when measured on strips of guinea pig lung parenchyma and ileum. RP-HPLC analyses of the incubation media revealed the formation of LTB4, LTC4, LTD4, and LTE4 from LTA4 and the formation of LTD4 and LTE4 from LTC4. LTD4 was converted to LTE4 whereas LTB4 and LTE4 were not catabolized to an appreciable extent during a 2-h incubation period. Supernatants (20,000 g) of human fetal lung homogenates also contain the enzymatic activities to transform LTC4 into LTD4 and LTE4; however, LTA4 was mainly converted to LTB4 and to products of the nonenzymatic hydrolysis of LTA4 such as the delta 6-trans-LTB4, delta 6 -trans-12-epi-LTB4 and the 5,6-dihyroxyeicosatetraenoic acids; much smaller quantities of the peptidoleukotrienes were formed than in adult lung homogenates.

Adult↗
PubMed1985

Stimulation of lipoxygenase product synthesis in human leukocytes and platelets by melittin.

The effects of melittin on the synthesis of lipoxygenase metabolites of arachidonic acid in human leukocytes and platelets were studied using high performance liquid chromatography. Melittin was found to stimulate strongly the formation of leukotrienes and hydroxy-eicosatetraenoic acids (HETEs) in a concentration-dependent fashion. The metabolites detected were LTB4, omega-OH-LTB4, omega-COOH-LTB4, LTC4, 5-HETE, 12-HETE, 15-HETE, 5S,12S-DiHETE, and 5S,15S-DiHETE. These results suggest that the action of melittin on the formation of arachidonic acid metabolites might be involved in its ability to release endogenous substrates required for the synthesis of 5-, 15-, and 12-lipoxygenase products in leukocytes and platelets, respectively.

Arachidonic Acid↗
PubMed1985

Activated platelets stimulate human neutrophils functions.

Opsonized zymosan is able to induce polymorphonuclear leucocyte activation as reflected by lysosomal degranulation and light emission. However this stimulus is a weak inducer of arachidonic acid metabolism in these cells. We have studied the effects of co-incubation of polymorphonuclear leucocytes and platelets, each of them exposed with its specific stimulus (i.e. opsonized zymosan and thrombin). The granule constituent release was enhanced in the presence of activated platelets, but not the chemiluminescence. The same results were found in time-course experiments. Another important effect of this co-incubation was the potentiation of the synthesis of 5-lipoxygenase metabolites of arachidonic acid by activated platelets. The in vitro study of cellular cooperation may be of great interest in evaluating the role of the messenger processes occurring from one cell to another.

Blood Platelets↗
PubMed1984

Association of leukotriene B4 with the cytoskeleton of rabbit neutrophils. Effect of chemotactic factor and phorbol esters.

Following its addition to a suspension of rabbit neutrophils, leukotriene B4 is rapidly (less than 1 min) recovered from the cytoskeletal fraction (Triton X-100 insoluble pellet) of these cells. The association of leukotriene B4 with the cytoskeleton can be competed with by leukotriene B4 itself and by 20-OH leukotriene B4 but not by 20-COOH leukotriene B4. In addition, the preincubation of the cells with fMet-Leu-Phe or with phorbol 12-myristate 13-acetate, but not with 4 alpha-phorbol 12,13-didecanoate, results in a greatly decreased association of leukotriene B4 with the cytoskeleton. These results suggest that a specific association between the leukotriene B4 receptors and the cytoskeleton may be involved in signal transduction in the leukotriene B4 stimulated neutrophils.

Animals↗
PubMed1984

Arachidonic acid metabolism among human mononuclear leukocytes. Lipoxygenase-related pathways.

Human peripheral blood mononuclear cells were isolated and assessed for the presence of contaminating polymorphonuclear leukocytes and platelets. Incubations of these cell isolates were performed in the presence or absence of the calcium ionophore A23187 and/or 1-14C-labeled or unlabeled arachidonic acid. Using reverse phase high pressure liquid chromatography with simultaneous monitoring of ultraviolet light absorption at 229 and 280 nm and, where appropriate, of radioactivity, our studies reveal that human peripheral blood mononuclear cells generate leukotrienes C4 and B4 (LTC4 and LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE) following stimulation with A23187. The ratio of LTC4 to LTB4 was approximately 10-fold greater among the mononuclear cells than among similar incubations of polymorphonuclear leukocytes. Furthermore, the mononuclear cells failed to metabolize LTB4 into the omega-hydroxy or omega-carboxy derivatives that were always present in, and very characteristic of incubations of polymorphonuclear leukocytes. Depletion of monocytes from the mononuclear cells by double adherence resulted in virtual loss of the generation of 5-lipoxygenase-derived products by the remaining nonadherent cells, supporting the conclusion that the monocytes and not the lymphocytes were the source of LTC4, LTB4, and 5-HETE. The presence of both 12-HETE and the cyclooxygenase-derived 12-hydroxyheptadecatrienoic acid correlated with the degree of platelet contamination, suggesting that the platelets account for the presence of these compounds.

Arachidonic Acids↗
PubMed1984

Activation of prostacyclin synthesis in cultured aortic smooth muscle cells by 'diuretic-antihypertensive' drugs.

In cultured smooth muscle cells of rat aorta, four diuretic agents, furosemide, bumetanide, cicletanide and piretanide (all at 10(-6)-10(-5) M), significantly enhanced the transformation of exogenously added arachidonic acid (AA) to prostacyclin. Studies with cultured smooth muscle cells and human leukocytes revealed that these same agents failed to inhibit lipoxygenase pathways. Taken together, these results indicate that the diuretic properties of these agents might be associated with a general activation of the AA cascade.

Animals↗
PubMed1984

[Leukotrienes].

Leukotrienes are released in inflammatory and immediate hypersensitivity reactions. Leukotrienes are novel metabolites of arachidonic acid produced by the lungs and leucocytes. Their formation is catalyzed by a specific 5-lipoxygenase. The key compound of this pathway is leukotriene A4 which is transformed either into leukotriene B4 by enzymatic hydrolysis or into leukotriene C4 by addition of glutathione. Leukotriene D4 and E4, as well as their precursor leukotriene C4, are the myotropic constituents of the "Slow Reacting Substance of Anaphylaxis" (SRS-A). Leukotrienes are potent bronchoconstrictors in vitro and in vivo. They induce the production of mucus by the respiratory tract and decrease its transport. Leukotrienes (chiefly leukotrienes C4, D4 and E4) induce the vasoconstriction of large vessels and capillaries. Leukotriene B4 stimulates several leukocyte functions related to inflammation (chemotaxis, aggregation, release of lysosomal enzymes and production of superoxide anion). In addition, it induces the formation of suppressive and cytotoxic T-Lymphocytes. The actions of leukotrienes are mediated by specific receptors and, in certain organs, their mechanism of action involves a stimulation of the formation of prostaglandins and thromboxanes. Non-steroidal antiinflammatory drugs (aspirin) inhibit the biosynthesis of prostaglandins and thromboxanes, whereas steroidal antiinflammatory agents (dexamethasone) should inhibit the production of leukotrienes as well as of prostaglandins and thromboxanes (through an indirect action on phospholipase A2).

Animals↗
PubMed1984

[Prostaglandins, thromboxanes and leukotrienes. Their role in cardiovascular diseases, allergic reactions and inflammation].

Prostaglandins, thromboxanes and leukotrienes are oxygen metabolites of arachidonic acid forming a family of lipidic substances with intrinsic biological activities. The significance of biosynthesis of these mediators in response to cell stimulation remains unclear. Numerous data suggest that these compounds, produced by blood cells and vascular cells, play an important role in cardiovascular pathology, allergy or inflammation. The concept, based on biochemistry, of distinct metabolic pathways should be reappraised, using a physiological approach that involves a biological effect resulting from a synergistic action of different compounds. The development of specific assay methods will permit to investigate compounds obtained from biological fluids or from cells present in recognized pathological situations. Such in vitro data should help to clarify the role of these autacoids in cardiovascular, allergic or inflammatory diseases.

Animals↗
PubMed1984

Mechanism of action of leukotriene B4: intracellular calcium redistribution in rabbit neutrophils.

The possible involvement of membrane-bound calcium in the mechanism of action of leukotriene B4 was examined using the fluorescent chelate probe, chlortetracycline. Leukotriene B4 was found to cause a rapid release of membrane-bound calcium at physiologically relevant concentrations. This effect of leukotriene B4 is stereospecific and its magnitude is decreased upon the transformation of leukotriene B4 into its omega-hydroxy and omega-carboxy metabolites. The pool of calcium affected by leukotriene B4 appears to be the same as that released by other chemotactic factors such as formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). Similarly, preincubation with f-Met-Leu-Phe results in a decreased responsiveness of the cells to the addition of leukotriene B4. These results extend further the analogy between the mechanism of action of peptidic and lipid chemotactic factors, and emphasize the central role of the intracellular redistribution of calcium, as inferred and monitored by chlortetracycline fluorescence and steady-state isotopic flux studies, in neutrophil activation.

Animals↗