Tachykinins stimulate lyso-PAF:acetyl-CoA acetyltransferase activity in neutrophils.
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Acetyltransferases↗
Biomedical subjects
R Fantozzi
Publications and source records attributed to R Fantozzi.
Tachykinins activate guinea-pig alveolar macrophages: involvement of NK2 and NK1 receptors.
1. The effects of substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) were evaluated on superoxide anion (O2-.) production by guinea-pig alveolar macrophages (AM). 2. SP dose-dependently (ED50 = 0.7 nM) evoked O2-. production from guinea-pig AM; the N-terminal heptapeptide, SP(1-7), was ineffective. In the presence of thiorphan (10(-5) M), an enkephalinase inhibitor, the stimulating effects of SP were not significantly modified. NKA and NKB were both able to induce O2-. production from guinea-pig AM, ED50 values being 0.1 and 1.3 nM, respectively. Therefore, the rank order of activity of natural tachykinins was NKA greater than SP greater than NKB. Tachykinin-evoked effects were quantitatively similar to those elicited by the autacoid mediator PAF-acether and less than those induced by the synthetic peptide N-formylmethionyl-leucyl-phenylalanine (FMLP). 3. The NK2 receptor agonist [beta-Ala8]-NKA (4-10) dose-dependently evoked O2-. production from guinea-pig AM; the NK1 receptor agonist [Pro9]-SP sulphone acted only at high concentrations, while the NK3 receptor agonist [Me,Phe7]-NKB was ineffective. 4. These findings indicate that guinea-pig AM possess NK2 and possibly some NK1 tachykinin receptors and further suggest tachykinin involvement in lung pathophysiology.
Animals↗
Interference of WEB 2086 and BN 52021 with Paf-induced effects on guinea-pig trachea.
1. The thienotriazolodiazepine WEB 2086 and the gingkolide BN52021 have been evaluated as antagonists of Paf-acether (Paf) by studying their effects on Paf-induced relaxation and Paf-induced prostaglandin E2 (PGE2) production in histamine-contracted guinea-pig tracheal preparations. 2. Relaxation induced by Paf 4 microM in histamine-contracted guinea-pig tracheal preparations was 39.67 +/- 3.5% (n = 30). At the same concentration, Paf significantly increased PGE2 production from histamine-contracted guinea-pig tracheal preparations. 3. WEB 2086 inhibited in a dose-related manner (IC50 = 21.2 nM) the relaxant effect induced by Paf and, at 1 microM, suppressed Paf-induced release of PGE2. 4. BN 52021 100 microM inhibited to about 60% Paf-induced relaxation of histamine-contracted guinea-pig tracheal preparations, but completely abolished Paf-induced increase in PGE2. 5. Both antagonists had no effects on relaxations induced by arachidonic acid 10 microM or PGE2 0.1-1 microM in histamine-contracted guinea-pig tracheal preparations. 6. The results are consistent with the presence of specific Paf receptors in guinea-pig trachea and indicate that a relaxant prostanoid, namely PGE2, at least partially mediates Paf-induced relaxation in this experimental model.
Animals↗
Effects of diacerein on the quantity and phagocytic activity of thioglycollate-elicited mouse peritoneal macrophages.
Diacerein (DAR: 1,8-diacetoxy-9,10-dioxo-dihydroanthracene-3-carboxylic acid) is an anthraquinone drug which displays anti-inflammatory effects in experimental animals and antirheumatic activity in humans. The drug was administered for orally for four consecutive days to mice injected intraperitoneally with thioglycollate. The following dose levels of DAR were used: 2.5, 5 and 10 mg/kg/day. At the end of the experimental period the macrophage content of peritoneal exudate was dose-dependent and significantly lower in DAR-treated mice compared with animals that were given saline orally. The macrophages isolated from the peritoneal exudate of mice that received DAR displayed a dose-dependent reduced phagocytosis. The effects of DAR were found to be similar to those of indometacin and dexamethasone, which were used as reference drugs. The ability of DAR to interfere with macrophage functioning may contribute to its overall therapeutic activity.
Animals↗
Detection of clonally expanded salivary gland lymphocytes in Sjögren's syndrome.
Recurrent swelling of the parotid and submandibular salivary glands occurs in some patients with Sjögren's syndrome (SS). Using Southern blot methods, we analyzed immunoglobulin and T cell antigen receptor (TCAR) gene rearrangements in DNA obtained from salivary gland lymphocytes of 9 SS patients. Based on histologic appearance of the biopsy specimens, these patients were diagnosed as having myoepithelial sialadenitis. We found oligoclonal rearrangements of the kappa gene (4 patients) and lambda gene (1 patient), and oligoclonal rearrangement of the TCAR beta chain in 2 additional SS patients. Patients with Ig gene rearrangements did not show rearrangements of their TCAR gene, nor did patients with TCAR rearrangements exhibit Ig rearrangements. The observed oligoclonal rearrangements probably derive from 5-10% of the salivary gland B cells or T cells. Three of these SS patients developed non-Hodgkin's lymphoma 2-8 years after the initial biopsy. Our results suggest that minor populations of B cells or T cells may clonally expand in the salivary gland tissues of SS patients with pseudolymphoma, and that such lymphocyte expansions may be controlled by the endogenous immune response and/or medications. However, continued lymphoproliferation in these salivary gland tissues may eventually lead to emergence of a neoplastic clone that escapes immunologic control and develops into a non-Hodgkin's lymphoma as a result of a multistep process.
Adult↗
Rhein reduces proteoglycan loss during the autolytic breakdown of cultured cartilage.
Rhein (R: 1,8-dihydroxy-3-carboxyanthraquinone) is the active metabolite of the drug diacerhein (DAR), an anthraquinone molecule which has recently been proposed for the long-term treatment of osteoarthrosis. In the present study we have examined the effects of rhein, as compared to indomethacin or hydrocortisone, on an in-vitro model of cartilage degradation, represented by the autolytic breakdown of the articular cartilage excised from rabbit knee and cultured for seven days. During this period there is a spontaneous loss of proteoglycans. At the end of the period we measured the amount of proteoglycans which remained bound to the cartilage. The samples treated with R revealed dose-dependent modifications in the amounts of cartilage-bound proteoglycans, with a 40% increase as compared with non-treated samples at the dose of 7 x 10(-5) M. We conclude that R shows a protective effect on the articular cartilage, and that at least a part of the beneficial effect that DAR has shown in the course of clinical trials in osteoarthrosis may be due to direct effects of its active metabolite (R) on cartilaginous tissue.
Animals↗
Pathophysiological significance of the distribution of histamine receptor sub-types: a proposed dual role for histamine in inflammation and type I hypersensitivity reactions.
The pathophysiological significance of histaminergic receptors located on the membranes of immunocompetent cells is reviewed. H2-receptor agonists decrease the immunological histamine release from isolated serosal mast cells and from isolated hearts taken from actively sensitised guinea-pigs. Histamine and H2-receptor agonists inhibit the generation of superoxide anion from human neutrophils activated by FMLP and by substance P. These observations lend further support to the hypothesis of an immunodepression exerted by the activation of H2-receptors, which can be converted to immunostimulation by treatment with H2-receptor antagonists.
Animals↗
Clinical experiences with Ro 15-1788 (anexate) in benzodiazepine and mixed-drug overdoses.
Benzodiazepine overdose is the most common of admission to the Toxicological Unit of the University of Florence. The aim of this study has been to evaluate the efficiency of Ro 15-1788 in benzodiazepine and mixed drug overdoses. The administration of Ro 15-1788 was followed by a quick reversal of central nervous system depression and was more effective in benzodiazepine overdoses than in mixed drug overdoses. The dose was titrated individually and the range 2-10 mg was effective according to the conditions of the patient. In some cases, the comatose state relapsed; further administration of Ro 15-1788 again promptly reversed the condition. On awakening, two patients displayed anxiety and restlessness.
Adult↗
[Abuse of licit drugs in heroin addicts].
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Adolescent↗
Biological markers and therapeutic outcome in alcoholic disease: a twelve-year survey.
The early diagnosis and evaluation of the biological consequences of alcohol abuse are reviewed in a population of 401 chronic alcoholics admitted to our Toxicological Unit from January 1973 to the end of December 1984; selected cases were treated with disulfiram implantation. The results of the study indicate that anemia with increased globular volume of erythrocytes, elevated serum gamma-glutamyl-transferase activity, increased postprandial cholalemia, and increased elimination of pentane in the breath can be considered suitable markers for the early diagnosis of alcohol abuse. Disulfiram implantation significantly prolonged the abstinence duration in the treated patients.
Adult↗
Histamine release from serosal mast cells by intermediate products of arachidonic acid metabolism.
In the present paper we report the results of experiments carried out to measure the release of histamine from isolated rat mast cells during the metabolic activation of arachidonic acid. Arachidonic acid (10(-8)-10(-4) M) and the terminal products (10(-6) M) of the arachidonic acid pathways were devoid of any significant histamine releasing properties. A substantial amount of histamine was released from rat mast cells by low concentrations of arachidonic acid during incubation with prostanoid generating systems, such as guinea-pig lung microsomes, rat serosal macrophages and polymorphonuclear cells and prostaglandin-H-synthase from calf seminal vesicles. The release of histamine was not accompanied by a leakage of lactate dehydrogenase and was blocked by D-mannitol and by lipoxygenase and cyclooxygenase pathway inhibitors. The data are consistent with the hypothesis that free radical derivatives of arachidonic acid, originating from hydroperoxy fatty acids, are generated during catalysis, causing mast cell histamine release.
Animals↗
The antianaphylactic action of histamine H2-receptor agonists in the guinea-pig isolated heart.
The effects of histamine and of H1- and H2-receptor agonists on the response to specific antigen were studied in isolated hearts taken from actively sensitized guinea-pigs. Histamine and H2-receptor agonists (dimaprit, impromidine) dose-dependently decrease the positive chronotropic and inotropic effects, and the severity of arrhythmias evoked by the challenge of sensitized hearts with specific antigen. Nordimaprit and the selective H1-receptor agonist 2-pyridyl-ethyl-amine (2-PEA) did not modify the patterns of cardiac anaphylaxis. The positive inotropic and chronotropic responses of the isolated heart to exogenous histamine appear to be partly reduced in the presence of dimaprit. The H2-receptor agonists decrease the amount of histamine released during cardiac anaphylaxis which is increased by cimetidine, while nordimaprit and PEA were ineffective, indicating an inhibitory function afforded by H2-receptors in cardiac anaphylaxis.
Anaphylaxis↗
Rhein: an anthraquinone that modulates superoxide anion production from human neutrophils.
Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), the active metabolite of diacetylrhein, which has been reported as an effective antirheumatic drug in man, inhibited superoxide anion production from human neutrophils challenged with N-formylmethionyl-leucyl-phenylalanine (FMLP: IC50, 2 x 10(-5) M) and A23186 (IC50, 10(-5) M), but not with phorbol myristate acetate. In the same concentration range (10(-6)-10(-3) M), the drug did not affect oxy-radical production by a cell-free hypoxanthine-xanthine oxidase system and exerted weak inhibitory effects on FMLP-evoked lysosomal enzyme release. Rhein inhibitory effects on neutrophil functioning may contribute to the overall therapeutic activity of the parent drug, diacetylrhein.
Adult↗
Mast cell histamine release induced by intermediate products of arachidonic acid metabolism.
This study was performed to evaluate the role of intermediate products of arachidonic acid metabolism on histamine release from rat serosal mast cells. Arachidonic acid in concentrations ranging from 10(-9) to 10(-4) M caused no histamine release from purified rat peritoneal mast cells. High concentrations (10(-6)-10(-6) M) of the terminal products of the arachidonic acid metabolism were also devoid of any significant histamine-releasing properties. The metabolic activation of arachidonic acid with prostaglandin-H-(PGH)-synthase isolated from calf seminal vesicles, evoked a significant release of histamine from rat serosal mast cells. The liberation of histamine was not accompanied by a significant leakage of lactic dehydrogenase (LDH) and the electron microscopical features were consistent with an exocytotic release. The phenomenon was blocked by reduced glutathione (GSSH) and by D-mannitol, a hydroxyl free-radical scavenger. These results suggest that free radical derivatives of arachidonic acid are generated during the catalysis which triggers mast cell histamine release.
Animals↗
The pharmacological properties of 1,4-dihydro-1-ethyl-7-phenylpyrrol (1,2-a)-pyrimidine-4-one, a new antipyretic and analgesic drug.
The antipyretic, analgesic, antinflammatory and antiulcerogenic properties of a new compound 1,4 dihydro-1-ethyl-7-phenylpyrrol (1,2-a)-pyrimidine-4-one (V33) are described. V33 on a mg/kg basis possesses antipyretic and analgesic properties at doses lower than paracetamol and which do not produce hypothermia or motor impairment. V33 possesses antiinflammatory activity and decreases the production of LTB4 from inflammatory exudates without affecting PGE2 content. V33 is not only devoid of gastric ulcerogenic properties but exerts antiulcer activity toward various ulcerogenic stimuli. Lethal dose 50% (LD50) of V33 is higher that of paracetamol.
Analgesics↗
Clinical findings and follow-up evaluation of an outbreak of mushroom poisoning--survey of Amanita phalloides poisoning.
One hundred and sixty cases of mushroom poisoning during the period July-November 1981 are reported. The survey details 116 observations of short incubation syndromes and 44 cases of delayed syndrome, identified as Amanita Phalloides poisoning. Of the latter, 40 patients were adult (mean age 46 years, range 20-77; 18 females and 22 males) and 4 were children (less than or equal to 12 years old; 3 females and 1 male). All the patients with Amanita Phalloides poisoning were treated according to a therapeutic protocol, based on the infusion of high doses of penicillin G, administration of dexamethasone and thioctic acid, careful correction of water and electrolyte unbalance. The severity of the disease varied in the population of 44 patients: 4 patients died (2 females, 10 and 77 years old; 2 males, 56 and 64 years old); 26 patients were discharged from the hospital as clinically cured; 14 were discharged with persistently abnormal levels of transaminases and they were advised of a follow-up evaluation. The average length of stay in hospital was 2 weeks. Of the patients followed-up, 6 were symptom-free after 6 months, with normal transaminase values and a normal histopathological picture of liver biopsy specimens. In the remaining patients, there was no normalization of transaminase values and liver biopsy specimens showed a picture of chronic active hepatitis. These patients displayed abnormal immunological tests, with presence of immune complexes and of anti-smooth muscle autoantibodies. The results indicate that Amanita Phalloides poisoning represents a threat not only in the high mortality acute phase, but also in the development of chronic active hepatitis in some survivors.
Adolescent↗
Expression of histocompatibility antigen HLA-DR by salivary gland epithelial cells in Sjögren's syndrome.
Recent studies have suggested that the induction of HLA-DR antigens on epithelial cells plays an important role in the pathogenesis of autoimmune endocrine-exocrine disorders. We found that salivary gland epithelial cells (i.e., acinar and ductal cells) in salivary gland biopsy specimens from patients with primary Sjögren's syndrome (keratoconjunctivitis sicca) expressed high levels of HLA-DR antigen, which were detected by staining frozen tissue sections with monoclonal antibodies and immunoperoxidase technique. In contrast, salivary gland epithelial cells from normal subjects did not express this antigen. Lymphocytes eluted from the salivary gland biopsy specimens of patients who had Sjögren's syndrome produced a soluble factor that stimulated HLA-DR synthesis by a salivary gland-derived cell line (Sal-1). These tissue culture supernatants contained gamma-interferon, and their ability to induce HLA-DR synthesis was blocked by monoclonal anti-gamma-interferon antibody. These results demonstrate the presence of HLA-DR antigen on salivary gland epithelial cells and suggest that local production of gamma-interferon plays a role in this induction.
Cells, Cultured↗
Histamine release by free radicals: paracetamol-induced histamine release from rat peritoneal mast cells after in vitro activation by monooxygenase.
The incubation of paracetamol with isolated rat serosal mast cells evokes the release of histamine only in the presence of (S10) liver microsomes obtained from PCB or phenobarbital treated rats. The release of histamine was not accompanied by a leakage of lactate dehydrogenase and was blocked by the antioxidant alpha-tocopherol and by D-mannitol, an hydroxyl free radicals scavenger. The data are consistent with the metabolic oxidation of paracetamol in the generation of reactive intermediates capable of activating the sequential exocytosis.
Acetaminophen↗