RESUMO
The effects of the beta-receptor blockading agents, metoprolol and sotalol on neutrophil random motility, chemotaxis, post-phagocytic glycolysis, superoxide production, hexose monophosphate shunt activity, myeloperoxidase (MPO) mediated protein iodination and hydrogen peroxide production were assessed in vitro. The concentration range investigated was 10(-8)--10(-2) M for each drug. Both agents caused significant stimulation of neutrophil motility at concentrations of more than 10(-4) M. Increased migration was not associated with increased glycolysis or significant cyclic nucleotide fluctuations, but was inversely related to inhibition of superoxide and hydrogen peroxide generation and MPO mediated iodination with both drugs. In a further series of experiments to determine the relationship between the drug induced inhibition of H2O2 production and MPO mediated protein iodination to stimulation of motility it was found that concentrations of sotalol and metoprolol that caused these effects prevented HRP/H2O2/I- induced inactivation of the leucoattractant and inhibition of neutrophil chemotactic responsiveness. Neither drug inhibited the activity of MPO per se nor the reduction of ferricytochrome c by superoxide generated by the xanthine: xanthine oxidase system in vitro. It is suggested that enhanced neutrophil motility is not related to beta-receptor blockade but rather to restricting the availability of hydrogen peroxide and reactive products of the MPO/H2O2/halide system.
Assuntos
Metoprolol/farmacologia , Neutrófilos/imunologia , Propanolaminas/farmacologia , Sotalol/farmacologia , Movimento Celular/efeitos dos fármacos , Peroxidase do Rábano Silvestre/farmacologia , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Iodetos/metabolismo , Lipopolissacarídeos/farmacologia , N-Formilmetionina/análogos & derivados , N-Formilmetionina/farmacologia , N-Formilmetionina Leucil-Fenilalanina , Oligopeptídeos/farmacologia , Peroxidases/metabolismo , Fagocitose , Superóxidos/biossínteseRESUMO
The effects of sodium aurothiomalate, levamisole, its active metabolite OMPI and the anti-inflammatory agents indomethacin and tolmetin on neutrophil motility and post-phagocytic hexose monophosphate shunt activity, superoxide and H2O2 generation and myeloperoxidase (MPO) mediated iodination of Candida albicans were investigated in vitro. All five agents caused stimulation of neutrophil random motility and migration towards the leucoattractants f-met-met-phe and EAS. Only levamisole caused inhibition of H2O2 and superoxide production, which was associated with inhibition of HMS activity and not related to superoxide scavenging activity. All five agents caused inhibition of MPO mediated iodination of C. albicans. The relationship between inhibition of peroxidase mediated iodination and enhanced motility was further investigated using the horseradish peroxidase (HRP) H2O2/iodide system. Incubation of neutrophils with this system caused inhibition of neutrophil motility. However in the presence of the various drugs neutrophils were protected from inhibition of motility by the HRP/H2O2/iodide system. Further experiments showed that lymphocyte transformation to mitogens was also inhibited by the HRP/H2O2/iodide system. Incubation of lymphocytes with the various drugs prior to exposure to HRP/H2O2/iodide protected the lymphocyte mitogenic responsiveness.
Assuntos
Anti-Inflamatórios/farmacologia , Ouro/farmacologia , Imidazóis/farmacologia , Imidazolidinas , Levamisol/farmacologia , Neutrófilos/metabolismo , Oxigênio/metabolismo , Superóxidos/metabolismo , Inibição de Migração Celular , Humanos , Técnicas In Vitro , Indometacina/farmacologia , Ativação Linfocitária , Neutrófilos/imunologia , Peroxidase/metabolismo , Fagocitose , Tolmetino/farmacologiaRESUMO
The effects of thiamine on neutrophil functions and mitogen-induced lymphocyte transformation were investigated in vitro and in vivo in adult volunteers following the injection of 50 mg thiamine intramuscularly. Thiamine caused stimulation of neutrophil motility in vitro and in vivo and increased lymphocyte transformation in vivo. Enhancement of these functions was related to inhibition of neutrophil post-phagocytic iodination of Candida albicans by the MPO/H2O2/halide system. The horseradish peroxidase/-H2O2/125 I-mediated iodination of bovine serum albumin was also inhibited by thiamine concentrations which caused increased neutrophil motility. It was found that preincubation of neutrophils and lymphocytes with the horseradish peroxidase/H2O2/halide system caused considerable inhibition of the migratory and proliferative responses respectively. Inclusion of thiamine at concentrations which were found to inhibit the peroxidase/-H2O2/halide system protected the neutrophil migratory and lymphocyte proliferative responses from inactivation by this system. It is suggested that thiamine may cause increased neutrophil migration and lymphocyte transformation by protecting these cells from toxic oxidative products generated by the peroxidase/H2O2/halide system.
Assuntos
Ativação Linfocitária/efeitos dos fármacos , Neutrófilos/imunologia , Tiamina/farmacologia , Adulto , Candida albicans , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Peróxido de Hidrogênio/metabolismo , Iodo/metabolismo , Peroxidase/metabolismo , Peroxidases/metabolismo , Fagocitose , Soroalbumina Bovina/metabolismo , Xantina Oxidase/metabolismoRESUMO
The effects of lithium sulphate (LiSO4) at concentrations ranging from 10(-7)M to 10(-2)M on human polymorphonuclear leucocyte (PMNL) and lymphocyte functions in vitro were investigated. The leucocyte function assessed were PMNL motility, post-phagocytic hexose-monophosphate shunt activity, myeloperoxidase-mediated iodination of Candida albicans and lymphocyte transformation to mitogens. These same functions as well as the results of serological studies were assessed in normal volunteers prior to ingestion of lithium carbonate (LiCO3), 2 hours and 24 hours after the ingestion of a single oral dose of 480 mg LiCO3, and on the 4th day of ingestion of 2 X 480 mg LiCO3 tablets daily. Incubation of PMNL with LiSO4 at concentrations up to 10(-3)M had no detectable effects on motility or post-phagocytic metabolic activity. Higher concentrations (10(-3)M) inhibited these functions. Likewise, at concentrations up to 1 X 10(-4)M LiSO4 had no effects on mitogen-induced transformation of lymphocytes, although higher concentrations did inhibit this activity. These same leucocyte functions were unaffected by ingestion of LiCO3. Levels of serum immunoglobulins and complement components, total haemolytic complement activity and salivary IgA values also remained unaltered. In vitro investigations showed that at a concentration of 10(-3)M LiSO4 had no inhibitory effects on the stimulation of PMNL motility mediated by ascorbate, levamisole and thiamine.
Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Lítio/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Adulto , Hexosefosfatos/metabolismo , Humanos , Iodo , Neutrófilos/efeitos dos fármacos , Peroxidase/metabolismo , Fagócitos/efeitos dos fármacos , Proteínas/metabolismoRESUMO
The effects of sulfamethoxazole and trimethoprim individually and in combination on in vitro neutrophil random migration, chemotaxis to autologous endotoxin-activated serum and the synthetic chemotactic tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine, phagocytosis and postphagocytic Nitro Blue Tetrazolium reduction, glycolysis, hexose monophosphate shunt activity, myeloperoxidase-mediated protein iodination, hydrogen peroxide production, and degranulation were assessed. The effects on lymphocyte mitogen-induced transformation were also evaluated. It was found that the test agents individually and in combination at high concentrations (> 100 microgram/ml) caused the inhibition of neutrophil postphagocytic myeloperoxidase-mediated protein iodination, which was related to the interference with H2O2 formation as the enzyme per se was unaffected. Both agents caused the inhibition of lymphocyte transformation at high concentrations (> 100 microgram/ml). In vivo studies before and after the ingestion of co-trimoxazole by three individuals showed no inhibition of any of the neutrophil functions tested. The inhibition of lymphocyte transformation was observed in one individual after the ingestion of the chemotherapeutic agent. These findings indicate that the concentrations which inhibit neutrophil H2O2 production and lymphocyte transformation in vitro are not attainable in vivo.
Assuntos
Linfócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Sulfametoxazol/farmacologia , Trimetoprima/farmacologia , Adulto , Quimiotaxia de Leucócito/efeitos dos fármacos , Combinação de Medicamentos , Humanos , Técnicas In Vitro , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/imunologia , Neutrófilos/fisiologia , Fagocitose/efeitos dos fármacosRESUMO
The effects of dapsone on polymorphonuclear leukocyte functions and lymphocyte mitogen-induced transformation were assessed in vitro and in vivo in normal individuals and in newly diagnosed untreated patients with lepromatous leprosy. The effects of dapsone on the cell-free generation of superoxide by the xanthine: xanthine oxidase system and iodination of bovine serum albumin by horseradish peroxidase were also investigated. In normal individuals dapsone mediated stimulation of polymorphonuclear leukocyte migration in vitro and vivo. Dapsone had no effect on postphagocytic hexose monophosphate shunt activity in vivo. Similar effects were found in patients with lepromatous leprosy. Dapsone also decreased the inhibitory activity of serum from patients with lepromatous leprosy on normal polymorphonuclear leukocyte migration in vitro. Progressive loss of serum-mediated inhibition of migration was observed after ingestion of dapsone by the patients. Further experiments showed that stimulation of polymorphonuclear leukocyte motility was related to inhibition of lymphocyte transformation at high concentrations in vitro, but had slight stimulatory activity on phytohemagglutinin-induced transformation in controls and patients in vivo.