RESUMEN
Epidemiological studies have identified abuse of nitrite inhalants as an independent co-factor in HIV infection and in Kaposi's sarcoma (KS) in AIDS patients. In the present study we investigated the ability of macrophages from mice exposed to isobutyl nitrite to produce the inflammatory cytokine IL-1beta, upon stimulation with IFN-gamma and LPS. The production of IL-1beta was inhibited up to 55%. IL-1beta mRNA transcription was reduced by 35% following nitrite inhalant exposure, consistent with inhibition of activation-induced phosphorylation of macrophage mitogen-activated protein kinase p38. However, synthesis of the 31 kDa IL-1beta precursor protein was only marginally inhibited. Caspase-1, which cleaves the precursor IL-1beta into mature 17 kDa IL-1beta, was examined. Nitrite inhalant exposure blocked activation-induced increases in caspase-1 activity, consistent with a 50% reduction in 17 kDa IL-1beta shown in Western blots. Thus, exposure to nitrite inhalants reduced macrophage production of IL-1beta by reducing transcription, as well as post-translational processing mediated by caspase-1.
Asunto(s)
Caspasa 1/farmacología , Exposición por Inhalación , Interleucina-1/biosíntesis , Nitritos/toxicidad , Vasodilatadores/toxicidad , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Animales , Western Blotting , Femenino , Humanos , Inflamación , Interferón gamma/farmacología , Macrófagos , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/farmacología , Factores de Riesgo , Transcripción Genética , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
A history of abuse of nitrite inhalants has been correlated with HIV seropositivity and Kaposi's sarcoma. A series of 14 daily, 45-min exposures of mice to 900-ppm isobutyl nitrite in an inhalation chamber reduced the number of peritoneal exudate macrophages (PEM) by 35% and the number of resident peritoneal macrophages (RPM) by 18%. Although the tumoricidal activity of RPM was not affected by the inhalant, the cytotoxicity of PEM was reduced by 26%. The induction of nitric oxide (NO) and the inducible NO synthase (iNOS) protein in PEM were inhibited by the inhalant to a similar extent. Inhibition of NF-kappaB activation in PEM from mice exposed to the inhalant corresponded to reduced degradation of the NF-kappaB inhibitor, IkappaB alpha. Proteasome-associated, enzymatic activity was compromised in PEM from inhalant-exposed mice, suggesting that inhaled isobutyl nitrite compromised macrophage, tumoricidal activity by inhibiting proteasomal degradation of the NF-kappaB inhibitor, IkappaB alpha.
Asunto(s)
Butanos/farmacología , Inmunidad Celular/efectos de los fármacos , Síndromes de Inmunodeficiencia/inducido químicamente , Macrófagos Peritoneales/efectos de los fármacos , Complejos Multienzimáticos/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Nitratos/farmacología , Administración por Inhalación , Animales , Butanos/toxicidad , Cisteína Endopeptidasas , Citotoxicidad Inmunológica/efectos de los fármacos , Depresión Química , Susceptibilidad a Enfermedades , Femenino , Infecciones por VIH/epidemiología , Inflamación , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C57BL , Nitratos/toxicidad , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo II , Complejo de la Endopetidasa Proteasomal , Factores de Riesgo , Sarcoma de Kaposi/epidemiología , Trastornos Relacionados con Sustancias , Células Tumorales CultivadasRESUMEN
Treatment with essential metalloelement (Cu, Fe, Mn, and Zn) chelates or combinations of them before and/or after radiation injury is a useful approach to overcoming radiation injury. No other agents are known to increase survival when they are used to treat after irradiation, in a radiorecovery treatment paradigm. These chelates may be useful in facilitating de novo syntheses of essential metalloelement-dependent enzymes required to repair radiation injury. Reports of radioprotection, which involves treatment before irradiation, with calcium-channel blockers, acyl Melatonin homologs, and substituted anilines, which may serve as chelating agents after biochemical modification in vivo, as well as Curcumin, which is a chelating agent, have been included in this review. These inclusions are intended to suggest additional approaches to combination treatments that may be useful in facilitating radiation recovery. These approaches to radioprotection and radiorecovery offer promise in facilitating recovery from radiation-induced injury experienced by patients undergoing radiotherapy for neoplastic disease and by individuals who experience environmental, occupational, or accidental exposure to ultraviolet, x-ray, or gamma-ray radiation. Since there are no existing treatments of radiation-injury intended to facilitate tissue repair, studies of essential metalloelement chelates and combinations of them, as well as combinations of them with existing organic radioprotectants, seem worthwhile.
RESUMEN
Isobutyl nitrite is an inhalant abused principally by male homosexuals. We have reported that subchronic inhalation exposure (45 min/day for 14 days) to 900 ppm isobutyl nitrite was immunosuppressive. In the present study, the effects of acute exposure to the inhalant were examined. Mice were exposed in an inhalation chamber to 900 ppm isobutyl nitrite for 45 min. One day later, spleen cellularity was reduced by 39% without selectively depleting CD4(+) or CD8(+) cells. The numbers of peripheral blood leukocytes and peritoneal cells were also reduced. Following acute inhalation exposure, T cell proliferative responses stimulated with allogeneic cells or anti-CD3 and anti-CD28 antibodies were inhibited, while mitogen-induced responses were not affected. Purified T cells exposed to the inhalant also had compromised responses, suggesting a direct effect on T cells. However, the cumulative effects of multiple exposures were necessary to inhibit T-dependent antibody responses or T cell or macrophage cytotoxicity.
Asunto(s)
Inmunosupresores/toxicidad , Nitritos/toxicidad , Bazo/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Administración por Inhalación , Animales , Antígenos CD28/fisiología , Recuento de Células , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Receptores de Hialuranos/biosíntesis , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Bazo/patologíaRESUMEN
Nitrite inhalant abuse has been correlated epidemiologically with HIV seropositivity and with Kaposi's sarcoma. Using a mouse model, we have shown that inhaled isobutyl nitrite caused anemia and severely depressed immunity. In the present study, we showed that both isobutyl and cyclohexyl nitrites in air liberated nitric oxide (NO). An immunotoxic dose of 900 ppm isobutyl nitrite liberated 115 ppm NO. Mice were exposed in an inhalation chamber to 115 ppm NO, 900 ppm isobutyl nitrite, or 900 ppm cyclohexyl nitrite for 45 min/day. Following a single exposure, NO did not affect peripheral blood cell counts, while isobutyl and cyclohexyl nitrites reduced cell numbers. After 14 daily exposures, isobutyl nitrite, but not cyclohexyl nitrite or NO, reduced peritoneal macrophage tumoricidal activity. The nitrite esters likely caused immunotoxicity by mechanisms other than NO release.
Asunto(s)
Citotoxicidad Inmunológica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Óxido Nítrico/biosíntesis , Nitritos/toxicidad , Animales , Femenino , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
Epidemiological studies have correlated the incidence of Kaposi's sarcoma (KS) in AIDS with a history of abuse of nitrite inhalants. To determine if exposure to nitrite inhalants could alter tumor growth, syngeneic PYB6 tumor cells were injected into groups of mice. Exposure of these mice to inhaled isobutyl nitrite increased both the tumor incidence and the tumor growth rate by almost 4-fold. Following only five daily exposures to the inhalant, the induction of specific T cell mediated cytotoxicity was inhibited by 36%. Similar inhalation exposures inhibited the tumoricidal activity of activated macrophages by 86%. The data suggest that exposure to abuser levels of a nitrite inhalant compromised tumor surveillance mechanisms.
Asunto(s)
Drogas Ilícitas/efectos adversos , Nitritos/toxicidad , Sarcoma Experimental/patología , Administración por Inhalación , Animales , División Celular/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Nitritos/administración & dosificación , Estimulación Química , Linfocitos T Citotóxicos/efectos de los fármacos , Células Tumorales CultivadasAsunto(s)
Inmunosupresores/farmacología , Óxido Nítrico/metabolismo , Nitritos/farmacología , Administración por Inhalación , Animales , Femenino , Inmunosupresores/metabolismo , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/fisiología , Nitritos/metabolismo , Bazo/efectos de los fármacos , Bazo/inmunologíaRESUMEN
Epidemiological studies indicating that nitrite inhalant abuse is a co-factor in HIV infection and in Kaposi's sarcoma are supported by recent experimental studies, described in this review. Inhalation exposure to the nitrites produce a nonspecific cytotoxicity, depleting many cells of the immune system. Apparently distinct from this cytotoxicity, inhalation of the nitrites impairs a variety of immune mechanisms, affecting both humoral and cell-mediated immunity. In addition, the inhalant-increased macrophage production of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), can directly stimulate HIV replication and can also stimulate the growth of Kaposi's sarcoma cells. Thus, nitrite inhalants may impair immune resistance to infection and actively promote viral replication and tumor growth.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Neuroinmunomodulación/efectos de los fármacos , Nitritos/toxicidad , Sarcoma de Kaposi/inmunología , Trastornos Relacionados con Sustancias/inmunología , Vasodilatadores/toxicidad , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Administración por Inhalación , Humanos , Nitritos/administración & dosificación , Factores de Riesgo , Sarcoma de Kaposi/epidemiología , Trastornos Relacionados con Sustancias/virología , Vasodilatadores/administración & dosificaciónRESUMEN
Cyclohexyl nitrite is an abused nitrite inhalant. This is the first report of toxicity of cyclohexyl nitrite. Mice were exposed to 300-900 ppm cyclohexyl nitrite in an inhalation chamber for 45 min and then bled. Such treatment resulted in a 7-10% reduction in red blood cell counts, haemoglobin and haematocrit levels. Both blood leucocyte counts and spleen cellularity were reduced by 40%. Unlike isobutyl nitrite, subchronic treatment of mice with cyclohexyl nitrite did not impair macrophage tumoricidal activity or production of reactive nitrogen intermediates, but did modulate B and T cell mitogen responses. The data suggest that cyclohexyl nitrite had cytotoxic activity, comparable to that of isobutyl nitrite, which might be related to the anaemia reported in abusers. The immunomodulatory properties of cyclohexyl nitrite differed from those of isobutyl nitrite.
Asunto(s)
Recuento de Células Sanguíneas/efectos de los fármacos , Drogas Ilícitas , Nitritos/toxicidad , Vasodilatadores/toxicidad , Administración por Inhalación , Animales , Linfocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ratones , Nitritos/administración & dosificación , Vasodilatadores/administración & dosificaciónRESUMEN
Abuse of nitrite inhalants, widespread among male homosexuals, has been identified by epidemiological studies as an independent risk factor for AIDS and for Kaposi's sarcoma. Subchronic exposure of mice to inhaled isobutyl nitrite was previously found to impair the tumoricidal activity of peritoneal macrophages. Because inhalants would be expected to have the greatest effects on cells in the lung, alveolar macrophages from exposed mice were examined in this study. Mice were exposed to 900 ppm isobutyl nitrite in an inhalation chamber for 45 min/day for 14 days. Following this treatment, the lungs of exposed mice had large increases in cellularity, both in the alveolar septa and within the alveoli. Bronchoalveolar lavages also contained increased numbers of cells. Alveolar macrophages collected from treated mice had increased tumoricidal activity compared with controls and produced higher levels of inducible nitric oxide and tumor necrosis factor-alpha (TNF-alpha). The frequency of alveolar cells secreting TNF-alpha was increased ninefold in mice exposed to the inhalant. Cell influx into the lung, as indicated by the presence of red blood cells in lung lavages, was evident after only a single 45-min exposure to inhaled isobutyl nitrite at doses as low as 300 ppm.
Asunto(s)
Macrófagos Alveolares/efectos de los fármacos , Óxido Nítrico/biosíntesis , Nitritos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Aerosoles , Animales , Supervivencia Celular/efectos de los fármacos , Infecciones por VIH/etiología , Inflamación/diagnóstico , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/patología , Macrófagos Alveolares/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Nitritos/administración & dosificación , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patología , Factores de RiesgoRESUMEN
Isobutyl nitrite is representative of a group of inhalants abused primarily by male homosexuals; abuse of this drug may be a risk factor for AIDS or Kaposi's sarcoma. Using a 14-day exposure regimen, we previously reported that inhaled isobutyl nitrite was immunotoxic to mice, severely compromising T-dependent antibody responses and cytotoxic T cell and macrophage tumoricidal activity. In addition, exposure to the inhalant dramatically reduced spleen cellularity. A single 45-minute inhalation exposure produced anemia in mice. In the present study, we examined the effects of subchronic exposure to the drug on peripheral blood cellularity and hematopoietic activity. Mice were exposed to 900 ppm isobutyl nitrite in an inhalation chamber for 45 minutes/day for 14 days. One day after the final exposure, the number of peripheral blood leukocytes was reduced by 32%; however, the number of erythrocytes was increased by 7%. This was accompanied by an apparent shift from myelopoiesis to erythropoiesis. The numbers of bone marrow and spleen burst-forming units-erythroid (BFU-E) were increased about two-fold, while the numbers of colony-forming units-granulocyte/macrophage (CFU-GM) were decreased by about half. Bone marrow stromal cells also had reductions in the production of myeloid colony-stimulating activity after subchronic exposure to the inhalant. In addition, the numbers of hematopoietic stem cells, colony-forming units-spleen (CFU-S), were reduced in both bone marrow and spleen. Peripheral blood erythrocyte and leukocyte counts returned to normal levels by 7 days after the final exposure, as did the number of BFU-E. The number of CFU-GM remained depressed, however, even after 7 days of recovery. These data suggest that repeated exposures nonspecifically depleted cells and that erythropoiesis was stimulated, apparently at the expense of myelopoiesis.
Asunto(s)
Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Drogas Ilícitas/toxicidad , Leucopenia/inducido químicamente , Nitritos/toxicidad , Vasodilatadores/toxicidad , Administración por Inhalación , Animales , Recuento de Células Sanguíneas/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Tejido Conectivo/efectos de los fármacos , Tejido Conectivo/patología , Femenino , Hematócrito , Hemoglobinas/análisis , Síndromes de Inmunodeficiencia/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Nitritos/administración & dosificación , Bazo/efectos de los fármacos , Bazo/patología , Vasodilatadores/administración & dosificaciónRESUMEN
Abuse of nitrite inhalants is widespread among male homosexuals and has been epidemiologically correlated with seropositivity to human immunodeficiency virus (HIV) and to Kaposi's sarcoma. These drugs may act as cofactors in AIDS if they compromise the ability to resist infection or tumor growth. We have previously reported that 14 daily 45-minute exposure to 900 ppm isobutyl nitrite in an inhalation chamber did compromise the immunocompetence of mice. We now report that a single 45-minute exposure produced a transient anemia. Erythrocyte counts, hemoglobin, and hematocrit levels were reduced by 7% but rebounded to above-normal levels 24 hours later. In vitro exposure of blood to isobutyl nitrite vapors did not lyse the cells but did induce Heinz body formation and increase their binding to macrophages. Thus, it is likely that the red cells were removed by phagocytic clearance not by direct lysis. Blood leukocyte numbers were also reduced following a single exposure to the inhalant, but the cell loss was delayed until 24 hours after exposure. Recovery of peripheral blood leukocytes 72 hours after exposure coincided with a reduction in spleen cellularity, suggesting that spleen cells were mobilized to replace lost blood leukocytes.
Asunto(s)
Células Sanguíneas/efectos de los fármacos , Nitritos/administración & dosificación , Animales , Recuento de Células Sanguíneas/efectos de los fármacos , Recuento de Eritrocitos/efectos de los fármacos , Femenino , Gases , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos , Bazo/anatomía & histología , Factores de Tiempo , Vasodilatadores/farmacologíaAsunto(s)
Enfermedades Pulmonares/inmunología , Macrófagos/inmunología , Óxido Nítrico/biosíntesis , Nitritos/toxicidad , Factor de Necrosis Tumoral alfa/biosíntesis , Vasodilatadores/toxicidad , Administración por Inhalación , Animales , Femenino , Inflamación/inducido químicamente , Inflamación/inmunología , Enfermedades Pulmonares/inducido químicamente , Ratones , Ratones Endogámicos C57BLRESUMEN
Understanding essential metalloelement metabolism and its role in tissue maintenance and function, as well as the roles of essential metalloelement-dependent enzymes in responding to injury, offer a new approach to decreasing and/or treating radiation injury. This review presents the roles of some essential metalloelement-dependent enzymes in tissue maintenance and function, and their responses to radiation injury in accounting for radiation protection and recovery effects observed for nontoxic doses of essential metalloelement compounds. Effects of biochemicals including water undergoing bond radiolysis and the effects of free radicals derived from diatomic oxygen account for the acute and chronic aspects of radiation injury. Recognized biochemical roles of essential metalloelement-dependent enzymes and the observed pharmacological effects of small-molecular mass chelates predict the therapeutic usefulness of essential metalloelement complexes in decreasing and/or treatment of radiation injury. Copper chelates have radiation protection and radiation recovery activities and cause rapid recovery of immunocompetency and recovery from radiation-induced histopathology. Mice treated with Cu(II)2(3,5-diisopropylsalicylate)4[Cu (II)2(3,5-DIPS)4] had increased survival and corresponding increases in numbers of myeloid and multipotential progenitor cells early after irradiation and earlier recovery of immune reactivity. Examination of radiation-induced histopathology in spleen, bone marrow, thymus, and small intestine also revealed Cu(II)2(3,5-DIPS)4-mediated rapid recovery of radiation-induced histopathology. Most recently, Fe, Mn, and Zn complexes have also been found to prevent death in lethally irradiated mice. These pharmacological effects of essential metalloelement chelates can be understood as due to facilitation of de novo synthesis of essential metalloelement-dependent enzymes which have roles in preventing the accumulation of pathological concentrations of oxygen radicals or repairing biochemical damage caused by radiation-induced bond homolysis. Essential metalloelement chelates offer a physiological approach to prevention and/or treatment of radiation injury.
Asunto(s)
Quelantes , Metales/uso terapéutico , Traumatismos Experimentales por Radiación/prevención & control , Traumatismos por Radiación/metabolismo , Protectores contra Radiación/uso terapéutico , Animales , Humanos , Metales/metabolismo , Ratones , Traumatismos por Radiación/prevención & controlAsunto(s)
Inmunidad Celular/efectos de los fármacos , Nitritos/toxicidad , Vasodilatadores/toxicidad , Administración por Inhalación , Animales , Eritrocitos/inmunología , Femenino , Interleucina-1/biosíntesis , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/metabolismo , Nitritos/administración & dosificación , Ovinos/inmunología , Bazo/citología , Bazo/efectos de los fármacos , Trastornos Relacionados con Sustancias/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Vasodilatadores/administración & dosificaciónRESUMEN
Abuse of nitrite inhalants is common among male homosexuals and a history of abuse has been correlated with seropositivity to HIV and with the incidence of Kaposi's sarcoma among AIDS patients. The present study shows that inhalation exposure of mice to 900 ppm isobutyl nitrite for 45 min/day for 14 days compromised macrophage tumoricidal activity by up to 40% and it remained compromised for at least 7 days after terminating exposures. The inhalation exposures did not affect tumor cell binding but did inhibit inducible nitric oxide (NO zero). The NO zero synthase inhibitor NG-methyl-L-arginine totally inhibited both NO zero production and cytotoxicity, suggesting that reductions in NO zero due to inhalant exposure may be responsible for the reduced cytotoxic activity. Exposure to the inhalant increased constitutive production of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha has been reported to stimulate the replication of HIV and the proliferation of Kaposi's sarcoma cells in vitro.
Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Óxido Nítrico/metabolismo , Nitritos/toxicidad , Vasodilatadores/toxicidad , Administración por Inhalación , Animales , Arginina/análogos & derivados , Arginina/farmacología , Adhesión Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/patología , Células Cultivadas , Citotoxicidad Inmunológica/efectos de los fármacos , Citotoxicidad Inmunológica/inmunología , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Interferón gamma/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Lipopolisacáridos/farmacología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/fisiología , Nitritos/administración & dosificación , Sarcoma de Kaposi/etiología , Sarcoma de Kaposi/patología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/fisiología , Vasodilatadores/administración & dosificación , omega-N-MetilargininaRESUMEN
Isobutyl nitrite is representative of a group of inhalants abused by male homosexuals and adolescents. Inhalation exposure of mice to isobutyl nitrite at 900 ppm for 45 min per day for 14 days caused serious deficits in T cell-mediated immune responses. Cytotoxic T lymphocyte (CTL) activity was reduced by 36% following the exposure. T cell proliferative responses to mitogenic and allogeneic stimulation were reduced by 37% and 51%, respectively. The exposure did not directly alter the ability of cells to synthesize or respond to IL-2. Accessory cell function in facilitating T cell activation was inhibited by about 50% following exposure to the inhalant.
Asunto(s)
Nitritos/toxicidad , Linfocitos T/efectos de los fármacos , Vasodilatadores/toxicidad , Administración por Inhalación , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Inmunidad Celular/efectos de los fármacos , Interleucina-2/biosíntesis , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Nitritos/administración & dosificación , Bazo/citología , Linfocitos T/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Vasodilatadores/administración & dosificaciónRESUMEN
Because partial protection against reinfection is induced by experimental infection in the guinea-pig model of genital chlamydial infection, we sought to induce immunity by immunization. Female guinea-pigs were immunized subcutaneously with the major outer-membrane protein (MOMP) and the 61 kDa cysteine-rich outer-membrane protein (61 kDa) of the agent of guinea-pig inclusion conjunctivitis (GPIC) eluted from SDS-polyacrylamide gels (SDS-MOMP, SDS-61 kDa). Post-immunization sera and secretions contained antibodies to the SDS-purified proteins at high titre as measured by immunoblotting, whereas enzyme immunoassays (EIA) using whole elementary bodies as antigen showed significantly lower titres (P < 0.001). Likewise, blastogenic responses of peripheral mononuclear cells to GPIC elementary bodies were weak. Animals immunized with SDS-MOMP and SDS-61 kDa were fully susceptible to intravaginal challenge, as were control animals immunized with buffer without protein. Another group of animals were immunized with material prepared by extraction of chlamydial outer-membrane complexes with octyl beta-D-glucopyranoside (OGP) and dithiothreitol, which consisted largely of MOMP (OGP-MOMP). In contrast to the SDS-MOMP group, sera and secretions in the OGP-MOMP group showed high titres in EIA, and high titre antibodies to MOMP by immunoblot; however, most animals also had antibodies to 61 kDa, 72 kDa and ca. 84 kDa outer-membrane proteins. OGP-MOMP animals were partially protected against genital challenge as evidenced by low inclusion scores compared to control animals, although duration of infection measured by culture isolation was similar to controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/inmunología , Infecciones por Chlamydia/prevención & control , Chlamydia trachomatis/inmunología , Conjuntivitis de Inclusión/inmunología , Enfermedades de los Genitales Femeninos/prevención & control , Porinas , Animales , Anticuerpos Antibacterianos/sangre , Especificidad de Anticuerpos , Antígenos Bacterianos/genética , Proteínas de la Membrana Bacteriana Externa/genética , Secuencia de Bases , Infecciones por Chlamydia/inmunología , Chlamydia trachomatis/genética , ADN Bacteriano/genética , Modelos Animales de Enfermedad , Epítopos/genética , Femenino , Enfermedades de los Genitales Femeninos/inmunología , Cobayas , Inmunización , Datos de Secuencia MolecularRESUMEN
Habitual abuse of nitrite inhalants has been linked in epidemiological studies with seropositivity to human immunodeficiency virus and, separately, with Kaposi's sarcoma among AIDS patients. Mice exposed to isobutyl nitrite in an inhalation chamber for 45 min/day for 14 days had depressed IgM and IgG antibody responses. The inhibition was dose-dependent at 750-900 ppm, but antibody responses were increased at an intermediate (600 ppm) dose. Gender differences in immunotoxicity were not observed. Antibody responses to a T-independent antigen (DNP-ficoll) were not affected by the immunotoxic exposure, suggesting that B-cells were refractory to the toxic exposure. Toxic exposure to isobutyl nitrite did not selectively deplete a particular spleen cell population, but caused equivalent reductions of T-cells and B-cells. Finally, exposed mice remained immunocompromised for 3-5 days after terminating exposures. Normal immune responses returned by 5-7 days, suggesting that inhibition of cellular function was reversible.