RESUMO
Diesel exhaust particle (DEP) is the major components of PM2.5, and much attention has focused on PM2.5 in relation to adverse health effects, and many pulmonary diseases. In the present study, we used a human bronchial epithelial cell (HBEC) line to investigate the anti-inflammatory effects of erythromycin (EM) and EM703 - a new derivative of erythromycin without antibacterial effects on the expressions of IL-8 caused by DEP exposure. DEP showed a dose-dependent stimulatory effect on IL-8 product in HBEC. Increases of IL-8 expression by DEP stimulation were significantly blocked by both EM and EM703 pretreatment. Furthermore, NF-κB and Nrf2 activation, the antioxidant enzymes such as HO-1, NQO-1 mRNA expression were increased by DEP exposure and these increases were blocked by both of EM and EM703 pretreatment. Our results suggest that, EM and EM703 may have an inhibitory effect on expression inflammatory cytokines in HBEC induced by DEP not only as an anti-inflammation but also an antioxidant drug. EM and EM703 might contribute to chemical prevention of the risk of pulmonary diseases induced by oxidative stress from environmental pollutant, such as DEP.
Assuntos
Anti-Inflamatórios/farmacologia , Eritromicina/análogos & derivados , Eritromicina/farmacologia , Material Particulado/farmacologia , Emissões de Veículos/toxicidade , Linhagem Celular , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-8/biossíntese , Fator 2 Relacionado a NF-E2 , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologiaRESUMO
In spite of the importance of hyaluronan in host protection against infectious organisms in the alveolar spaces, its role in mycobacterial infection is unknown. In a previous study, we found that mycobacteria interact with hyaluronan on lung epithelial cells. Here, we have analyzed the role of hyaluronan after mycobacterial infection was established and found that pathogenic mycobacteria can grow by utilizing hyaluronan as a carbon source. Both mouse and human possess 3 kinds of hyaluronan synthases (HAS), designated HAS1, HAS2, and HAS3. Utilizing individual HAS-transfected cells, we show that HAS1 and HAS3 but not HAS2 support growth of mycobacteria. We found that the major hyaluronan synthase expressed in the lung is HAS1, and that its expression was increased after infection with Mycobacterium tuberculosis. Histochemical analysis demonstrated that hyaluronan profoundly accumulated in the granulomatous legion of the lungs in M. tuberculosis-infected mice and rhesus monkeys that died from tuberculosis. We detected hyaluronidase activity in the lysate of mycobacteria and showed that it was critical for hyaluronan-dependent extracellular growth. Finally, we showed that L-Ascorbic acid 6-hexadecanoate, a hyaluronidase inhibitor, suppressed growth of mycobacteria in vivo. Taken together, our data show that pathogenic mycobacteria exploit an intrinsic host-protective molecule, hyaluronan, to grow in the respiratory tract and demonstrate the potential usefulness of hyaluronidase inhibitors against mycobacterial diseases.
Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Ácido Hialurônico/metabolismo , Mycobacterium tuberculosis/fisiologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Contagem de Colônia Microbiana , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Glicosaminoglicanos/farmacologia , Histocitoquímica , Humanos , Hialuronan Sintases , Ácido Hialurônico/farmacologia , Pulmão/química , Pulmão/metabolismo , Pulmão/microbiologia , Macaca mulatta , Masculino , Camundongos , Mycobacterium bovis/fisiologia , Mycobacterium tuberculosis/metabolismo , RatosRESUMO
CD4(+)CD25(+) regulatory T (Treg) cells cause immune suppression by inhibiting T cell effector functions and play pivotal roles not only in self-tolerance but also in immune response to parasitic microbial pathogens. Mycobacteria are major parasitic bacterial pathogens, but the role of CD4(+)CD25(+) Treg cells in mycobacterial infection is not yet defined. In this study we found that, at the early stage of infection, depletion of CD25(+) cells reduced both bacterial load and granuloma formation in mice infected with Mycobacterium tuberculosis strains, such as M. tuberculosis Erdman or M. tuberculosis Kurono. However, at a later stage of infection, bacterial burden and histopathology were similar regardless of depletion of CD25(+) cells. Severe combined immunodeficient (SCID) mice reconstituted with CD4(+)CD25(-) T cells alone or a combination of CD4(+)CD25(+) and CD4(+)CD25(-) T cells showed similar bacterial loads and survival kinetics after infection with M. tuberculosis Erdman. Consistent with in vivo data, in vitro studies revealed that mycobacterial antigens, purified protein derivative of tuberculin (PPD), failed to induce the suppressive function of CD4(+)CD25(+) Treg cells to CD4(+)CD25(-) effector T cells, as demonstrated by the lack of response of CD4(+)CD25(+) T cells to PPD, in mice chronically infected with Mycobacterium bovis bacillus Calmette-Guérin and M. tuberculosis. Our data show that CD4(+)CD25(+) Treg cells have a transient effect at the early stage of mycobacterial infection but, contrary to the expectation, have little impact on the overall course of infection.
Assuntos
Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Tuberculose/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Separação Celular , Feminino , Citometria de Fluxo , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Camundongos SCID , Mycobacterium tuberculosis/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Tuberculina , Tuberculose/metabolismoRESUMO
We investigated whether pre- and postnatal low-dose exposure to diesel exhaust (DE) affects male reproductive function in mice. The DE concentration is less than that indicated as the environmental quality standard for suspended particulate matter (SPM) in Japan. ICR mice were exposed prenatally to low-dose diesel exhaust (0.17 mg of DE particles/m³) through the airway for 8 h/day in an exposure chamber from gestational day 2 until the examination. In the DE-exposed groups, normal sperm morphology in the epididymis was reduced (p < 0.01), and seminiferous tubules showed degenerative changes in which the number of Sertoli cells was decreased (p < 0.01). Those changes were observed at 6 and 12 weeks of age. Furthermore, ultrastructural studies revealed an increase in damaged mitochondria in Sertoli cells (p < 0.001) and variform spermatozoa. These results indicate that pre- and postnatal exposure of low-dose DE is detrimental to Sertoli cell function and may cause abnormal spermatozoa.
Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Emissões de Veículos/toxicidade , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Gravidez , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/patologia , Células de Sertoli/ultraestrutura , Espermatozoides/patologia , Espermatozoides/ultraestruturaRESUMO
We have recently reported that disruption of nuclear erythroid 2 P45-related factor 2 (Nrf2) enhances susceptibility to airway inflammatory responses induced by low-dose diesel exhaust particles (DEP) in mice. C57BL/6 Nrf2 knockout (Nrf2(-/-)) mice and wild-type (Nrf2(+/+)) mice were further exposed to low-dose DEP for 7h/day, 5 days/week, for a maximum of 8 weeks. After exposure to DEP for 5 weeks, allergic airway inflammation was generated in the mice by intraperitoneal sensitization with OVA followed by intranasal challenge. Nrf2(-/-) mice exposed to relatively low-dose DEP showed significantly increased percentage changes relative to the OVA alone group in terms of airway hyperresponsiveness (AHR) and inflammatory cells, levels of IL-5 and thymus and activation regulated chemokine (TARC) in bronchoalveolar lavage (BAL) fluid than did Nrf2(+/+) mice. Lung tissues of Nrf2(-/-) mice after DEP exposure showed inflammatory cell infiltrates, and increased PAS staining-positive mucus cell hyperplasia. In contrast, the percentage changes relative to the OVA group in the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio in whole blood was higher in Nrf2(+/+) mice than in Nrf2(-/-) mice. By using Nrf2(-/-) mice, it was shown for the first time that relatively low-dose DEP exposure induces oxidant stress, and that host anti-oxidant responses play a key role in the development of DEP-induced exacerbation of allergic airway inflammation.
Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Hipersensibilidade Respiratória/imunologia , Emissões de Veículos/toxicidade , Animais , Hiper-Reatividade Brônquica/fisiopatologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Quimiocinas/metabolismo , Citocinas/metabolismo , Glutationa/sangue , Dissulfeto de Glutationa/sangue , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Leucócitos/patologia , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , Ovalbumina/imunologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/patologia , Hipersensibilidade Respiratória/fisiopatologiaRESUMO
BACKGROUND: Species identification of isolates belonging to the Mycobacterium tuberculosis complex (MTC) seems to be important for the appropriate treatment of patients, since M. bovis is naturally resistant to a first line anti-tuberculosis (TB) drug, pyrazinamide, while most of the other MTC members are susceptible to this antimicrobial agent. A simple and low-cost differentiation method was needed in higher TB burden countries, such as Bangladesh, where the prevalence of M. bovis among people or cattle has not been investigated. METHODS: Genetic regions cfp32, RD9 and RD12 were chosen as targets for a species distinguishable multiplex PCR and the system was evaluated with twenty reference strains of mycobacterial species including non-tubercular mycobacteria (NTM). A total of 350 clinical MTC isolates obtained in Bangladesh were then analyzed with this multiplex PCR. RESULTS: All of the MTC reference strains gave expected banding patterns and no non-specific amplifications were observed in the NTM strains. Out of 350 clinical isolates examined by this method, 347 (99.1%) were positive for all of the cfp32, RD9 and RD12 and determined as M. tuberculosis. Two isolates lacked cfp32 PCR product and one lacked RD12, however, those three samples were further examined and identified as M. tuberculosis by the sequence analyses of hsp65 and gyrB. CONCLUSIONS: The MTC-discrimination multiplex PCR (MTCD-MPCR) developed in this study showed high specificity and was thought to be very useful as a routine test because of its simplicity. In the current survey, all the 350 MTC isolates obtained from Bangladesh TB patients were determined as M. tuberculosis and no other MTC were detected. This result suggested the general TB treatment regimen including pyrazinamide to be the first choice in Bangladesh.
Assuntos
Técnicas Bacteriológicas/métodos , Mycobacterium bovis/classificação , Mycobacterium tuberculosis/classificação , Reação em Cadeia da Polimerase/métodos , Tuberculose/microbiologia , Proteínas de Bactérias/genética , Bangladesh , DNA Bacteriano/genética , Humanos , Mycobacterium bovis/genética , Mycobacterium bovis/isolamento & purificação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Epidemiological studies have suggested that suspended particulate matter (SPM) causes detrimental health effects such as respiratory and cardiovascular diseases, and that diesel exhaust particles from automobiles is a major contributor to SPM. It has been reported that neonatal and adult exposure to diesel exhaust damages the central nervous system (CNS) and induces behavioral alteration. Recently, we have focused on the effects of prenatal exposure to diesel exhaust on the CNS. In this study, we examined the effects of prenatal exposure to low concentration of diesel exhaust on behaviour and the monoaminergic neuron system. Spontaneous locomotor activity (SLA) and monoamine levels in the CNS were assessed. METHODS: Mice were exposed prenatally to a low concentration of diesel exhaust (171 microg DEP/m(3)) for 8 hours/day on gestational days 2-16. SLA was assessed for 3 days in 4-week-old mice by analysis of the release of temperature-associated infrared rays. At 5 weeks of age, the mice were sacrificed and the brains were used for analysis by high-performance liquid chromatography (HPLC). RESULTS AND DISCUSSION: Mice exposed to a low concentration of diesel exhaust showed decreased SLA in the first 60 minutes of exposure. Over the entire test period, the mice exposed prenatally to diesel exhaust showed decreased daily SLA compared to that in control mice, and the SLA in each 3 hour period was decreased when the lights were turned on. Neurotransmitter levels, including dopamine and noradrenaline, were increased in the prefrontal cortex (PFC) in the exposure group compared to the control group. The metabolites of dopamine and noradrenaline also increased in the PFC. Neurotransmitter turnover, an index of neuronal activity, of dopamine and noradrenaline was decreased in various regions of the CNS, including the striatum, in the exposure group. The serum corticosterone level was not different between groups. The data suggest that decreased SLA in mice exposed prenatally to diesel exhaust is due to facilitated release of dopamine in the PFC. CONCLUSIONS: These results indicate that exposure of mice in utero to a low concentration of diesel exhaust decreases SLA and alters the neurochemical monoamine metabolism of several regions of the brain.
Assuntos
Poluentes Atmosféricos/toxicidade , Comportamento Animal/efeitos dos fármacos , Catecolaminas/metabolismo , Locomoção/efeitos dos fármacos , Exposição Materna/efeitos adversos , Emissões de Veículos/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica , Cromatografia Líquida de Alta Pressão , Feminino , Exposição por Inalação , Masculino , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologiaRESUMO
Mycobacterium tuberculosis, the causative agent of tuberculosis, is a tenacious and remarkably successful pathogen that has latently infected one third of the world's population, according to the World Health Organization (WHO) statistics. It is anticipated that 10% of these infected individuals will develop active tuberculosis at some point in their lifetime. The long-term use of the current drug regimen, the emergence of drug-resistant strains, and HIV co-infection have resulted in a resurgence of research efforts to address the urgent need for new anti-tuberculosis drugs. A number of potential candidate drugs with novel modes of action have entered clinical trials in recent years, and these are likely to be effective against anti-tuberculosis drug-resistant strains. They include neuroquinolone derivatives, a modified ethambutol, nitro-imidazole groups and so on. This mini-review summarizes the latest information about eight new anti-tuberculosis drug candidates and describes their activities, pharmacokinetics, mechanisms of action, and mechanisms of drug-resistance induced by these drug candidates.
Assuntos
Antituberculosos/uso terapêutico , Descoberta de Drogas , Tuberculose/tratamento farmacológico , Antituberculosos/farmacocinética , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/fisiologia , Tuberculose/microbiologiaRESUMO
Diesel exhaust (DE) is composed of particles and gaseous compounds. It has been reported that DE causes pulmonary and cardiovascular disease. We have previously reported that fetal exposure to DE had deleterious effects to the reproductive system of mice offspring. However, there is still little known about the effects of prenatal exposure to DE to the central nervous system (CNS). In the present study, we found that prenatal exposure to DE induced reduction of locomotion, furthermore, dopamine (DA) turnover was significantly decreased in the striatum and nucleus accumbens. These results suggest that prenatal exposure to DE has an effect on the CNS. Hypolocomotion could be due to a decrease in DA turnover associated with DA nervous system abnormality. The present study provides the possibility that maternally inhaled DE might influence the development of central dopaminergic system and result in behavior disorder.
Assuntos
Dopamina/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Emissões de Veículos , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Encéfalo/metabolismo , Ritmo Circadiano/fisiologia , Feminino , Ácido Homovanílico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores de TempoRESUMO
An association between diabetes mellitus (DM) and tuberculosis (TB) has been implied for a long time. We previously reported that KDP type 1 diabetic rats and GK type 2 diabetic rats are highly susceptible to Mycobacterium tuberculosis infection. As a next step, we conducted a retrospective analysis of 2,141 patients with pulmonary TB newly diagnosed during the period from 2008 to 2009 to evaluate the influence of DM on the drug response rate and the long-term relapse rate of TB. There were 203 DM patients with TB (type 1 DM, 7 [3.4%]; type 2 DM, 196 [96.6%]). The TB relapse rate (2 years after discharge) was higher in DM patients than in non-diabetic patients (20% versus 5.3%). The frequency of multidrug-resistant-TB among DM patients with TB was higher than that among TB patients (17.7% versus 8.4%, P<0.01). These results suggest that the period of TB treatment should be prolonged, and that in the meantime the blood glucose level should be maintained within a reference value range.
Assuntos
Complicações do Diabetes/epidemiologia , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/complicações , Tuberculose/epidemiologia , Adulto , China , Feminino , Hospitais , Humanos , Incidência , Masculino , Recidiva , Estudos Retrospectivos , Tuberculose/tratamento farmacológicoRESUMO
There exists latent tuberculosis, in which small numbers of tubercle bacilli remain viable in the host without visible granulomatous lesions. As few data exist on the mechanisms of latent tuberculosis, it is important to examine latent tuberculosis in terms of pathogenesis and efficacy of chemotherapy. As a first step, we used green fluorescent protein (GFP)-introduced H37Rv Mycobacterium tuberculosis to establish latent tuberculosis in the guinea pig that provides one of the best animal models of tuberculosis. We inoculated the guinea pigs subcutaneously with 100 or 1,000 colony-forming unit (CFU) of tubercle bacilli. During the 300-day follow-up period after infection, there were no clinical signs of disease, suggesting a lack of visible granulomatous lesions. In fact, upon necropsy, no macroscopic tuberculous lesions were recognized, but histopathological examination of the lung, spleen and liver revealed microgranulomas consisting of epithelioid macrophages and lymphocytes without central necrosis. Importantly, photon imaging visualized granulomatous lesions corresponding to these histologically apparent microgranulomas. Tuberculin skin testing of infected guinea pigs showed strong positivity (> or = 10 mm induration) until the end of the experiments. Real-time PCR analysis showed a significant increase in the expression levels of interferon-gamma, tumor necrosis factor-alpha, interleukin-12, and inducible nitric oxide synthase mRNAs in infected lung tissues after 300 days (P < 0.01). As human samples are hardly available to study latent tuberculosis, our guinea pig model would be useful for examining the pathogenesis and molecular mechanisms of latent tuberculosis as well as for monitoring the results of chemotherapy with green fluorescence emission of tubercle bacilli.
Assuntos
Proteínas de Fluorescência Verde/metabolismo , Cobaias/microbiologia , Tuberculose Latente/microbiologia , Tuberculose Latente/patologia , Mycobacterium tuberculosis/fisiologia , Animais , Diagnóstico por Imagem , Modelos Animais de Doenças , Fígado/microbiologia , Fígado/patologia , Pulmão/microbiologia , Pulmão/patologia , Especificidade de Órgãos , Fótons , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tela Subcutânea/microbiologia , Tela Subcutânea/patologia , Teste TuberculínicoRESUMO
We have recently reported that airway inflammatory responses to the oxidative stress induced by prolonged low-dose diesel exhaust particle (DEP) exposure differ markedly between BALB/c and C57BL/6 mice. In the present study, the effects of genetic differences in the response to prolonged low-dose DEP exposure on the generation of ovalbumin-induced allergic airway inflammation were further explored using the same mouse strains. In BALB/c mice, eosinophils and mucous goblet cells in histopathological pulmonary specimens increased significantly after DEP exposure, and were more marked than in C57BL/6 mice. Interleukin (IL)-5 and IL-13 levels in bronchoalveolar lavage (BAL) fluid were increased significantly by DEP exposure only in BALB/c mice. The DEP-induced increases in peribronchial eosinophils and mucous goblet cells in the lung tissues, and of IL-5 and IL-13 in the BAL fluid, were significantly attenuated by the antioxidant N-acetylcysteine. Thus, the effects of prolonged low-dose DEP exposure on the generation of allergic airway inflammation differed markedly between the mouse strains. These differences may be caused by different antioxidant responses to the oxidative stress induced by DEP exposure. Our results contribute more information to the search for genetic susceptibility factors in the response to DEP, and may thus assist in the discovery of new biomarkers for DEP-related disease.
Assuntos
Estresse Oxidativo , Material Particulado/toxicidade , Hipersensibilidade Respiratória/induzido quimicamente , Emissões de Veículos/toxicidade , Acetilcisteína/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/análise , Citocinas/imunologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/imunologia , Células Caliciformes/patologia , Imunoglobulina E/análise , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/patologiaRESUMO
PURPOSE: Although adverse health effects of environment (such as cadmium, pesticides, diesel exhaust, etc.) on the male reproductive system have been suggested, there is little experimental evidence of such an effect of atmospheric sand dust. In the present study, the effects of sand dust (mineral particles) were investigated on the male reproductive system of mice. METHODS: Two types of sand dusts (Asian sand dust and Arizona sand dust) were intratracheally administered (0.1 mg/mouse 4 times every other week) to ICR male mice and then male reproductive organ weight, daily sperm production (DSP), histological analysis and serum testosterone level were measured. RESULTS: Histological examination showed that interstitial edema was produced by both sand dust types, and partial vacuolation of the seminiferous tubules was detected in the exposed mice. Moreover, exposure to these natural sand dusts significantly decreased DSP. On the other hand, there was no significant differences in serum testosterone concentration. CONCLUSIONS: These results suggest that natural sand dust-exposure produced adverse effects on mouse male reproductive function.
RESUMO
When Mycobacterium tuberculosis infects humans, about 20% of those infected actually develop tuberculosis (TB). In Japan, the incidence of TB in 2008 was 24,760 cases (19.4/100,000 persons) and the rate has been decreasing gradually, but is still higher than in the USA, Holland, and Belgium, for example. Histologically, tuberculosis displays exudative inflammation, proliferative inflammation and productive inflammation depending on the time course. In productive inflammation, granulomatous lesions with necrotic centers are formed. The typical granulomas consist of epithelioid macrophages, Langhans' multinucleated giant cells, lymphocytes and fibroblasts, and the process of their formation involves many cytokines, chemokines and transcription factors. These findings have been derived primarily from animal experiments utilizing an airborne infection apparatus. The conditions for airborne infection have been described in detail elsewhere. This mini-review focuses on what has been found through animal experiments, and also indicates areas for which data are not currently available.
Assuntos
Inflamação/etiologia , Tuberculose/complicações , Animais , Apoptose/fisiologia , Parede Celular , DNA Bacteriano , Genoma Bacteriano , Células Gigantes de Langhans/imunologia , Humanos , Sistema Imunitário/imunologia , Inflamação/patologia , Interferon gama/fisiologia , Macrófagos Alveolares/imunologia , Mycobacterium tuberculosis/citologia , Mycobacterium tuberculosis/genética , Neutrófilos/imunologia , Óxido Nítrico/fisiologia , Fatores de Risco , Tuberculose/imunologia , Tuberculose/patologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
To test our hypothesis that diesel exhaust particle (DEP)-induced oxidative stress and host antioxidant responses play a key role in the development of DEP-induced airway inflammatory diseases, C57BL/6 nuclear erythroid 2 P45-related factor 2 (Nrf2) knockout (Nrf2(-/-)) and wild-type mice were exposed to low-dose DEP for 7 h/day, 5 days/week, for 8 weeks. Nrf2(-/-) mice exposed to low-dose DEP showed significantly increased airway hyperresponsiveness and counts of lymphocytes and eosinophils, together with increased concentrations of IL-12 and IL-13, and thymus and activation-regulated chemokine (TARC), in BAL fluid than wild-type mice. In contrast, expression of antioxidant enzyme genes was significantly higher in wild-type mice than in Nrf2(-/-) mice. We have first demonstrated that disruption of Nrf2 enhances susceptibility to airway inflammatory responses induced by inhalation of low-dose DEP in mice. These results strongly suggest that DEP-induced oxidative stress and host antioxidant responses play some role in the development of DEP-induced airway inflammation.
Assuntos
Hiper-Reatividade Brônquica/etiologia , Suscetibilidade a Doenças , Inflamação/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Emissões de Veículos/toxicidade , Animais , Antioxidantes/metabolismo , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/análise , Indução Enzimática , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Inflamação/metabolismo , Exposição por Inalação , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Sistema Respiratório/imunologia , Sistema Respiratório/metabolismoRESUMO
We analysed the genotypes of 325 Mycobacterium tuberculosis clinical isolates obtained during 2002 throughout Japan. The genotyping methods included insertion sequence IS6110 RFLP, spoligotyping and variable number of tandem repeat (VNTR) analyses. Clustered isolates revealed by IS6110 RFLP analysis accounted for 18.5 % (60/325) of the isolates. Beijing genotype tuberculosis (TB) accounted for 73.8 % (240/325) of the isolates. Using VNTR, we analysed 35 loci, including 12 standard mycobacterial interspersed repetitive units and 4 exact tandem repeats. The discriminatory power of these 16 loci was low. Using VNTR analyses of the 35 loci, 12 loci (VNTRs 0424, 0960, 1955, 2074, 2163b, 2372, 2996, 3155, 3192, 3336, 4052 and 4156) were selected for the genotyping of Beijing genotype strains. Comparison of the discriminatory power of the 12-locus VNTR [Japan Anti-Tuberculosis Association (JATA)] to that of the 15-locus and 24-locus VNTRs proposed by Supply et al. (2006) showed that our established VNTR system was superior to the reported 15-locus VNTR and had almost equal discriminatory power to the 24-locus VNTR. This 12-locus VNTR (JATA) can therefore be used for TB genotyping in areas where Beijing family strains are dominant.
Assuntos
Técnicas de Tipagem Bacteriana , Surtos de Doenças , Repetições Minissatélites/genética , Mycobacterium tuberculosis/classificação , Reação em Cadeia da Polimerase/métodos , Tuberculose Pulmonar/epidemiologia , Elementos de DNA Transponíveis/genética , Genótipo , Humanos , Japão/epidemiologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Oligonucleotídeos/análise , Polimorfismo de Fragmento de Restrição , Tuberculose Pulmonar/microbiologiaRESUMO
The aim of this study was to classify the histopathological features of pigs infected with Mycobacterium avium complex (MAC). We used slaughtered pig organs systemically infected with MAC. The results showed granulomatous lesions which were observed predominantly in the digestive organs and regional lymph nodes rather than respiratory organs. The histological picture showed a wide range of granulomatous stages from exudative to fibrotic reactions to the MAC infection. Eosinophils and giant cells were characteristically observed in the exudative reactions. The histopathological type in primary focus tended to be maintained in the respective organs. Most strains with the same genotype showed pathogenicity for guinea pigs irrespective of the type of granuloma. Although these findings suggest that different stages of a granulomatous lesion originating from the same causative agent might influence histological patterns, other possibilities such as the hereditary background of the host, or the effects of viral infections should be considered.
Assuntos
Granuloma/veterinária , Fígado/patologia , Linfonodos/patologia , Complexo Mycobacterium avium/classificação , Infecção por Mycobacterium avium-intracellulare/veterinária , Doenças dos Suínos/patologia , Animais , Genótipo , Granuloma/microbiologia , Granuloma/patologia , Fígado/microbiologia , Linfonodos/microbiologia , Complexo Mycobacterium avium/genética , Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/patologia , Sus scrofa , Doenças dos Suínos/microbiologiaRESUMO
We recently showed that prenatal exposure to diesel exhaust (DE) disrupts spermatogenesis in mouse offspring. This study was undertaken to determine whether filtered DE in which 99.97% of diesel exhaust particles >0.3 microm in diameter were removed affects spermatogenesis in growing mice. After prenatal exposure to filtered DE for 2-16 days postcoitum, we examined daily sperm production (DSP), testicular histology, serum testosterone levels and mRNA expression of hormone synthesis process-related factors. In the filtered DE exposed group, DSP was markedly reduced at 12 weeks compared with the control group; clean air exposed group. Histological examination showed multinucleated giant cells and partial vacuolation in the seminiferous tubules of the exposed group. Testosterone was elevated significantly at 5 weeks. Moreover, luteinizing hormone receptor mRNA at 5 and 12 weeks, 17alpha-hydroxylase/C17-20-lyase and 17beta-hydroxysteroid dehydrogenase mRNAs at 12 weeks were significantly elevated. These results suggest that filtered DE retains its toxic effects on the male reproductive system following prenatal exposure.
Assuntos
Efeitos Tardios da Exposição Pré-Natal , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Emissões de Veículos/toxicidade , 17-Hidroxiesteroide Desidrogenases/efeitos dos fármacos , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células Gigantes/efeitos dos fármacos , Células Gigantes/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Tamanho da Partícula , Gravidez , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores do LH/efeitos dos fármacos , Receptores do LH/metabolismo , Túbulos Seminíferos/efeitos dos fármacos , Contagem de Espermatozoides , Esteroide 17-alfa-Hidroxilase/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/metabolismo , Testículo/metabolismo , Testosterona/sangue , Fatores de Tempo , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismoRESUMO
An association between diabetes mellitus and tuberculosis has been implicated for a long time. We have previously reported that Goto Kakizaki type 2 diabetic rats are highly susceptible to Mycobacterium (M.) tuberculosis infection. As a next step, we attempted to clarify whether type 1 diabetic rats are more susceptible to M. tuberculosis than non-diabetic wild-type (WT) rats. Here, we used the Komeda diabetes-prone (KDP) rat, as a model of type 1 diabetes mellitus. The infected KDP rats developed large granulomas without central necrosis in their lungs, liver or spleen. This was consistent with a significant increase in the number of colony-forming units (cfu) of M. tuberculosis in the lungs and spleen (p < 0.01). Insulin treatment resulted in significant reduction of tubercle bacilli in the infected KDP rats (p < 0.01). Pulmonary levels of interferon-gamma, tumor necrosis factor-alpha and interleukin-1beta mRNAs were higher in the infected diabetic rats than in WT rats. Alveolar macrophages from KDP rats were not fully activated by M. tuberculosis infection because the macrophages did not secrete nitric oxide (NO) that can kill M. tuberculosis (p < 0.01), but no significant difference in phagocytosis of tubercle bacilli by alveolar macrophages was observed between KDP and WT rats. Taken together, our findings indicate that type 1 diabetic rats are more susceptible to M. tuberculosis that WT rats.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Suscetibilidade a Doenças , Mycobacterium tuberculosis , Tuberculose/etiologia , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/microbiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/veterinária , Feminino , Glucose/farmacologia , Pulmão/microbiologia , Pulmão/patologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Óxido Nítrico/análise , Ratos , Ratos Endogâmicos , Ratos Long-Evans , Baço/microbiologia , Baço/patologia , Tuberculose/patologia , Tuberculose/veterináriaRESUMO
PURPOSE: The discriminatory power of each locus in variable numbers of tandem repeats (VNTR) analyses was evaluated for development of the genotyping method of Mycobacterium tuberculosis (TB) in Japan. METHOD: By using 325 TB strains collected from whole Japan and 24 mass infection cases (74 isolates), IS6110 restriction fragment length polymorphism (RFLP), spoligotyping and VNTR (35 loci) were analyzed. RESULTS AND DISCUSSION: We excluded 4 loci (VNTRs 2163a, 3232, 3820, and 4120) and selected in top 12 loci (VNTRs 0424, 0960, 1955, 2074, 2163b, 2372, 2996, 3155, 3192, 3336, 4052, and 4156). The cluster rate of IS6110 RFLP was higher than that of 12-locus [Japan Anti-Tuberculosis Association (JATA)] VNTR. And in comparison of the discriminatory power of 12-locus JATA VNTR and that of Supply (15)-VNTR, the JATA (12)-VNTR was superior, even though less loci analyses. Therefore, this JATA (12)-VNTR could be used for TB genotyping in areas where Beijing strains are prevalent.