RESUMO
The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l-DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Mesencéfalo/fisiopatologia , Transtornos dos Movimentos/fisiopatologia , Estresse Oxidativo/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Antidiscinéticos/farmacologia , Morte Celular/fisiologia , Citosol/efeitos dos fármacos , Citosol/metabolismo , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Levodopa/farmacologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Destreza Motora/efeitos dos fármacos , Destreza Motora/fisiologia , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/patologia , Transtornos Parkinsonianos/fisiopatologia , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
The arctic tundra and boreal forest were once considered the last frontiers on earth because of their vast expanses remote from agricultural land-use change and industrial development. These regions are now, however, experiencing environmental and social changes that are as rapid as those occurring anywhere on earth. This paper summarizes the role of northern regions in the global system and provides a blueprint for assessing the factors that govern their sensitivity to social and environmental change.
Assuntos
Conservação dos Recursos Naturais , Efeito Estufa , Árvores , Regiões Árticas , Ecossistema , Poluentes Ambientais/intoxicação , Condições SociaisRESUMO
Mortality related to bacteremic pneumonia remains high, and the role of sepsis in inflammation, pulmonary injury, and death remains unclear, mostly in leukopenic states. In the present study, the microbiology, histopathology, and host response to Streptococcus pneumoniae and Klebsiella pneumoniae infection were determined in an experimental model of bacteremia in immunocompetent and leukopenic mice. Leukocyte depletion by cyclophosphamide did not impair the early clearance of pneumococci from blood but facilitated growth in lungs. By contrast, klebsiellae rapidly grew in blood of leukopenic mice. These observations suggest that tissue-based phagocytes and circulating leukocytes, respectively, play prominent roles in S. pneumoniae and K. pneumoniae eradication. The kinetics of leukocyte recruitment in lungs during S. pneumoniae bacteremia suggested early strong inflammation in immunocompetent mice that is associated with tumor necrosis factor alpha release and histological disorders, including cell debris and surfactant in alveolar spaces. Leukocyte depletion further stimulated pulmonary capillary leakage both in S. pneumoniae and K. pneumoniae bacteremia, which seemed attributable to bacterial virulence factors. Nitric oxide production did not differ significantly among groups. Leukopenia and low platelet counts characterized the late stage of bacteremia for both strains, but only K. pneumoniae altered renal function. Understanding the pathogenesis of bacteremia will help establish beneficial therapies for both sepsis and pneumonia.
Assuntos
Bacteriemia/fisiopatologia , Infecções por Klebsiella/fisiopatologia , Klebsiella pneumoniae/imunologia , Infecções Pneumocócicas/fisiopatologia , Streptococcus pneumoniae/imunologia , Animais , Bacteriemia/imunologia , Bacteriemia/microbiologia , Sangue/microbiologia , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Testes Hematológicos , Imunocompetência , Mediadores da Inflamação/metabolismo , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/crescimento & desenvolvimento , Contagem de Leucócitos , Leucopenia , Pulmão/irrigação sanguínea , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Streptococcus pneumoniae/crescimento & desenvolvimentoRESUMO
Pneumococcal pneumonia still is associated with a high mortality rate, despite appropriate antimicrobial therapy. Many gaps remain in the understanding of the pathogenesis of this deadly infection. The microbial and inflammatory events that characterize survival or death after intranasal inoculation of mice with an LD(50) inoculum of Streptococcus pneumoniae were investigated. Survival was associated with rapid bacterial clearance and low inflammation (surfactant and red blood cells in alveoli), but no neutrophil recruitment or lung tissue injury was noted. By contrast, death was preceded by strong bacterial growth that peaked 48 h after the infection and was associated with gradual increases in pulmonary levels of interleukin-6, macrophage inflammatory protein (MIP)-1alpha, MIP-2, monocyte chemoattractant protein-1, KC, and neutrophil recruitment. The injection of tumor necrosis factor-alpha or the addition of lipopolysaccharide or heat-killed S. pneumoniae to the inoculum enhanced early host response and survival. These observations may help develop appropriate markers of evolution of pneumonia, as well as new therapeutic strategies.
Assuntos
Pulmão/imunologia , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/fisiopatologia , Streptococcus pneumoniae/fisiologia , Animais , Formação de Anticorpos , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Quimiocina CCL2/análise , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CXCL2 , Fatores Quimiotáticos/análise , Escherichia coli/imunologia , Feminino , Inflamação , Interleucina-6/análise , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Proteínas Inflamatórias de Macrófagos/análise , Camundongos , Monocinas/análise , Neutrófilos/fisiologia , Pneumonia Pneumocócica/imunologia , Proteínas Recombinantes/farmacologia , Streptococcus pneumoniae/crescimento & desenvolvimento , Fatores de Tempo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
STUDY DESIGN: A prospective double-blind randomized controlled trial was performed. OBJECTIVE: To assess the efficacy of percutaneous radiofrequency articular facet denervation for low back pain. SUMMARY OF BACKGROUND DATA: Uncontrolled observational studies in patients with low back pain have reported some benefits from the use of facet joint radiofrequency denervation. Because the efficacy of percutaneous radiofrequency had not been clearly shown in previous studies, a randomized controlled trial was conducted to assess the efficacy of the technique for improving functional disabilities and reduce pain. METHODS: For this study, 70 patients with low back pain lasting of more than 3 months duration and a good response after intraarticular facet injections under fluoroscopy were assigned randomly to receive percutaneous radiofrequency articular facet denervation under fluoroscopic guidance or the same procedure without effective denervation (sham therapy). The primary outcomes were functional disabilities, as assessed by the Oswestry and Roland-Morris scales, and pain indicated on a visual analog scale. Secondary outcomes included spinal mobility and strength. RESULTS: At 4 weeks, the Roland-Morris score had improved by a mean of 8.4% in the neurotomy group and 2.2% in the placebo group, showing a treatment effect of 6.2% (P = 0.05). At 4 weeks, no significant treatment effect was reflected in the Oswestry score (0.6% change) or the visual analog pain score (4.2% change). At 12 weeks, neither functional disability, as assessed by the Roland-Morris scale (2.6% change) and Oswestry scale (1.9% change), nor the pain level, as assessed by the visual analog scale (-7.6% change), showed any treatment effect. CONCLUSIONS: Although radiofrequency facet joint denervation may provide some short-term improvement in functional disability among patients with chronic low back pain, the efficacy of this treatment has not been established.
Assuntos
Ablação por Cateter/métodos , Denervação/métodos , Dor Lombar/terapia , Articulação Zigapofisária/inervação , Adulto , Idoso , Pessoas com Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Placebos , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Host-derived chemoattractant factors are suggested to play crucial roles in leukocyte recruitment elicited by inflammatory stimuli in vitro and in vivo. However, in the case of acute bacterial infections, pathogen-derived chemoattractant factors are also present, and it has not yet been clarified how cross-talk between chemoattractant receptors orchestrates diapedesis of leukocytes in this context of complex chemoattractant arrays. To investigate the role of chemokine (host-derived) and formyl peptide (pathogen-derived) chemoattractants in leukocyte extravasation in life-threatening infectious diseases, we used a mouse model of pneumococcal pneumonia. We found an increase in mRNA expression of eight chemokines (RANTES, macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta, MIP-2, IP-10, monocyte chemoattractant protein (MCP)-1, T cell activation 3, and KC) within the lungs during the course of infection. KC and MIP-2 protein expression closely preceded pulmonary neutrophil recruitment, whereas MCP-1 protein production coincided more closely than MIP-1alpha with the kinetics of macrophage infiltration. In situ hybridization of MCP-1 mRNA suggested that MCP-1 expression started at peribronchovascular regions and expanded to alveoli-facing epithelial cells and infiltrated macrophages. Interestingly, administration of a neutralizing Ab against MCP-1, RANTES, or MIP-1alpha alone did not prevent macrophage infiltration into infected alveoli, whereas combination of the three Abs significantly reduced macrophage infiltration without affecting neutrophil recruitment. The use of an antagonist to N-formyl peptides, N-t-Boc-Phe-D-Leu-Phe-D-Leu-Phe, reduced both macrophages and neutrophils significantly. These data demonstrate that a complex chemokine network is activated in response to pulmonary pneumococcal infection, and also suggest an important role for fMLP receptor in monocyte/macrophage recruitment in that model.
Assuntos
Quimiocinas/fisiologia , Quimiotaxia de Leucócito/imunologia , Macrófagos/imunologia , Monócitos/imunologia , N-Formilmetionina Leucil-Fenilalanina/imunologia , Pneumonia Pneumocócica/imunologia , Animais , Especificidade de Anticorpos , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Quimiocina CCL2/fisiologia , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CCL5/biossíntese , Quimiocina CCL5/genética , Quimiocina CCL5/fisiologia , Quimiocinas/biossíntese , Quimiocinas/genética , Quimiocinas CC/imunologia , Modelos Animais de Doenças , Feminino , Soros Imunes/fisiologia , Hibridização In Situ , Proteínas Inflamatórias de Macrófagos/biossíntese , Proteínas Inflamatórias de Macrófagos/genética , Proteínas Inflamatórias de Macrófagos/fisiologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Monócitos/metabolismo , Monócitos/patologia , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Pneumonia Pneumocócica/patologia , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , RNA Mensageiro/biossíntese , Receptores de Formil Peptídeo , Receptores Imunológicos/antagonistas & inibidores , Receptores de Peptídeos/antagonistas & inibidoresRESUMO
In the 'Des Vieux Arbres' ecological reserve situated within northwestern Quebec, 40 band dendrometers were installed on 7 of the major boreal tree species. The late Spring-early Summer daily radial activity registered in 1997 was related to daily weather variables. For each tree species, the daily mean i) cumulative radial increment and ii) radial activity indexed series obtained by first-difference standardization were analyzed. The results indicate the existence of strong similarities among the 7 species. All showed strong synchronous fluctuations in radius during late winter and early spring. This period ended with a short but sharp increase in radial increments that marked the passage of water into the stem. This initial swelling, less obvious in Pinus species was followed by a prolonged period of little change in radial activity. Meteorological data indicated that air temperature was positively related to stem swelling during the late winter-early spring period. Both air and soil temperatures became negatively related to radial expansion once the passage of water has occurred in the stem. Starting in early June, all species registered a sustained increase in radial increments possibly associated with active cell division. After this, radial expansion was negatively related to air temperature and positively to rainfall.
Assuntos
Clima , Árvores/crescimento & desenvolvimento , Monitoramento Ambiental , Estações do Ano , Solo , Temperatura , Árvores/fisiologiaRESUMO
Patients still die from Streptococcus pneumoniae pneumonia after initiation of antibiotic therapy, when tissues are sterile and the pneumonia is clearing. There is growing evidence that overwhelming inflammation resulting from toxin release contributes to tissue injury, shock, and death. Monitoring host response may help us understand the consequences of antibiotic therapy for the inflammatory processes that occur in bacterial pneumonia. HMR 3004 is a ketolide that displays excellent in vitro activity against S. pneumoniae. In the present experiment, we investigated the chronology of inflammatory events that occur during pneumococcal pneumonia in mice treated with HMR 3004. Infection of mice with 10(7) CFU of living S. pneumoniae resulted in 100% mortality within 5 days. HMR 3004 given at 12.5 mg/kg of body weight/dose twice daily from 48 h postinfection achieved complete bacterial clearance from lungs and blood within 36 h and ensured survival of mice. Recruitment of neutrophils and monocytes from blood to lungs was significantly reduced, and nitric oxide release was totally prevented. Interleukin-6 secretion in lungs and blood became rapidly undetectable after initiation of therapy. Histological examination of lung tissue showed protection of interstitium against edema. By controlling bacterial invasion, HMR 3004 led to rapid and profound modifications of the host response in lungs, which may protect mice from deleterious inflammatory reactions.
Assuntos
Antibacterianos/uso terapêutico , Inflamação/microbiologia , Inflamação/patologia , Cetolídeos , Macrolídeos , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/patologia , Streptococcus pneumoniae/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Interleucina-6/metabolismo , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Neutrófilos/metabolismo , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Fagócitos/efeitos dos fármacos , Fagócitos/microbiologia , Fagócitos/patologia , Infecções Pneumocócicas/tratamento farmacológico , Edema Pulmonar/microbiologia , Edema Pulmonar/prevenção & controle , Análise de SobrevidaRESUMO
The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in a murine model of pneumococcal pneumonia was examined. Intranasal inoculations were 10(7) cfu/mouse (high inoculum) and 5 x 10(4) cfu/mouse (low inoculum) of Streptococcus pneumoniae, which induced severe or mild lung inflammation, respectively. With the low inoculum, rhG-CSF significantly improved survival when initiated 24 h or 10 min before, but not when initiated 24 h after, infection. Pretreatment with rhG-CSF significantly increased myeloperoxidase (MPO) activity in lungs 8 h after the infection and increased circulating neutrophil count 24, 48, and 72 h after infection. In contrast, rhG-CSF did not improve survival of animals infected with the high inoculum and did not increase MPO activity or neutrophil count in blood over those of sham-treated controls. These data strongly suggest that the severe inflammatory response typically observed in pneumococcal pneumonia recruits a maximum number of neutrophils in the lungs and thus masks the beneficial effect of rhG-CSF.
Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Pulmão/efeitos dos fármacos , Pneumonia Pneumocócica/tratamento farmacológico , Streptococcus pneumoniae , Animais , Modelos Animais de Doenças , Feminino , Humanos , Contagem de Leucócitos , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Neutrófilos/imunologia , Peroxidase/metabolismo , Pneumonia Pneumocócica/sangue , Pneumonia Pneumocócica/metabolismo , Fatores de TempoRESUMO
Interleukin (IL)-10 is a biologically active anti-inflammatory and immunomodulatory cytokine. The respective effects or combined effect of ceftriaxone (Ctri) and IL-10 on host response was studied in a mouse model of lethal pneumococcal pneumonia. A once daily intraperitoneal (ip) injection of IL-10 (1 microg/mouse) for 2 days did not affect inflammation but accelerated bacterial dissemination to the bloodstream. Of mice treated with 1 ip 20 mg/kg Ctri injection, 40% developed septicemia, and only 52% survived. However, the addition of IL-10 to Ctri enhanced bacterial clearance, prevented septicemia, and yielded a 95% survival rate (P<.001). This approach also significantly (P<.05) decreased IL-1beta, IL-6, macrophage inflammatory protein-2, and myeloperoxidase levels in lungs and the production of nitric oxide in bronchoalveolar lavage fluid. Furthermore, Ctri plus IL-10 significantly (P<.05) reduced pulmonary vascular leakage and the appearance of red blood cells in alveoli. These data indicate a beneficial role for IL-10 as an adjunctive therapy to antibiotics against pneumococcal pneumonia.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Ceftriaxona/uso terapêutico , Quimiocinas/análise , Citocinas/análise , Interleucina-10/uso terapêutico , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/fisiopatologia , Circulação Pulmonar/efeitos dos fármacos , Sepse/prevenção & controle , Animais , Permeabilidade Capilar/fisiologia , Feminino , Inflamação , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Pneumonia Pneumocócica/mortalidade , Pneumonia Pneumocócica/patologia , Circulação Pulmonar/fisiologia , Taxa de SobrevidaRESUMO
The effectiveness of ziracin (SCH27899), a novel everninomicin, was at first investigated against lethal pneumonia caused by a penicillin-susceptible Streptococcus pneumoniae strain. A single intravenous injection of ziracin at a dose of 60 mg/kg of body weight given at 18 h postinfection protected 100% mice and led to the complete clearance of bacteria from their lungs. The activity of ziracin was observed to be the same as that of ceftriaxone: the 50% protective doses (PD(50)s) of ziracin and ceftriaxone were 24.8 and 24.6 mg/kg, respectively. Evaluation of this therapy with leukopenic mice showed that a single injection of ziracin protected 75% of these mice. A delay in therapy with ziracin, which was initiated at 48 h postinfection with 30 mg/kg given once daily for 3 days, resulted in an 83% survival rate of immunocompetent mice. The efficacy of ziracin was further compared to that of vancomycin against lethal pneumonia caused by a penicillin-resistant S. pneumoniae strain in leukopenic mice. The PD(50)s of ziracin and vancomycin were 40.5 and 44.2 mg/kg, respectively. Treatment with ziracin at 30 mg/kg once daily for 2 days (initiated 18 h postinfection) yielded an 83% survival rate and achieved complete eradication of the bacteria. The results were the same as those obtained with vancomycin administered at 15 mg/kg twice daily for 2 days. It is notable that the high survival rates for mice treated with ziracin were associated with effective eradication of the bacteria and rapid recovery of pulmonary tissues from pneumonia. The pharmacokinetic properties of ziracin, ceftriaxone, and vancomycin were estimated following intravenous administration of a single dose of 30 mg/kg to immunocompetent mice. The half-life of ziracin was observed to be longer than those of ceftriaxone and vancomycin (2.3 h versus 1.0 and 0.36 h in the bloodstream and 3 h versus 1.9 and 0. 45 h in lung tissues). The areas under the concentration-time curves (AUCs) in lung tissue for ziracin versus those for ceftriaxone and vancomycin were 36 microg. h/g versus 20 and 9.5 microg. h/g. The prolonged half-life and high AUC for ziracin in tissue contributed to its excellent in vivo activities.
Assuntos
Aminoglicosídeos , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Pneumonia Pneumocócica/tratamento farmacológico , Animais , Ceftriaxona/farmacocinética , Ceftriaxona/uso terapêutico , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapêutico , Feminino , Leucopenia/complicações , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Testes de Sensibilidade Microbiana , Resistência às Penicilinas , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/patologia , Teste Bactericida do Soro , Streptococcus pneumoniae/efeitos dos fármacos , Análise de Sobrevida , Vancomicina/farmacocinética , Vancomicina/uso terapêuticoRESUMO
Studies of pollen source areas of closed-canopy sites are contradictory. Some authors found that closed-canopy sites mainly collect local pollen while others found more distant sources. This dichotomy might stem from the use of canopies of varying degrees of closure, and from variations in the pollen productivity of the local vegetation and the background pollen rain. Here, 30 islands were used to evaluate the pollen sources of closed-canopy sites. We compared pollen with the forest inventory in three quadrat sizes: 100, 400m(2) and on the whole island. Regression analyses showed that most pollen of Picea spp., Pinus spp., and Betula spp. comes from within the 400m(2) quadrat. Abies balsamea and Thuja occidentalis showed no relationship with vegetation in any of the quadrats considered, suggesting a more regional source. Insularity and island size are important factors influencing the pollen source area; correlations were stronger on islands located 120050ha. These results suggest that closed-canopy sites on islands may be useful in stand-level vegetation history reconstruction through pollen analysis, but that caution must be exercised in separating the local and regional signals.
RESUMO
Encapsulated Klebsiella pneumoniae strains frequently induce fatal nosocomial pneumonia. Cefodizime (CEF) as an antibiotic is suspected to enhance host resistance against various microbial invasions through interactions with bacteria and host cells. To investigate the influence of CEF on the pulmonary response to Klebsiella that does not merely result from direct bacterial clearance by the drug, we inoculated mice with heat-killed fluorescein isothiocyanate-labeled K. pneumoniae. CEF upregulated (P < 0.01) the early Klebsiella-induced secretion of tumor necrosis factor alpha, as well as the number (P < 0.01) and phagocytic efficacy (P < 0.001) of alveolar macrophages. By contrast, the late polymorphonuclear neutrophil recruitment (P < 0.05) and levels of interleukin-1 alpha (IL-1alpha) (P < 0.05) and IL-6 (P < 0.05) were reduced. The stimulation of an early immune response by CEF followed by late reduction in inflammation may be beneficial against bacterial pneumonia.
Assuntos
Cefotaxima/análogos & derivados , Cefalosporinas/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/química , Cefotaxima/farmacologia , Cefotaxima/uso terapêutico , Cefalosporinas/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/microbiologia , Injeções Subcutâneas , Interleucinas/metabolismo , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Camundongos , Neutrófilos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
It has recently become apparent that inflammatory reactions including nitric oxide (NO) release contribute to the outcome of pulmonary infections. To investigate the effect of N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor, on the pathogenesis of pneumococcal pneumonia, we inoculated CD(1) Swiss mice with 10(7) CFU of Streptococcus pneumoniae. Treatment with two daily subcutaneous injections of 3 mg of L-NMMA per kg of body weight (over a 5-day period) reproducibly delayed mortality, as the number of surviving mice 72, 84, and 96 h after infection was increased by 16.8% (P < 0.05), 25.0% (P < 0.005), and 11.5% (P < 0. 05), respectively. In fact, the following chronology of events was noted in L-NMMA-treated infected animals, compared to the untreated infected controls. (i) At 12 to 24 h after infection, larger amounts of leukotriene B(4) in bronchoalveolar lavage (BAL) fluid associated with greater neutrophilia in lung tissue and alveolar spaces and more persistent release of tumor necrosis factor alpha, interleukin-1 alpha (IL-1alpha), and IL-6 were observed. (ii) At 24 to 72 h, there was better preservation of lung ultrastructure, including reduction of edema in the interstitium and protection of alveolar spaces, despite identical bacterial growth in lungs, in L-NMMA-treated infected animals than in untreated animals. (iii) At 72 to 96 h, the death rate was delayed, despite the absence of antibiotic therapy. In our experiment, partial blockade of NO release was achieved. These data indicate that NO plays an important role in the induction of tissue injury and death during pneumococcal pneumonia and that L-NMMA is helpful for host protection.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Pneumonia Pneumocócica/terapia , ômega-N-Metilarginina/uso terapêutico , Animais , Líquido da Lavagem Broncoalveolar/química , Feminino , Interleucinas/metabolismo , Leucotrieno B4/metabolismo , Camundongos , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Pneumonia Pneumocócica/etiologia , Pneumonia Pneumocócica/metabolismo , Pneumonia Pneumocócica/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We investigated the influence of HMR 3004, a new ketolide antibiotic, on the pulmonary inflammation induced by heat-killed fluorescein isothiocyanate-labeled Streptococcus pneumoniae. HMR 3004 downregulated (P < 0.05) the pneumococcus-induced release of interleukin-6 (IL-6), IL-1beta, and nitric oxide in bronchoalveolar lavage fluid. The drug limited (P < 0.05) neutrophil recruitment to lung tissues and alveoli but did not interfere with phagocytosis. HMR 3004 totally abrogated lung edema. By reducing inflammation in addition to possessing antimicrobial properties, HMR 3004 may participate in improving the outcome of bacterial pneumonia.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antibacterianos/farmacologia , Inflamação/imunologia , Cetolídeos , Macrolídeos , Streptococcus pneumoniae/imunologia , Adjuvantes Imunológicos/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interleucinas/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
It has recently become apparent that overwhelming inflammatory reactions contribute to the high mortality rate associated with pneumococcal infection in immunocompetent hosts. Cefodizime (CEF) is an antibiotic that seems to be endowed with immunomodulating properties. To investigate the influence of CEF on the pulmonary inflammatory response induced by Streptococcus pneumoniae, we infected mice with repeated intranasal inoculations of 10(7) CFU of heat-killed fluorescein isothiocyanate-labeled bacteria, which are insensitive to the killing properties of the drug. CEF downregulated but did not abolish the strong polymorphonuclear leukocyte (PMN) recruitment induced by S. pneumoniae. PMN recruitment was not primarily mediated by leukotriene B4 in this model. The drug did not interfere with intrinsic mechanisms of phagocytosis by PMNs and alveolar macrophages. CEF totally abrogated the pneumococcus-induced tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) secretion in bronchoalveolar lavage fluid. The drug also prevented IL-6 release in lung homogenates and partly inhibited TNF-alpha, but it did not interfere with IL-1alpha secretion in the lungs of infected mice. The fractional and selective downregulation of inflammatory cells and cytokines by CEF suggests cell-specific and intracellular specific mechanisms of interaction of the drug. The immunomodulatory properties of CEF may help restrain excessive inflammatory reactions, thus contributing to the reported good clinical efficacy of the drug against lower respiratory tract infections.
Assuntos
Cefotaxima/análogos & derivados , Cefalosporinas/uso terapêutico , Pneumonia Pneumocócica/tratamento farmacológico , Animais , Cefotaxima/uso terapêutico , Citocinas/metabolismo , Feminino , Mediadores da Inflamação/fisiologia , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Fagocitose/efeitos dos fármacos , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/patologiaRESUMO
The sequential pathogenesis of pulmonary aspergillosis was studied and the role of inflammatory cytokines in host response to Aspergillus fumigatus was characterized in immunocompetent and immunosuppressed mice. Two distinct phases were observed in immunocompetent mice: First, an intense clearance of A. fumigatus occurred, possibly through alveolar macrophages and recruited neutrophils (PMNL), accompanied by rapid release of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1beta, and second, cellular and fungal debris were cleaned by recruited monocytes, cytokine production rapidly decreased, and pneumonia self-healed. In contrast, cortisone-treated animals had, first, an altered clearance of conidia and delayed cytokine production and inflammatory cell recruitment; second, an invasive process in lungs, recruitment of PMNL, and release of IL-6 and IL-1beta; and third, widespread tissue necrosis, sustained release of IL-6 and IL-1beta, further increases in PMNL trafficking but no monocyte recruitment, respiratory failure, and 100% mortality within 5 days. These insights may be useful in the development of new treatment strategies for pulmonary aspergillosis.
Assuntos
Corticosteroides/farmacologia , Aspergilose/imunologia , Aspergillus fumigatus/imunologia , Terapia de Imunossupressão , Pneumopatias Fúngicas/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Cinética , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
There is a need for more insight into the pathogenesis of Streptococcus pneumoniae pneumonia, as the fatality rate associated with this disease remains high despite appropriate antibiotherapy. The host response to pneumococci was investigated after intranasal inoculation of CD1 mice with 10(7) log-phase CFU of bacteria. We identified five major pathogenesis steps from initial infection to death. In step 1 (0 to 4 h), there was ineffective phagocytosis by alveolar macrophages, with concurrent release of tumor necrosis factor alpha (TNF), interleukin-6 (IL-6), and nitric oxide (NO) in bronchoalveolar lavage (BAL) fluid, TNF, IL-6, and interleukin-1 alpha (IL-1) in lung tissues, and IL-6 in serum, which were associated with tachypnea and hemoconcentration. In step 2 (4 to 24 h), bacterial growth in alveoli and polymorphonuclear cell recruitment from bloodstream to lung tissue (high myeloperoxidase levels) to alveoli were associated with high release of all three cytokines and leukotriene B4 (LTB4) in tissue and BAL fluid, as well as transient spillover of IL-1 in serum. In step 3 (24 to 48 h), despite downregulation of TNF and IL-1 in BAL fluid and lungs, there was appearance of injury to alveolar ultrastructure, edema to interstitium, and increase in lung weight as well as regeneration of type II pneumocytes and increased secretion of surfactant; bacteria progressed from alveoli to tissue to blood, and body weight loss occurred. In step 4 (48 to 72 h), strong monocyte recruitment from blood to alveoli was associated with high NO release in tissue and BAL fluid, but there was also noticeable lymphocyte recruitment and leukopenia; bacteremia was associated with TNF and IL-6 release in blood and thrombocytopenia. In step 5 (72 to 96 h), severe airspace disorganization, lipid peroxidation (high malondialdehyde release in BAL fluid), and diffuse tissue damage coincided with high NO levels; there was further increase in lung weight and bacterial growth, loss in body weight, and high mortality rate. Delineation of the sequential steps that contribute to the pathogenesis of pneumococcal pneumonia may generate markers of evolution of disease and lead to better targeted intervention.
Assuntos
Citocinas/biossíntese , Pneumonia Pneumocócica/imunologia , Animais , Feminino , Mediadores da Inflamação/fisiologia , Pulmão/patologia , Camundongos , Neutrófilos/imunologia , Óxido Nítrico/fisiologia , Pneumonia Pneumocócica/patologiaRESUMO
While forest ecosystem classification work in Quebec has traditionally concentrated on inventory and mapping, more effort is now being placed on developing field guides similar to those produced in other Canadian provinces. As part of a project to produce a practical forest ecosystem field guide for the Amos Lowlands Ecological Region in northwestern Quebec, existing sub-regional ecological studies were exploited in order to develop a regional classification of forest ecosystems, or forest stations. Review of four fundamental studies provided a list of 107 ecological phases, each representing a particular combination of forest composition, surface deposit type and moisture regime. A series of silvicultural and environmental interpretations were developed and values for each were attributed to the ecological phases. Cluster analysis was then performed to classify phases into 29 broader units. A large, regional biophysical database which became available later in the project provided a means of validating and effectively modifying the classification. The justifications for using the original approach are discussed.
RESUMO
In Quebec, forest stations are defined as forest units that are reasonably homogeneous in terms of forest composition and site characteristics - as expressed by surficial deposit and moisture regime - and within which similar operational constraints for silvicultural potential and productivity levels may be expected. In the course of developing a field guide to the forest stations of the Amos Lowlands Ecological Region in northwestern Quebec, classifications of 12 site types and 72 forest stations (38 forest cover types or 16 general cover types) were developed. The classifications were based on a hybrid approach involving cluster analysis of forest ecological units inventoried in subregional studies, classical classification and ordination analyses performed on a regional biophysical inventory database, and empirically associating forest cover types to site types. The guide, while similar to other published forest ecosystem classification guides, emphasizes forest dynamics by presenting forest stations common to a given site type according to their successional stage. Field keys and general interpretations of forest potential and operational constraints are included in the guide. A summary description of the guide and accompanying documents is provided. A first draft has been distributed recently for feedback from industrial and government foresters and researchers in the region. Analyses of inventory data is continuing and modifications will be incorporated into a second draft before publication in 1995.