RESUMEN
SETTING: The World Health Organization (WHO) recommends that multidrug-resistant tuberculosis (MDR-TB) treatment should be managed in collaboration with multidisciplinary advisory committees (consilia). A formal national Consilium has been established in France since 2005 to provide a centralised advisory service for clinicians managing MDR-TB and extensively drug-resistant (XDR-TB) cases.OBJECTIVE: Review the activity of the French TB Consilium since its establishment.DESIGN: Retrospective description and analysis of the activity of the French TB Consilium.RESULTS: Between 2005 and 2016, 786 TB cases or contacts of TB cases were presented at the French TB Consilium, including respectively 42% and 79% of all the MDR-TB and XDR-TB cases notified in France during this period. Treatment regimens including bedaquiline and/or delamanid were recommended for 42% of the cases presented at the French TB Consilium since 2009. Patients were more likely to be presented at the French TB Consilium if they were born in the WHO Europe Region, had XDR-TB, were diagnosed in the Paris region, or had resistance to additional drugs than those defining XDR-TB.CONCLUSION: The French TB Consilium helped supervise appropriate management of MDR/XDR-TB cases and facilitated implementation of new drugs for MDR/XDR-TB treatment.
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Comités Consultivos/organización & administración , Antituberculosos/administración & dosificación , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Notificación de Enfermedades , Femenino , Francia , Humanos , Comunicación Interdisciplinaria , Masculino , Estudios RetrospectivosRESUMEN
UNLABELLED: Few data are available on the impact of a tuberculosis exposure on newborns in a maternity ward. OBJECTIVES: To describe the screening and clinical course of infants exposed during the neonatal period to a caregiver with bacillary tuberculosis. PATIENTS AND METHODS: Infants exposed during the postnatal period in a maternity unit in Paris, from March to August 2005, to a caregiver with bacillary tuberculosis were included in a standardized screening protocol. The screening performed at baseline (M0) and at 3 months (M3) included a clinical evaluation, a tuberculin skin test (TST), and a chest X-ray. A preventive treatment for tuberculosis with isoniazid and rifampicin for 3 months was systematically proposed. RESULTS: At M0, 182 of the 217 infants (84%) with significant exposure were evaluated. Data were available for 172 infants. The median age at M0 was 4.9 months (IQR=3.8-6.2). At M0, 4 of 172 infants (2.3%) had latent TB infection. Between M0 and M3, 19 infants (11%) were lost to follow-up and 1 on 153 developed a latent TB infection. No cases of tuberculosis disease were diagnosed. The treatment was administered properly in 83% of cases and side effects were observed in 11% of infants without any serious adverse event. Four infants received no treatment and 11 stopped their treatment prematurely. CONCLUSION: In the absence of neonatal massive exposure, although low (2.9%), the risk of latent TB infection requires close monitoring of the infants exposed. However, in the context of a mild exposure in the maternity unit, surveillance without systematic initiation of TB preventive treatment could be discussed.
Asunto(s)
Infección Hospitalaria/transmisión , Transmisión de Enfermedad Infecciosa de Profesional a Paciente , Tuberculosis Latente/transmisión , Tamizaje Masivo , Tuberculosis Pulmonar/transmisión , Antituberculosos/uso terapéutico , Estudios de Cohortes , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/prevención & control , Femenino , Estudios de Seguimiento , Humanos , Lactante , Isoniazida/uso terapéutico , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/prevención & control , Masculino , Radiografías Pulmonares Masivas , Servicio de Ginecología y Obstetricia en Hospital , Paris , Rifampin/uso terapéutico , Factores de Riesgo , Prueba de Tuberculina , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/prevención & controlRESUMEN
SETTING: Drug-resistant tuberculosis (DR-TB) is increasing worldwide and may be a source of diagnostic and therapeutic problems in young exposed children. In France exposed children are systematically treated with 3-month isoniazid-rifampicin prophylaxis. OBJECTIVE: To describe the characteristics and management of children aged <2 years in contact with an adult case of DR-TB in France over a 5-year period (2004-2008). METHODS: Children were retrospectively identified by sending questionnaires to all the members of the Paediatric Infectious Diseases Group and the Paediatric Pulmonology Group of the French Paediatric Society. RESULTS: Ten children, all infants, in contact with an adult case of DR-TB were identified: six cases of DR-TB (mean age 4.6 months), one case of TB infection and three cases of exposure (mean age 3.1 months). The children were mainly in contact with poly- or multidrug-resistant TB. Time to initiation of appropriate treatment was 39 days for TB disease and 58 days for TB infection or exposure. One child with TB infection developed TB disease due to failure to adapt prophylaxis. Treatment was variable and centre-dependent. Short-term follow-up showed complete recovery of all children. CONCLUSION: Management of young children in contact with adult DR-TB requires rapid identification of the drug resistance profile. Molecular techniques should be used to reduce delays in initiating appropriate treatment.
Asunto(s)
Antituberculosos/uso terapéutico , Isoniazida/uso terapéutico , Rifampin/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/prevención & control , Adulto , Quimioterapia Combinada , Estudios de Seguimiento , Francia , Humanos , Lactante , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Tuberculosis Resistente a Múltiples Medicamentos/microbiologíaRESUMEN
Tuberculin skin test is still the only proven method for identifying infection wtih M. tuberculosis in persons who do not have active disease. Targeted tuberculin testing for latent tuberculosis infection is a strategic component of tuberculosis control in low prevalence countries. This report describes indication, technical method, interpretation of this test and guidelines when the tuberculin test is positive.
Asunto(s)
Guías de Práctica Clínica como Asunto , Prueba de Tuberculina , Tuberculosis Pulmonar/diagnóstico , Antituberculosos/uso terapéutico , Niño , Protección a la Infancia , Humanos , Planificación de Atención al Paciente , Tuberculosis Pulmonar/tratamiento farmacológicoRESUMEN
Progression of pulmonary sarcoidosis in children remains poorly documented. The aim of this work was to gather follow-up information on pulmonary outcomes in children with sarcoidosis and to obtain data of relevance to a discussion of the optimal length and regimen of glucocorticoid therapy. In the present study, the authors experience of pulmonary sarcoidosis in 21 children referred to the paediatric pulmonary department over a 10-yr period is reported with a documented follow-up of at least 4 yr. Evaluation of the disease during the follow-up included analysis of clinical manifestations, chest radiographs, pulmonary function tests with measurements of the vital capacity (VC), dynamic lung compliance (CL,dyn), lung transfer for CO (TL,CO), and arterial blood gases, as well as bronchoalveolar lavage (BAL) with determination of total and differential cell counts. After initial evaluation the decision was a careful observation of four children without therapy. Corticosteroid treatment was initiated in 17 children. Analysis of results indicated that after 6-12 months of treatment most clinical manifestations of the disease and chest radiograph abnormalities disappeared, and beneficial effects on VC and TL,CO were apparent. After 18 months of steroids no benefit on pulmonary function tests could be noticed, with mainly persistence of alterations of CL,dyn. Results of BAL studies documented the presence of an alveolitis with increased lymphocyte populations throughout the follow-up. Relapses were observed in four children during tapering of prednisone; they were not reported after discontinuation of steroid therapy. Taken together data obtained in the presented population can lead to the following suggestions for the management of pulmonary sarcoidosis in children. BAL should be performed at the initial evaluation to document alveolitis; however, nothing seems to be gained from repeating this investigation during follow-up in the absence of specific reasons. Once the decision to initiate glucocorticoid therapy is made, 18 months may be a reasonable treatment duration. Discontinuation of therapy can be decided even if the pulmonary function tests remain abnormal, but the child should then be carefully monitored for a relapse.
Asunto(s)
Glucocorticoides/uso terapéutico , Prednisona/uso terapéutico , Sarcoidosis Pulmonar/tratamiento farmacológico , Adolescente , Análisis de los Gases de la Sangre , Lavado Broncoalveolar , Recuento de Células , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Humanos , Rendimiento Pulmonar , Masculino , Prednisona/administración & dosificación , Intercambio Gaseoso Pulmonar , Radiografía Torácica , Sarcoidosis Pulmonar/fisiopatología , Resultado del Tratamiento , Capacidad VitalRESUMEN
Oxygen (O(2)) species are involved in a large variety of pulmonary diseases. Among the various cell types that compose the lung, the epithelial cells of the alveolar structure appear to be a major target for oxidant injury. Despite their importance in the repair processes, the mechanisms which regulate the replication of the stem cells of the alveolar epithelium, the type 2 cells, remain poorly understood. Based on the results of several studies which have documented the involvement of the insulin-like growth factor (IGF) system in lung epithelial cell replication, and which have also suggested a role for IGF binding proteins (IGFBPs) in the control of cell proliferation, the aim of the present work was to determine whether IGFBPs could be involved in the modulation of growth of human lung epithelial cells exposed to oxidants. Experiments were performed using a human lung adenocarcinoma cell line (A549) which was exposed for various durations to hyperoxia (95% O(2)). We observed a rapid and reversible growth arrest of the cells after only 24 h of O(2) exposure. When oxidant injury was prolonged, growth arrest was followed by induction of apoptosis with activation of the Fas pathway. These effects were associated with an increased expression of IGFBP-2 and IGFBP-3. In addition, study of localization of these proteins revealed distinct patterns of distribution. IGFBP-3 was mainly present in the extracellular compartment. In comparison, the fraction of IGFBP-2 secreted was less abundant whereas the IGFBP-2 fraction in the intracellular compartment appeared stronger. In addition, analysis of the subcellular localization provided data indicating the presence of IGFBP-2 in the nucleus. Taken together these data support a role for IGFBP-2 and IGFBP-3 in the processes of growth arrest and apoptosis in lung epithelial cells upon oxidant exposure. They also suggest that distinct mechanisms may link IGFBP-2 and IGFBP-3 to the key regulators of the cell cycle.
Asunto(s)
Células Epiteliales/efectos de los fármacos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Pulmón/efectos de los fármacos , Oxidantes/farmacología , Naranja de Acridina , Apoptosis , Western Blotting , División Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Células Epiteliales/metabolismo , Técnica del Anticuerpo Fluorescente , Formaldehído , Humanos , Hiperoxia , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/análisis , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/análisis , Pulmón/metabolismo , Microscopía Confocal , Polímeros , Coloración y Etiquetado , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
The dominant role of inflammation in airways disease progression in cystic fibrosis (CF) is now well established and, based on recent findings, the possibility of an inappropriate inflammatory response in the lung of patients with CF has emerged. In order to characterize this response, the aim of the present work was to evaluate the levels of a number of pro- and anti-inflammatory cytokines in the sputum of CF children and to compare these levels to those observed in the sputum from non-CF children with diffuse bronchiectasis (DB). Three groups of patients were investigated: a group of 25 CF children (mean age: 12.2 yrs), a group of 10 non-CF children with DB (mean age 11.5 yrs), and a group of five healthy young adults (mean age 24 yrs). Elevated concentrations of pro-inflammatory cytokines, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-8 were found in children with CF and in non-CF children with DB, with significantly higher concentrations of IL-1beta in CF children. Analysis of the natural anti-inflammatory cytokine IL-1 receptor antagonist (IL-1ra) and type II TNF soluble receptor (sTNFRII) concentrations showed distinct patterns, with elevated levels of both inhibitors in CF patients, whereas only sTNFRII was found to be increased in non-CF children with DB. IL-10 data indicated low concentrations in the CF group. In all CF children, the concentrations of IL-6 in the airways were extremely low, independent of the clinical, bacteriological or functional status. By contrast, significantly increased IL-6 levels were found in non-CF children with DB. These results document distinct cytokine profiles in cystic fibrosis patients and noncystic fibrosis patients. They also suggest that impairment of interleukin-6 expression may represent an important component of the excessive inflammatory response observed in cystic fibrosis.
Asunto(s)
Bronquiectasia/inmunología , Fibrosis Quística/inmunología , Citocinas/metabolismo , Esputo/inmunología , Adolescente , Adulto , Bronquiectasia/diagnóstico , Niño , Fibrosis Quística/diagnóstico , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Masculino , Valores de ReferenciaRESUMEN
UNLABELLED: The aim of this prospective study was to evaluate the consequences of neonatal treatment with a venovenous extracorporeal respiratory assistance. POPULATION AND METHODS: Thirty nine neonates (28 boys) with acute respiratory failure were included. Extracorporeal respiratory assistance consisted of an apnoeic oxygenation with low frequency positive pressure ventilation and extracorporeal membrane CO2 removal through a venous single canula perfusion circuit. The causes of respiratory distress were: 15 meconium aspiration syndrome, 12 respiratory distress syndrome, six hyaline membrane disease, three sepsis, two diaphragmatic hernia, and one post-surgery Mendelson syndrome. The mean duration of mechanical ventilation was 18 days, including 5 days of extracorporeal respiratory assistance. The prospective follow-up included physical examination, chest radiographs, scintigraphy and pulmonary function tests. These tests studied the following parameters: functional residual capacity by helium dilution technique, lung resistance and dynamic lung compliance by the esophageal balloon technique and blood gases with arterialized blood samples. RESULTS: The mean duration of the follow-up was 21.3 months (6 months to 5 years). Results showed in the first year 33% of children with chronic obstructive pulmonary disease and chest (X-ray abnormalities, such as bronchopulmonary dysplasia in 23% of children. Data of pulmonary function test at the end of the first year: lung resistance and functional residual capacity were within limits of predicted values for height, and dynamic lung compliance was slightly decreased; according to the analysis of the functional profile: 31% without abnormality, 41% of obstructive syndrome and 26% with restrictive pattern. Blood gases were normal in 37 children. At the end of the second year, we noticed normal functional residual capacity, an increase of lung resistance while lung compliance was normalized; functional profile was quite different: with a decrease of the number of patients without abnormality (22%) and increase of those with obstructive syndrome (56%). CONCLUSION: The percentage of abnormalities is high but these are moderate in most cases, especially if we compare with the initial seriousness of the pulmonary pathology. We suggest a regular follow-up to study the respective incidence of pulmonary disease and/or extracorporeal respiratory assistance over these abnormalities.
Asunto(s)
Hemofiltración , Insuficiencia Respiratoria/terapia , Enfermedad Aguda , Resistencia de las Vías Respiratorias , Displasia Broncopulmonar/etiología , Displasia Broncopulmonar/fisiopatología , Femenino , Capacidad Residual Funcional , Hemofiltración/efectos adversos , Hemofiltración/instrumentación , Hemofiltración/métodos , Humanos , Recién Nacido , Rendimiento Pulmonar , Enfermedades Pulmonares Obstructivas/etiología , Enfermedades Pulmonares Obstructivas/fisiopatología , Masculino , Estudios Prospectivos , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/fisiopatología , Resultado del TratamientoRESUMEN
The involvement of the insulin-like growth factor (IGF) system in lung growth and repair following injury is sustained by a number of studies. Based on this knowledge, the aim of the present work was to document the expression of the IGFs and their binding proteins by alveolar cells obtained by bronchoalveolar lavage (BAL). Two groups were investigated: a control group of five children and a group of 11 children referred to the department for exploration of interstitial lung disease (ILD). Components of the IGF system studied included IGF-I, IGF-II and IGF-binding proteins (IGFBP). Expression of these factors was analysed at the level of messenger ribonucleic acid (mRNA) (by semi-quantitative reverse transcription polymerase chain reaction techniques), and of protein for the IGFBPs. In addition, expression of two major cytokines associated with the inflammatory process, tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), was also documented. In children without parenchymal disease, the growth factor expressed was IGF-I, in association with the presence of mRNA for IGFBP-2 in all cases. In children with ILD, expression of IGF-I was observed in nine patients and of IGF-II in three patients, and the presence of IGFBP-2 was found in all extracts analysed (mRNA and proteins). Evaluation of IGFBP-2 expression indicated an increase in the group of children with ILD. Interestingly, a significant association was observed between the increase in IGFBP-2 expression and TGF-beta expression. The present data emphasize the presence on insulin-like growth factor-binding protein-2 in the BAL of all patients, and suggest that this protein may be an important factor of the injury/repair processes during the progression of alveolar inflammation.
Asunto(s)
Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Enfermedades Pulmonares Intersticiales/metabolismo , Alveolos Pulmonares/metabolismo , Somatomedinas/biosíntesis , Adolescente , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , Niño , Preescolar , Femenino , Humanos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Masculino , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In the development of lung damage induced by oxidative stress, it has been proposed that changes in alveolar macrophages (AM) function with modifications in cytokine production may contribute to altered repair processes. To characterize the changes in profiles of cytokine production by macrophages exposed to oxidants, the effects of hyperoxia (95% O2) on interleukin (IL)-1 beta, IL-6, IL-8, and tumour necrosis factor-alpha (TNF-alpha) expression were studied. Experiments were first performed using AM obtained from control subjects and children with interstitial lung disease. Results showed that a 48 h O2 exposure was associated with two distinct patterns of response: a decrease in TNF-alpha, IL-1 beta and IL-6 expression, and an increase in IL-8. To complete these observations we used U937 cells that were exposed for various durations to hyperoxia. We confirmed that a 48 h O2 exposure led to similar changes with a decrease in TNF-alpha, IL-1 beta and IL-6 production and an increase in IL-8. Interestingly, this cytokine response was preceded during the first hours of O2 treatment by induction of TNF-alpha, IL-1 beta and IL-6. These data indicate that hyperoxia induces changes in the expression of macrophages inflammatory cytokines, and that these modifications appear to be influenced by the duration of O2 exposure.
Asunto(s)
Citocinas/metabolismo , Hiperoxia/metabolismo , Enfermedades Pulmonares Intersticiales/metabolismo , Macrófagos Alveolares/metabolismo , Líquido del Lavado Bronquioalveolar , Células Cultivadas , Niño , Amplificación de Genes , Regulación de la Expresión Génica , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Estrés Oxidativo , ARN Mensajero , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
STUDY OBJECTIVE: The development of BAL in children for both research and clinical purposes has been limited so far by the difficulty in establishing reference values. The aim of the study was (1) to define composition of BAL cellular components in control children and to evaluate the ability of these cells to express various cytokines, and (2) to study modifications of differential cytology and BAL cell cytokine responses in children with interstitial lung disorders. POPULATIONS AND METHODS: Two groups were investigated: a control group of 16 children who were concluded to be free of parenchymal lung disease after complete pulmonary investigation, and a group of 11 children with pulmonary sarcoidosis. Differential cytology was evaluated by standard techniques. BAL cell cytokine expression was studied at the level of messenger RNA (mRNA) by reverse transcription-polymerase chain reaction (RT-PCR) methods. RESULTS: In the control group, differential cell counts appeared to be similar to values reported in adult populations with normal distribution of the data and no influence of age. In this group, no transcripts for interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and transforming (correction of tranforming) growth factor-beta (TGF-beta) could be detected. In children with sarcoidosis, different profiles of IL-1beta, TNF-alpha, IL-6, and TGF-beta expression were individualized which seemed to be related to the activity and/or severity of the disease, IL-6 and TGF-beta mRNA being observed only in the more severe forms. CONCLUSION: These data provide information on BAL cell number and function in children. Characterization of BAL cytokine expression patterns during the course of interstitial lung diseases in children may be of great interest for evaluation of disease activity and/or severity and therefore for planning of therapy.
Asunto(s)
Líquido del Lavado Bronquioalveolar/citología , Citocinas/metabolismo , Sarcoidosis Pulmonar/metabolismo , Sarcoidosis Pulmonar/patología , Actinas/genética , Actinas/metabolismo , Adolescente , Secuencia de Bases , Southern Blotting , Líquido del Lavado Bronquioalveolar/química , Recuento de Células , Niño , Preescolar , Femenino , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Rendimiento Pulmonar , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Capacidad de Difusión Pulmonar , ARN Mensajero/análisis , Sarcoidosis Pulmonar/fisiopatología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Pulmonary alveolar type 2 cells act as a reservoir of stem cells which can be induced to proliferate during periods of lung growth and repair after lung injury. Despite the importance of this process, the mechanisms that regulate type 2 cell proliferation have not been well characterized. We show in this study that insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) accumulates to high levels in culture medium of growth-arrested type 2 cells. This is associated with an increased expression of IGFBP-2 messenger RNA (mRNA). Study of the other components of the IGF system also reveals induction of IGF-II and type 2 IGF receptor mRNA during the process of type 2 cell block of proliferation. When growth-arrested cells are allowed to resume proliferation by the addition of serum, the level of expression of IGFBP-2, type 2 IGF receptor, and IGF-II rapidly decreased. Despite the similarities in the timing of induction, it is likely that these components are not necessarily linked to mediate effects through a single pathway. Indeed, we show that the addition of conditioned medium from growth-arrested cells on proliferative cells results in down-regulation of IGFBP-2 and increased expression of IGF-II and type 2 IGF receptor mRNA. Treatment of the cells with various concentrations of IGF-II affects only the level of expression of type 2 IGF receptor, whereas IGF-I and insulin appear to influence only the expression of IGFBP-2. From the results presented in this study, it can be suggested that IGFBP-2, IGF-II, and type 2 IGF receptor play an important role in the transition of lung alveolar epithelial cells in and out of the cell cycle.
Asunto(s)
Proteínas Portadoras/genética , Expresión Génica , Factor II del Crecimiento Similar a la Insulina/genética , Alveolos Pulmonares/fisiología , Receptor IGF Tipo 2/genética , Animales , Secuencia de Bases , Proteínas Portadoras/metabolismo , División Celular , Células Epiteliales , Epitelio/metabolismo , Epitelio/fisiología , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina , Sondas Moleculares/genética , Datos de Secuencia Molecular , Alveolos Pulmonares/citología , Alveolos Pulmonares/metabolismo , Ratas , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 2/metabolismo , Somatomedinas/genética , Somatomedinas/metabolismoRESUMEN
The epithelium of the pulmonary alveolus is a major target for oxidant injury, and its proper repair following injury is dependent on the proliferative response of its stem cells, the type 2 cells. We have recently shown that hyperoxia arrests proliferation of an immortalized type 2 cell line (SV40T-T2) and that expression of several growth-related genes, normally induced near the G1/S and boundary was altered with a block of translation of their mRNA. In the present study we examined the possible role of the insulin-like growth factor (IGF) system and of transforming growth factor-beta 1 (TGF-beta 1) in the arrest of proliferation induced by hyperoxia. We show that IGF-binding protein 2 (IGFBP-2) accumulates to higher levels in culture medium of SV40T-T2 cells whose proliferation has been arrested by hyperoxia. This proliferation arrest is associated with increased expression of IGFBP-2 mRNA and with induction of type 2 IGF receptor and IGF-II mRNAs. When O2-arrested cells were allowed to resume proliferation in normoxia, the level of expression of these genes rapidly decreased to control levels. We also, found that TGF-beta 1 was induced by O2 exposure, that TGF-beta 1 inhibited SV40T-T2 proliferation, and that TGF-beta 1 itself was a potent stimulator of IGFBP-2 expression. These studies suggest a regulatory link between components of the IGF system and TGF-beta 1 in hyperoxic control of cell proliferation of alveolar epithelial cells.
Asunto(s)
Proteínas Portadoras/metabolismo , Oxidantes/farmacología , Alveolos Pulmonares/metabolismo , Somatomedinas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Secuencia de Bases , Proteínas Portadoras/genética , División Celular/efectos de los fármacos , Células Cultivadas , Cartilla de ADN , Células Epiteliales , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina , Datos de Secuencia Molecular , Oxígeno/farmacología , Alveolos Pulmonares/citología , Alveolos Pulmonares/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Somatomedinas/genética , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
The clinical course of sarcoidosis in children has not been well defined. Eight children with symptomatic sarcoidosis included in this study underwent pulmonary function tests and bronchoscopy with bronchoalveolar lavage (BAL) before treatment and during steroid therapy. At the start of therapy, functional parameters, mostly dynamic lung compliance and lung transfer factor for CO, were impaired. This was associated with abnormalities of BAL cell populations: increased total cell number with a high proportion of lymphocytes, modifications of lymphocyte subpopulation with an elevated CD4+/CD8+ ratio, and enhanced ability of alveolar macrophages to release hydrogen peroxide. Although respiratory abnormalities seemed to be similar at the initial stage of sarcoidosis in children and adults, the course of the disease appeared to be different. Despite the absence of respiratory symptoms and disappearance of chest radiographic abnormalities on prolonged steroid treatment, we found slow improvement of pulmonary functions associated with persistence of BAL lymphocytosis and elevated CD4+/CD8+ ratios. However, the ability of alveolar macrophages to release hydrogen peroxide was significantly reduced after 6 months of steroid treatment, and it remained identical to the control group. Therefore, the evaluation of disease activity appears to be critical for therapy in pediatrics, and for this purpose studies of alveolar macrophage activation may be of particular interest.
Asunto(s)
Líquido del Lavado Bronquioalveolar/citología , Enfermedades Pulmonares/patología , Macrófagos Alveolares/patología , Sarcoidosis/patología , Subgrupos de Linfocitos T/patología , Linfocitos T/patología , Adolescente , Broncoscopía , Relación CD4-CD8 , Niño , Femenino , Estudios de Seguimiento , Humanos , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/inmunología , Masculino , Prednisona/uso terapéutico , Recurrencia , Pruebas de Función Respiratoria , Sarcoidosis/diagnóstico , Sarcoidosis/tratamiento farmacológico , Sarcoidosis/inmunologíaRESUMEN
The alveolar surface of the lung is a major target for oxidant injury. After injury, repair of the alveolar epithelium is dependent on the ability of epithelial type 2 (T2) cells to proliferate. The regulation of T2 cell proliferation and the effect of reactive oxygen (O2) species on this lung cell proliferation have not been well defined. To investigate this process we focused on the regulation of two late cell cycle genes, histone and thymidine kinase, in T2 cells and fibroblasts exposed in vitro to varying periods of hyperoxia (95% O2). Hyperoxia for 24 to 48 h arrested cell proliferation in a SV40T-immortalized T2 cell line we have developed and in primary and SV40T-immortalized lung fibroblasts. Despite the cessation of proliferation, histone and TK mRNA continued to be expressed at high levels; mRNA half-lives were markedly prolonged but neither protein was translated. Thus proliferation arrest induced by hyperoxia was associated with posttranscriptional control of at least two late cell cycle-related genes. This form of proliferation arrest is also seen when primary and SV40T-T2 cells but not fibroblasts are serum deprived, suggesting that T2 cells in vitro may be uniquely sensitive to alterations in their redox state and that these alterations in turn affect translational control of a subset of proliferation-related genes.
Asunto(s)
Hipoxia de la Célula , Regulación de la Expresión Génica , Histonas/genética , Pulmón/patología , Timidina Quinasa/genética , Transcripción Genética , Animales , División Celular , Línea Celular , Pulmón/metabolismo , ARN Mensajero/análisis , RatasRESUMEN
The predominant inflammatory cell type within the alveolar structure in bronchopulmonary dysplasia (BPD) is the alveolar macrophage (AM). AM ability to release hydrogen peroxide, a way to evaluate the cell status, was studied in nine infants who developed clinical and radiological evidence of BPD, and was compared to those from infants without lung parenchymal disorders (n = 6). AM were collected by bronchoalveolar lavage which was done after the mechanical ventilation stage in the BPD group. The experiments were performed on unstimulated AM and on AM stimulated by phorbol myristate acetate. Results revealed that the amount of hydrogen peroxide accumulated in the culture medium was significantly enhanced in the BPD group, in both experimental conditions (p less than 0.01 and less than 0.001, respectively). Furthermore, improvement of patients treated with glucocorticoids was closely related to a reduction of the alveolitis with a decrease of AM ability to generate hydrogen peroxide. These data indicate that AM activation is a central component of alveolitis in BPD and that extracellular production of oxidants by stimulated AM may play a critical role in the pathogenesis of the disease.
Asunto(s)
Displasia Broncopulmonar/inmunología , Prednisona/uso terapéutico , Alveolos Pulmonares/inmunología , Displasia Broncopulmonar/tratamiento farmacológico , Displasia Broncopulmonar/metabolismo , Adhesión Celular , Células Cultivadas , Humanos , Peróxido de Hidrógeno/metabolismo , Lactante , Recién Nacido , Alveolos Pulmonares/citología , Alveolos Pulmonares/metabolismoRESUMEN
The ability of alveolar macrophages (AM) to release hydrogen peroxide (H2O2), an indicator of AM function, was studied in five children with the acquired immunodeficiency syndrome (AIDS) related complex and, for comparison, in 11 children without disorders of the lung parenchyma. In the AIDS-related complex group, pulmonary manifestations were mild, and lung involvement was suspected by moderate clinical and/or radiological features. None had a past history of opportunistic infections; neither did any have lymphopenia. Cytologic study of the bronchoalveolar lavage (BAL) fluid revealed increased cellularity with increased percentage of lymphocytes. The study of H2O2 release was performed on unstimulated AM and on AM stimulated by phorbol myristate acetate (PMA). Under both experimental conditions, the amount of H2O2 accumulated in the medium was significantly increased in the group with AIDS-related complex (P less than 0.001). As no enhanced oxidative activity has been reported in AM from patients with full-blown AIDS, an increased ability of AM to release oxygen metabolites from children with AIDS-related complex may reflect an initial and temporary step in the course of the LAV/HTLV-III pulmonary disease. Determining AM activation might be a reliable method of assessing the evolution of lung disorder in AIDS.
Asunto(s)
Complejo Relacionado con el SIDA/inmunología , Líquido del Lavado Bronquioalveolar/patología , Activación de Macrófagos , Líquido del Lavado Bronquioalveolar/inmunología , Recuento de Células , Inhibición de Migración Celular , Niño , Preescolar , Femenino , Humanos , Peróxido de Hidrógeno/biosíntesis , MasculinoRESUMEN
The ability of alveolar macrophages (AM) to release O2 metabolites was studied in 8 children with interstitial lung disease (ILD), and in 11 children without lung parenchyma disorder. AM were collected by bronchoalveolar lavage. The experiments were performed on unstimulated AM and on AM stimulated by phorbol myristate acetate (PMA) or zymosan. Our results indicated that, with or without triggering agent, the amount of O2 metabolites release was a linear function pattern with time. The accumulation of superoxide anion (O2-) and hydrogen peroxide (H2O2) into the extracellular medium differed depending on the triggering agent used: with PMA, the amount of O2- released was threefold the amount of H2O2 detected in the medium, whereas with zymosan the O2- accumulation was tenfold higher than the amount of H2O2 measured. In patients with ILD, a significant increase in the amount of H2O2 release was observed for both unstimulated and stimulated AM (p less than 0.001). In this group, the measurement was repeated after a 2-month steroid treatment: prednisone had markedly improved the clinical, radiologic, and functional status of the patients, and this improvement was in good correlation with the decrease of O2 metabolite production. The amount of H2O2 release in each case was within the range of control values. Evaluation of O2 metabolite release by AM could be a useful parameter in the assessment of the activity of ILD.