RESUMEN
BACKGROUND: The British Thoracic Society (BTS) Standards of Care (SoC) Committee produced a standard of care for occupational asthma (OA) in 2008, based on a systematic evidence review performed in 2004 by the British Occupational Health Research Foundation (BOHRF). METHODS: BOHRF updated the evidence base from 2004-2009 in 2010. RESULTS: This article summarises the changes in evidence and is aimed at physicians, nurses and other healthcare professionals in primary and secondary care, occupational health and public health and at employers, workers and their health, safety and other representatives. CONCLUSIONS: Various recommendations and evidence ratings have changed in the management of asthma that may have an occupational cause.
Asunto(s)
Asma Ocupacional/terapia , Salud Laboral/normas , Guías de Práctica Clínica como Asunto , Calidad de la Atención de Salud , Asma Ocupacional/diagnóstico , Pruebas de Provocación Bronquial/métodos , Medicina Basada en la Evidencia/métodos , Humanos , Educación del Paciente como Asunto/métodos , Vigilancia de la Población/métodos , Pruebas de Función Respiratoria/métodosRESUMEN
BACKGROUND: We have previously shown that NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells are reduced in both numbers and cytotoxicity in peripheral blood. The aim of the present study was to investigate their numbers and function within induced sputum. METHODS: Induced sputum cell numbers and intracellular granzyme B and perforin were analysed by flow cytometry. Immunomagnetically selected CD56+ cells (NK and NKT-like cells) were used in an LDH release assay to determine cytotoxicity. RESULTS: The proportion of NK cells and NKT-like cells in smokers with COPD (COPD subjects) was significantly higher (12.7% and 3%, respectively) than in healthy smokers (smokers) (5.7%, p < 0.01; 1%, p < 0.001) and non-smoking healthy subjects (HNS) (4.2%, p < 0.001; 0.8%, p < 0.01). The proportions of NK cells and NKT-like cells expressing both perforin and granzyme B were also significantly higher in COPD subjects compared to smokers and HNS. CD56+ cells from COPD subjects were significantly more cytotoxic (1414 biological lytic activity) than those from smokers (142.5; p < 0.01) and HNS (3.8; p < 0.001) and were inversely correlated to FEV1. (r = -0.75; p = 0.0098). CONCLUSION: We have shown an increased proportion of NK and NKT-like cells in the induced sputum of COPD subjects and have demonstrated that these cells are significantly more cytotoxic in COPD subjects than smokers and HNS.
Asunto(s)
Citotoxicidad Inmunológica , Pulmón/inmunología , Células T Asesinas Naturales/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Esputo/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Complejo CD3/metabolismo , Antígeno CD56/metabolismo , Linfocitos T CD8-positivos/inmunología , Técnicas de Cocultivo , Femenino , Citometría de Flujo , Volumen Espiratorio Forzado , Granzimas/metabolismo , Humanos , Separación Inmunomagnética , Integrina alfa4beta1/metabolismo , Células K562 , Pulmón/fisiopatología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Perforina/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Receptores CXCR3/metabolismo , Fumar/efectos adversos , Esputo/citología , Capacidad VitalRESUMEN
BACKGROUND: There is mounting evidence that perforin and granzymes are important mediators in the lung destruction seen in COPD. We investigated the characteristics of the three main perforin and granzyme containing peripheral cells, namely CD8+ T lymphocytes, natural killer (NK; CD56+CD3-) cells and NKT-like (CD56+CD3+) cells. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated and cell numbers and intracellular granzyme B and perforin were analysed by flow cytometry. Immunomagnetically selected CD8+ T lymphocytes, NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells were used in an LDH release assay to determine cytotoxicity and cytotoxic mechanisms were investigated by blocking perforin and granzyme B with relevant antibodies. RESULTS: The proportion of peripheral blood NKT-like (CD56+CD3+) cells in smokers with COPD (COPD subjects) was significantly lower (0.6%) than in healthy smokers (smokers) (2.8%, p < 0.001) and non-smoking healthy participants (HNS) (3.3%, p < 0.001). NK (CD56+CD3-) cells from COPD subjects were significantly less cytotoxic than in smokers (16.8% vs 51.9% specific lysis, p < 0.001) as were NKT-like (CD56+CD3+) cells (16.7% vs 52.4% specific lysis, p < 0.001). Both cell types had lower proportions expressing both perforin and granzyme B. Blocking the action of perforin and granzyme B reduced the cytotoxic activity of NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells from smokers and HNS. CONCLUSION: In this study, we show that the relative numbers of peripheral blood NK (CD56+CD3-) and NKT-like (CD56+CD3+) cells in COPD subjects are reduced and that their cytotoxic effector function is defective.
Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/patología , Linfocitos T Citotóxicos/fisiología , Adulto , Anciano , Anticuerpos Bloqueadores/farmacología , Complejo CD3/metabolismo , Antígeno CD56/metabolismo , Linfocitos T CD8-positivos/fisiología , Supervivencia Celular , Femenino , Citometría de Flujo , Granzimas/antagonistas & inhibidores , Granzimas/fisiología , Humanos , Células Asesinas Naturales/fisiología , L-Lactato Deshidrogenasa/metabolismo , Masculino , Persona de Mediana Edad , Perforina/antagonistas & inhibidores , Perforina/fisiología , Fumar/patologíaRESUMEN
BACKGROUND: Animal and human studies have implicated an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the pathogenesis of chronic obstructive pulmonary disease (COPD). MMP-9 protein is increased in COPD and we hypothesized that total MMP activity would be raised although this has not previously been measured. METHODS: Using fluorescence and biotin labelled MMP assays, RT-PCR, western blotting and enzyme-linked immunosorbent assay we examined total MMP activity, specific gelatinase, elastase, collagenase activity, TIMP-1 and TIMP-2 in induced sputum from smokers with COPD and smokers without COPD. RESULTS: Induced sputum was obtained from 15 smokers with COPD and 14 smokers without COPD. MMP-9 levels were higher in those with COPD compared with controls (p<0.05). Total MMP activity, specific gelatinase, collagenase and elastase activities were not higher in COPD patients. In addition, reduced MMP activity was correlated with increasing airflow obstruction in COPD (p=0.016). CONCLUSION: MMP-9 protein but not MMP activity was higher in sputum of COPD patients compared with controls. These results suggest that MMP-9 levels may not reflect the overall MMP activity in the airways of patients with COPD suggesting a complex relationship between MMP-9 protein and activity. Further studies of MMPs in COPD should comprise activity measures in addition to protein levels.
Asunto(s)
Metaloproteinasas de la Matriz/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Líquido del Lavado Bronquioalveolar/química , Colagenasas/metabolismo , Femenino , Volumen Espiratorio Forzado , Gelatinasas/metabolismo , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Elastasa Pancreática/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Esputo/enzimología , Esputo/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Capacidad VitalRESUMEN
BACKGROUND: CD8(+) T-lymphocytes, natural killer T-like cells (NKT-like cells, CD56(+)CD3(+)) and natural killer cells (NK cells, CD56(+)CD3(-)) are the three main classes of human killer cells and they are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Activation of these cells can initiate immune responses by virtue of their production of inflammatory cytokines and chemokines that cause lung tissue damage, mucus hypersecretion and emphysema. The objective of the current study was to investigate the activation levels of human killer cells in healthy non-smokers, healthy smokers, ex-smokers with COPD and current smokers with COPD, in both peripheral blood and induced sputum. METHODS/PRINCIPAL FINDINGS: After informed consent, 124 participants were recruited into the study and peripheral blood or induced sputum was taken. The activation states and receptor expression of killer cells were measured by flow cytometry. In peripheral blood, current smokers, regardless of disease state, have the highest proportion of activated CD8(+) T-lymphocytes, NKT-like cells and NK cells compared with ex-smokers with COPD and healthy non-smokers. Furthermore, CD8(+) T-lymphocyte and NK cell activation is positively correlated with the number of cigarettes currently smoked. Conversely, in induced sputum, the proportion of activated killer cells was related to disease state rather than current smoking status, with current and ex-smokers with COPD having significantly higher rates of activation than healthy smokers and healthy non-smokers. CONCLUSIONS: A differential effect in systemic and lung activation of killer cells in COPD is evident. Systemic activation appears to be related to current smoking whereas lung activation is related to the presence or absence of COPD, irrespective of current smoking status. These findings suggest that modulating killer cell activation may be a new target for the treatment of COPD.
Asunto(s)
Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Fumar/efectos adversos , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Células Asesinas Naturales/metabolismo , Pulmón/inmunología , Pulmón/patología , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Receptores KIR3DL1/metabolismo , Esputo/citología , Esputo/inmunologíaRESUMEN
BACKGROUND: Rhinovirus infections cause exacerbations of asthma. We postulated that people with asthma are more susceptible to rhinovirus infection than people without the disease and compared the susceptibility of these groups. METHODS: We recruited 76 cohabiting couples. One person in every couple had atopic asthma and one was healthy. Participants completed daily diary cards of upper-respiratory-tract (URT) and lower-respiratory-tract (LRT) symptoms and measured peak expiratory flow twice daily. Every 2 weeks nasal aspirates were taken and examined for rhinovirus. Mixed models were used to compare risks of infection between groups. We also compared the severity and duration of infections. FINDINGS: We analysed 753 samples. Rhinovirus was detected in 10.1% (38/378) of samples from participants with asthma and 8.5% (32/375) of samples from healthy participants. After adjustment for confounding factors, asthma did not significantly increase risk of infection (odds ratio 1.15, 95% CI 0.71-1.87). Groups did not differ in frequency, severity, or duration of URT infections or symptoms associated with rhinovirus infection. First rhinovirus infection was associated more frequently with LRT infection in participants with asthma than in healthy individuals (12 of 28 infections vs four of 23, respectively, p=0.051). Symptoms of LRT associated with rhinovirus infection were significantly more severe (p=0.001) and longer-lasting in participants with asthma than in healthy participants (p=0.005). INTERPRETATION: People with atopic asthma are not at greater risk of rhinovirus infection than healthy individuals but suffer from more frequent LRT infections and have more severe and longer-lasting LRT symptoms.