Role of mucociliary clearance system in respiratory diseases / 中南大学学报(医学版)

Mucociliary clearance system is the primary innate defense mechanism of the lung. It plays a vital role in protecting airways from microbes and irritants infection. Mucociliary clearance system, which is mediated by the actions of airway and submucosal gland epithelial cells, plays a critical role in a multilayered defense system via secreting fluids, electrolytes, antimicrobial and anti-inflammatory proteins, and mucus onto airway surfaces. Changes in environment, drugs or diseases can lead to mucus overproduction and cilia dysfunction, which in turn decrease the rate of mucociliary clearance and enhance mucus gathering. The dysfunction of mucociliary clearance system often occurs in several respiratory diseases, such as primary ciliary dysfunction, cystic fibrosis, asthma and chronic obstructive pulmonary disease, which are characterized by goblet cell metaplasia, submucosal gland cell hypertrophy, mucus hypersecretion, cilia adhesion, lodging and loss, and airway obstruction.

Expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/Tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary diseases and their relationships with pulmonary vascular remodelling

SUMMARY OBJECTIVE: This study aims at investigating the expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/ tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary disease (COPD) and their relationships with pulmonary vascular remodelling (PVR). METHODS: 60 para-tumour tissues were divided into the COPD group and the control group (n=30); the inflammations, pulmonary artery wall area/total artery area (WA%), and wall thickness/vascular outer diameter (WT%) were compared. The expressions of TLR-4, MMP-9/TIMP-1, and PCNA in pulmonary vascular smooth muscle cells were detected, and their relationships with PVR were then analysed. RESULTS: The inflammations (1.6±0.8), WA% (44.0±6.4), and WT% (27.3±3.3) in the COPD group were higher than in the control group (0.3±0.5, 26.1±2.8, 15.6±1.8), and the expressions of TLR-4 (31.4±147) and MMP-9/TIMP-1 (2.2±2.6) were increased compared to the control group (4.7±4.5, 1.9±12). Correlation analysis: TLR-4 and MMP-9/TIMP-1 were positively correlated with the inflammations (r=0.18, P<0.01), WA% (r=0.68, P<0.01), and WT% (r=0.73, P<0.01), as well as positively correlated with the expression of PCNA (r=0.44, P<0.01); the upregulation of TLR-4 was positively correlated with the expressions of MMP-9 and TIMP-1. CONCLUSIONS: The upregulation of TLR-4 in the pulmonary arterial smooth muscle cells of COPD patients could promote the inflammations and the MMP-9 expression, thus causing abnormal degradation of extracellular matrix, so it played an important role in the process of PVR.

RESUMO OBJETIVO: Este estudo tem como objetivo investigar as expressões de TOLL-like receptor 4 (TLR-4) e metaloproteinase 9 da matriz (MMP-9)/inibidor de tecido da metaloproteinase 1 (TIMP-1) em vasos sanguíneos pulmonares com doença pulmonar obstrutiva crônica (DPOC) e suas relações com o remodelamento vascular pulmonar (PVR). MÉTODOS: Sessenta tecidos paratumorais foram divididos em grupo COPD e o grupo controle (n = 30). Foram comparadas as inflamações, área da parede da artéria pulmonar/área da artéria total (WA%) e espessura da parede/diâmetro externo vascular (WT%). As expressões de TLR-4, MMP-9/TIMP-1 e PCNA em células de músculo liso vascular pulmonar foram detectadas, e suas relações com PVR foram então analisadas. RESULTADOS: As inflamações (1,6 ± 0,8), WA% (44,0 ± 6,4) e WT% (27,3 ± 3,3) no grupo COPD foram maiores que no grupo controle (0,3 ± 0,5; 26,1 ± 2,8; 15,6 ± 1,8). E as expressões de TLR-4 (31,4 ± 14,7) e MMP-9/TIMP-1 (2,2 ± 2,6) foram aumentadas em relação ao grupo controle (4,7 ± 4,5, 1,9 ± 1,2). Na análise de correlação, TLR-4 e MMP-9/TIMP-1 foram positivamente correlacionadas com as inflamações (r = 0,18; P <0,01), WA% (r = 0,68; P <0,01) e WT% (r = 0,73; P <0,01), bem como correlacionadas positivamente com a expressão de PCNA (r = 0,44; P <0,01). A elevação da TLR-4 foi correlacionada positivamente com as expressões de MMP-9 e TIMP-1. CONCLUSÕES: A regulação positiva do TLR-4 nas células do músculo liso arterial pulmonar de pacientes com DPOC poderia promover as inflamações e a expressão de MMP-9, causando assim uma degradação anormal da matriz extracelular, por isso desempenhou um papel importante no processo de PVR.

Comparison between objective measures of smoking and self-reported smoking status in patients with asthma or COPD: are our patients telling us the truth? / Comparação entre medidas objetivas do tabagismo e tabagismo autodeclarado em pacientes com asma ou DPOC: será que nossos pacientes dizem a verdade?

OBJECTIVE: Smoking prevalence is frequently estimated on the basis of self-reported smoking status. That can lead to an underestimation of smoking rates. The aim of this study was to evaluate the difference between self-reported smoking status and that determined through the use of objective measures of smoking at a pulmonary outpatient clinic. METHODS: This was a cross-sectional study involving 144 individuals: 51 asthma patients, 53 COPD patients, 20 current smokers, and 20 never-smokers. Smoking status was determined on the basis of self-reports obtained in interviews, as well as through tests of exhaled carbon monoxide (eCO) and urinary cotinine. RESULTS: All of the asthma patients and COPD patients declared they were not current smokers. In the COPD and asthma patients, the median urinary cotinine concentration was 167 ng/mL (range, 2-5,348 ng/mL) and 47 ng/mL (range, 5-2,735 ng/mL), respectively (p < 0.0001), whereas the median eCO level was 8 ppm (range, 0-31 ppm) and 5 ppm (range, 2-45 ppm), respectively (p < 0.05). In 40 (38%) of the patients with asthma or COPD (n = 104), there was disagreement between the self-reported smoking status and that determined on the basis of the urinary cotinine concentration, a concentration > 200 ng/mL being considered indicative of current smoking. In 48 (46%) of those 104 patients, the self-reported non-smoking status was refuted by an eCO level > 6 ppm, which is also considered indicative of current smoking. In 30 (29%) of the patients with asthma or COPD, the urinary cotinine concentration and the eCO level both belied the patient claims of not being current smokers. CONCLUSIONS: Our findings suggest that high proportions of smoking pulmonary patients with lung disease falsely declare themselves to be nonsmokers. The accurate classification of smoking status is pivotal to the treatment of lung diseases. Objective measures of smoking could be helpful in improving clinical management ...

OBJETIVO: O tabagismo autodeclarado é usado frequentemente para estimar a prevalência dessa condição. As taxas de tabagismo podem ser subestimadas por esse método. O objetivo deste estudo foi avaliar a diferença entre o tabagismo autodeclarado e o tabagismo determinado pelo uso de medidas objetivas em um ambulatório de doenças respiratórias. MÉTODOS: Estudo transversal realizado em 144 indivíduos: 51 pacientes com asma, 53 pacientes com DPOC, 20 fumantes e 20 não fumantes. O tabagismo foi determinado por meio de autorrelato em entrevistas e medição de monóxido de carbono no ar exalado (COex) e de cotinina urinária. RESULTADOS: Todos os pacientes com asma e DPOC declararam não ser fumantes. Nos pacientes com DPOC e asma, a mediana de concentração de cotinina urinária foi de 167 ng/ml (variação, 2-5.348) e de 47 ng/ml (variação, 5-2.735 ppm), respectivamente (p < 0,0001), enquanto . a mediana de COex foi de 8 ppm (variação, 0-31) e 5,0 ppm (variação, 2-45 ppm), respectivamente (p < 0,05). Em 40 (38%) dos pacientes com asma ou DPOC (n = 104), houve discordâncias entre o tabagismo autodeclarado e a concentração de cotinina urinária (> 200 ng/mL). Em 48 (46%) desses 104 pacientes, o não tabagismo autodeclarado foi refutado por um nível de COex > 6 ppm, considerado indicativo de fumo atual. Em 30 (29%) dos pacientes com asma ou DPOC, a concentração de cotinina urinária e o nível de COex contradisseram o autorrelato desses como não fumantes. CONCLUSÕES: Nossos achados sugerem que altas proporções de pacientes fumantes com doenças respiratórias declaram ser não fumantes. A classificação correta do tabagismo é fundamental no tratamento dessas doenças. Medidas objetivas do tabagismo podem ser úteis na melhora do manejo clínico e no aconselhamento. .

Lung Retinoid Metabolism and Signaling in Chronic Obstructive Pulmonary Disease.

There are a number of sites that are required for the production and/or action of all-trans retinoic acid (ATRA). In particular, interruption of different components of the chain of trafficking and metabolism has been associated with cancers arising in numerous organs of the body. Preliminary work suggests that such interruptions may be a factor in lung disorders induced by the smoke exposure. The active metabolite of retinoid, ATRA offers a therapeutic strategy to protect against functional abnormality in the lung, including chronic obstructive pulmonary disease (COPD). This review deals with the lung retinoid metabolism and mediators of retinoid trafficking and signaling with special emphasis on their roles in health and disease.

COPD patients' oxygen uptake and heart rate on-kinetics at cycle-ergometer: correlation with their predictors of severity / COPD patients' oxygen uptake and heart rate on-kinetics at cycle-ergometer: correlation with their predictors of severity

OBJECTIVES: To assess whether there is a correlation between oxygen uptake (VO2) and heart rate (HR) on-kinetics in the constant-load cycle-ergometer test (CLT) and the BODE index and its isolated variables in patients with chronic obstructive pulmonary disease (COPD). METHOD: Fourteen male patients between 55 and 78 years of age with moderate to severe COPD were evaluated. Each patient underwent spirometry, the six-minute walk test (6MWT), the cycle-ergometer incremental test (IT) and CLT on alternate days. The exhaled gases were collected, and the VO2 and HR on-kinetics were analyzed. The BODE index was calculated. RESULTS: It was noted that the VO2 tau (τ) and mean response time (MRT) were significantly higher than HR τ and MRT. Moderate and strong correlations between τ and MRT of the VO2 and HR and the BODE index was noted (r=0.75 and r=0.78; r=0.62 and r=0.63, respectively), and there were correlations between the VO2 τ and MRT and the forced expiratory volume in one second (FEV1) (r=-0.60; r=-0.53) and the distance traveled at 6MWT (DT-6MWT) (r=-0.61; r=-0.44) and DT-6MWT % predicted (r=-0.62; r=-0.46). The HR τ and MRT were correlated with DT-6MWT (r=-0.59; r=-0.58) and DT-6MWT % predicted (r=-0.62; r=-0.62). CONCLUSION: The slowing of cycle-ergometer VO2, and especially of HR on-kinetics, may be key markers of disease severity. Furthermore, airflow obstruction and reduced exercise capacity are associated with the slowing of patients' VO2 and HR on-kinetics. .

OBJETIVOS: Verificar se há correlação entre a cinética-on do consumo de oxigênio (VO2) e da frequência cardíaca (FC) no teste de carga constante em cicloergômetro (TCC) com o índice BODE e suas variáveis isoladas em pacientes com doença pulmonar obstrutiva crônica (DPOC). MÉTODO: Foram avaliados 14 homens com DPOC de obstrução moderada a muito grave, entre 55 e 78 anos, submetidos em dias alternados à espirometria, teste de caminhada de seis minutos (TC6), teste incremental em cicloergômetro (TI) e TCC. Foram coletados os gases expirados, e a cinética-on do VO2 e da FC foi analisada. O índice BODE foi calculado. RESULTADOS: Observou-se que a tau (τ) e o tempo de resposta média (TRM) do VO2 foram significativamente maiores que a τ e o TRM da FC. Observou-se correlações moderadas e fortes entre a τ e o TRM do VO2 e da FC com o índice BODE (r=0,75 e r=0,78; r=0,62 e r=0,63, respectivamente) e correlações entre a τ e o TRM do VO2 com o volume expiratório forçado no primeiro segundo (VEF1) (r=-0,60; r=-0,53), a distância percorrida no TC6 (DP-TC6) (r=-0,61; r=-0,44) e a DP-TC6 %prevista (r=-0,62; r=-0,46). A τ e o TRM da FC correlacionaram-se com a DP-TC6 (r=-0,59; r=-0,58) e a DP-TC6 %prevista (r=-0,62; r=-0,62). CONCLUSÃO: A lentificação da cinética-on do VO2 e principalmente da FC em cicloergômetro pode ser um marcador importante de gravidade da doença. Adicionalmente, a limitação ao fluxo aéreo e a reduzida capacidade ao exercício estão associadas à lentificação da cinética-on do VO2 e da FC nesses pacientes. .

Respuesta ventilatoria al ejercicio post-entrenamiento de miembros superiores en la enfermedad pulmonar obstructiva crónica / Ventilatory response to upper limb exercise after training in COPD

Está poco estudiada la modificación de la respuesta ventilatoria al ejercicio de miembros superiores (MS) post-entrenamiento en la EPOC. Se realizó un estudio prospectivo, aleatorio y controlado en pacientes con EPOC, entrenando un grupo los miembros inferiores (GC) y otro adicionalmente los MS (GM). Se comparó la respuesta ventilatoria al ejercicio de MS pre y post-entrenamiento. Se estudiaron 43 pacientes, 84% varones, estadio GOLD II (moderado) 6 (14%), GOLD III (grave) 15 (35%) y GOLD IV (muy grave) 22 (51%). Veintiocho pacientes completaron el estudio. Post-entrenamiento: se observó en el grupo GM (N = 14) incrementos del V T isotiempo (p < 0.0001) y del % de capacidad inspiratoria (CI) isotiempo (8.8%, p = 0.001), mayores Ti isotiempo (29.3%, p = 0.022) y Ti/Tot isotiempo (37.4%, p = 0.0004) al ejercicio de MS. Se redujo el Te isotiempo (26%, p = 0.009). La CI isotiempo se incrementó (p = 0.01). Post-entrenamiento: en el grupo GC (N = 14) se incrementó el V T/Ti isotiempo (66.86%, p = 0.0005), y disminuyeron el Ti isotiempo (27.9%, p = 0.015) y el Ti/Tot isotiempo (22.74%, p = 0.00016) al ejercicio de MS. Se observó correlación moderada entre la Δ de frecuencia respiratoria y la Δ de CI al ejercicio de MS, post-entrenamiento solo para el grupo GM (r = -0.53, p< 0.001). Comparando ambos grupos en la respuesta al ejercicio de MS, se observó en el grupo GM, reducción del Te isotiempo (p = 0.049) y del V T/Ti (p = 0.0015), mayores Ti isotiempo (p = 0.0019), Ti/tot isotiempo (p = 0.000076) y CI (% predictivo, p = 0.01). El entrenamiento de MS modificó la respuesta ventilatoria, y también redujo el atrapamiento aéreo que se generó por el ejercicio de MS en la EPOC.

There are scarce studies evaluating the modification of ventilatory response to upper limb exercise (ULE) post-training in COPD patients. A prospective, randomized, controlled study was performed comparing two groups: training lower limbs (LL), vs. LL plus upper limb training (UL), in relation to their pre and post-training ventilatory response to ULE. A total of 43 COPD patients were included; 84% male, 6 (14%) GOLD moderate stage (II), 15 (35%) severe stage (III), and 22 (51%) very severe (IV); 28 patients completed the study. After ULE, in UL group (N = 14) a training increased isotime VT (p < 0.0001) was observed, as well as an increase in the inspiratory capacity isotime percentage (IC, 8.8%, p = 0.001), in the Ti isotime (29.3%, p = 0.022) and in the Ti/Tot isotime (37.4%, p = 0.0004). Also, Te isotime was reduced (26%, p = 0.009) and IC isotime was increased (p = 0.01) after ULE. In LL group (N = 14), training increased VT/Ti isotime (66.86%, p = 0.0005) after ULE. Also, after ULE a decrease in Ti isotime (27.9%, p = 0.015) and in Ti/Tot isotime (22.74%, p = 0.00016) were observed. A moderate correlation was observed between Δ respiratory rate and ΔIC after ULE, only for post-training in UL group (r = -0.53 , p < 0.001). Comparing both groups in relation to their responses to ULE, only in the UL group was a reduction observed in Te isotime (p = 0.049) and VT/Ti (p = 0.0015), higher Ti isotime (p = 0.0019), Ti/tot isotime (p = 0.000076) and IC isotime (% predictive, p = 0.01). UL training modified ventilatory response to ULE and it also reduced air trapping in COPD patients.

Interference of nail polish on the peripheral oxygen saturation in patients with lung problems during exercise / Interferência do esmalte de unha na saturação periférica de oxigênio em pacientes pneumopatas no exercício / La interferencia del esmalte de uñas en la saturación periférica de oxígeno en pacientes con pneumopatía en el ejercicio

AIM: To assess the interference of nail polish on the reading of peripheral oxygen saturation in patients with chronic obstructive pulmonary disease on the step exercise. METHODS: In this study, there was the inclusion of patients with chronic obstructive pulmonary disease, current non-smokers, of both sexes. Four different colours of nail polish were used in the present study (base, light pink, red and brown), randomly distributed among the fingers of the right hand, with the corresponding fingers on the opposite hand being controls. Saturation was measured at rest, with and without the polish, and also during the 4th, 5th and 6th minutes of the exercise programme. RESULTS: The experimental universe included 42 patients with ages of 62.9±8.7 years. In the exercise considered, the red colour reduced it in the fourth minute of the exercise (p=0.047). In contrast, the brown colour reduced saturation at rest and also during the course of exercise (p=0.01). CONCLUSION: In patients with chronic obstructive pulmonary disease, the red and brown colours interfered with the reading of the peripheral oxygen saturation during exercise. This study is registered at the Brazilian Register of Clinical Trials (Registro Brasileiro de Ensaios Clínicos) under No. RBR-9vc722.

OBJETIVO: avaliar a interferência do esmalte de unha na leitura da saturação periférica de oxigênio em pacientes com doença pulmonar obstrutiva crônica, no exercício do degrau. MÉTODOS: foram incluídos pacientes com doença pulmonar obstrutiva crônica estável, não fumantes atuais, de ambos os sexos. Utilizaram-se quatro cores de esmalte (base, rosa claro, vermelho e marrom), distribuídas aleatoriamente entre os dedos da mão direita, tendo os dedos contralaterais como controle. A saturação foi medida em repouso com e sem esmalte e durante o 4º, 5º e 6º minutos do exercício. RESULTADOS: foram incluídos 42 pacientes com idade de 62,9±8,7 anos. No exercício, a cor vermelha diminuiu a mesma no quarto minuto de exercício (p=0,047). A cor marrom reduziu a saturação no repouso e durante o exercício (p=0,01). CONCLUSÃO: em pacientes com doença pulmonar obstrutiva crônica, as cores marrom e vermelha interferem na leitura da saturação periférica de oxigênio no exercício. Este estudo está registrado no Registro Brasileiro de Ensaios Clínicos, sob número de registro: RBR-9vc722.

OBJETIVO: Evaluar la interferencia del esmalte de uñas en la lectura de la saturación periférica de oxígeno en pacientes con enfermedad pulmonar obstructiva crónica en el ejercicio de la etapa. MÉTODOS: Fueron incluidos pacientes con enfermedad pulmonar obstructiva crónica estable, no fumadores actuales, de ambos los sexos. Fueron utilizadas cuatro colores de esmalte (base, rosa claro, rojo y marrón) distribuidas aleatoriamente entre los dedos de la mano derecha teniendo los dedos contralaterales como control. La saturación fue medida en reposo con y sin esmalte y durante el 4º, 5º y 6º minutos del ejercicio. RESULTADOS: Fueron incluidos 42 pacientes con edad de 62,9±8,7 años. En el ejercicio el color rojo apocó la misma en el cuarto minuto de ejercicio (p=0,047). El color marrón redujo la saturación en el reposo y durante el ejercicio (p=0,01). CONCLUSIÓN: En pacientes con enfermedad pulmonar obstructiva crónica los colores marrón y rojo interfieren en la lectura de la saturación periférica de oxígeno en el ejercicio. Este estudio está registrado en el Registro Brasileño de Ensayos Clínicos bajo el número de registro: RBR-9vc722.

Força muscular como determinante da eficiência do consumo de oxigênio e da máxima resposta metabólica ao exercício em pacientes com DPOC leve/moderada / Muscle strength as a determinant of oxygen uptake efficiency and maximal metabolic response in patients with mild-to-moderate COPD

OBJETIVO: Comparar o comportamento de oxygen uptake efficiency slope (OUES, inclinação da eficiência do consumo de oxigênio) com o do consumo de oxigênio no pico do exercício (VO2pico). MÉTODOS: Estudo prospectivo transversal envolvendo 21 pacientes (15 homens) com DPOC leve/moderada que foram submetidos a espirometria, dinamometria de preensão palmar (DIN), teste cardiopulmonar de exercício e medida de lactato no pico do exercício (LACpico). RESULTADOS: A média de peso foi 66,7 ± 13,6 kg, e a de idade foi 60,7 ± 7,8 anos. Com exceção de VEF1 e relação VEF1/CVF (75,8 ± 18,6 do previsto e 56,6 ± 8,8, respectivamente), as demais variáveis espirométricas foram normais, assim como DIN. As médias, em % do previsto, para VO2pico (93,1 ± 15,4), FC máxima (92,5 ± 10,4) e OUES (99,4 ± 24,4), assim como a da taxa de troca respiratória (1,2 ± 0,1), indicaram estresse metabólico e hemodinâmico importante. A correlação entre o VO2pico e a OUES foi elevada (r = 0,747; p < 0,0001). A correlação entre DIN e VO2pico (r = 0,734; p < 0,0001) foi mais expressiva do que com aquela entre DIN e OUES (r = 0,453; p < 0,05). Resultados semelhantes ocorreram em relação às correlações de VO2pico e OUES com PImáx. Houve correlação significativa entre VO2pico e LACpico (r = -0,731; p < 0,0001), mas essa só ocorreu entre OUES e LACpico/potência máxima (r = -0,605; p = 0,004). CONCLUSÕES: Nossos resultados sugerem que, na DPOC leve/moderada, determinantes do VO2, além da força muscular global, têm um maior impacto na OUES do que no VO2pico.

OBJECTIVE: To compare the behavior of the oxygen uptake efficiency slope (OUES) with that of oxygen uptake at peak exertion (VO2peak). METHODS: This was a prospective cross-sectional study involving 21 patients (15 men) with mild-to-moderate COPD undergoing spirometry, handgrip strength (HGS) testing, cardiopulmonary exercise testing, and determination of lactate at peak exertion (LACpeak). RESULTS: Mean weight was 66.7 ± 13.6 kg, and mean age was 60.7 ± 7.8 years. With the exception of FEV1 and FEV1/FVC ratio (75.8 ± 18.6 of predicted and 56.6 ± 8.8, respectively), all spirometric variables were normal, as was HGS. The patients exhibited significant metabolic and hemodynamic stress, as evidenced by the means (% of predicted) for VO2peak (93.1 ± 15.4), maximum HR (92.5 ± 10.4), and OUES (99.4 ± 24.4), as well as for the gas exchange rate (1.2 ± 0.1). The correlation between VO2peak and OUES was significant (r = 0.747; p < 0.0001). The correlation between HGS and VO2peak (r = 0.734; p < 0.0001) was more significant than was that between HGS and OUES (r = 0.453; p < 0.05). Similar results were found regarding the correlations of VO2peak and OUES with MIP. Although LACpeak correlated significantly with VO2peak (r = -0.731; p < 0.0001), only LACpeak/maximum power correlated significantly with OUES (r = -0.605; p = 0.004). CONCLUSIONS: Our findings suggest that, in mild-to-moderate COPD, VO2 determinants other than overall muscle strength have a greater impact on OUES than on VO2peak.

Exhaled breath condensate analysis in chronic obstructive pulmonary disease.

The increasing focus on airway inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD) has led to development and evolution of tools to measure it. Direct assessment of airway inflammation requires invasive procedures, and hence, has obvious limitations. Non-invasive methods to sample airway secretions and fluids offer exciting prospects. Analysis of exhaled breath condensate (EBC) is rapidly emerging as a novel non-invasive approach for sampling airway epithelial lining fluid and offers a convenient tool to provide biomarkers of inflammation. It has definite advantages that make it an attractive and a feasible option. It is a source of mediators and molecules that are the causes or consequences of the inflammatory process. Measurement of such markers is increasingly being explored for studying airway inflammation qualitatively and quantitatively in research studies and for potential clinical applications. These biomarkers also have the potential to develop into powerful research tools in COPD for identifying various pathways of pathogenesis of COPD that may ultimately provide specific targets for therapeutic intervention. The EBC analysis is still an evolving noninvasive method for monitoring of inflammation and oxidative stress in the airways. The limited number of studies available on EBC analysis in COPD have provided useful information although definite clinical uses are yet to be defined. Evolving technologies of genomics, proteomics, and metabonomics may provide deeper and newer insights into the molecular mechanisms underlying the pathogenesis of COPD.

O envolvimento do estresse oxidativo e nitrosativo em modelo de doença pulmonar obstrutiva crônica (DPOC) induzido por elastase / The involvement of oxidative and nitrosative stress in model of chronic obstructive pulmonary disease (COPD) induced by elastase

Este estudo buscou investigar o papel do estresse oxidativo e nitrosativo no enfisema pulmonar induzido por elastase. Foram utilizados camundongos machos C57BL/6 submetidos a dois modelos de indução do enfisema por elastase pancreática suína (PPE): intratraqueal (i.t.) e intranasal (i.n.). No modelo intratraqueal a PPE foi instilada nas doses de 0,05 U ou 0,05 U/camundongo para avaliação temporal do enfisema 7, 14 e 21 dias após instilação de PPE. Em outra etapa, o papel da iNOS foi avaliado através da sua inibição farmacológica por aminoguanidina (AMG) 1% na água de beber ou pela sua exclusão genética em camundongos deficientes em iNOS que tiveram o enfisema induzido por 0,5 U PPE i.t. após 21 dias. No modelo intranasal a dose de PPE foi 3 U/camundongo para avaliação temporal do enfisema (1, 7, 14 e 21 dias após PPE). O papel do estresse oxidativo e nitrosativo foi avaliado com diferentes tratamentos antioxidantes na água de beber: tempol, apocinina+alopurinol, n-acetilcisteína, vitamina C+E, e aminoguanidina durante os 21 dias de indução do enfisema. Os grupos controles foram submetidos à instilação de salina. Lavado broncoalveolar, imunoensaios, análises bioquímicas de estresse oxidativo e ensaios morfométricos foram realizados nos pulmões dos animais. O enfisema foi histologicamente alcançado em 21 dias após 0,5 U PPE i.t., evidenciado pelo aumento do diâmetro alveolar médio - Lm e da densidade de volume dos espaços alveolares - Vvair em comparação ao grupo controle. TNF-a foi aumentado em 7 e 14 dias após 0,05 U PPE comparados ao controle, concomitante com a redução de IL-10 nos mesmos períodos, comparados ao controle. O estresse oxidativo foi observado na fase inicial do enfisema, com aumento dos níveis de nitrito, TBARS e superóxido dismutase no grupo 7 dias após 0,5 U PPE (i.t.) quando comparados ao controle ao passo que no modelo intranasal as alterações típicas do estresse foram vistas no grupo 1 dia após 3 U de PPE. Atividade da glutationa ...

This study investigated the role of oxidative and nitrosative stress in elastase-induced pulmonary emphysema. C57BL/6 male mice were used submitted to two models of emphysema induced by porcine pancreatic elastase (PPE): intratracheal (i.t.) and intranasal (i.n.). In the intratracheal model PPE was instilled at doses of 0.05 U or 0.5 U/mouse (i.t.) to temporal evaluation of emphysema 7, 14 and 21 days post-PPE instillation. Others sets of experiments, the role of iNOS was evaluated through its pharmacology inhibition by 1% aminoguanidine (AMG) into the drinking water or bt iNOS genetic exclusion in iNOS-deficient mice which had induced emphysema by 0.5 U PPE i.t. after 21 days. In the intranasal model the PPE dose was 3 U/mouse to temporal evaluation of emphysema (1, 7, 14 and 21 days after PPE). The role of oxidative and nitrosative stress was evaluated using different antioxidant treatments into the drinking water: tempol, apocynin+allopurinol, N-acetylcysteine, vitamin C+E and aminoguanidine during the 21 days of emphysema induction. Control groups were instilled with saline. Bronchoalveolar lavage, immunoassays, biochemical analysis of oxidative stress and morphometric tests were performed in the lungs of animals. The emphysema was histologically reached 21 days after 0.5 U PPE, as evidenced by an increase in alveolar diameter - Lm and volume density of the alveolar spaces - Vvair compared to the control group. TNF-a was increased in 7 and 14 days after 0.5 U PPE compared to the control, concomitant with reduction of IL-10 at the same time-points compared to the control. Oxidative stress was observed in the early stages of emphysema, with increased levels of nitrite, TBARS and superoxide dismutase in group 7 days after 0.5 U PPE (i.t.) compared to the control, while in the intranasal model the typical stress alterations were seen in group 1 day after 3 U PPE. Glutathione peroxidase activity was increased in all PPE groups (i.t.). Exposure to 0.5 U PPE ...

Níveis aumentados de bilirrubina estão associados com risco reduzido de doença pulmonar e mortalidade / Increased bilirubin levels are associated with reduced risk of lung disease and mortality

Níveis aumentados de bilirrubina (acima de 2,34 mg/dL para homens e 1,75 mg/dL para mulheres) estão associados com uma redução de risco de doença respiratória e mortalidade geral por todas as causas.

O papel do estresse oxidativo na DPOC: conceitos atuais e perspectivas / The role of oxidative stress in COPD: current concepts and perspectives

A DPOC é uma causa importante de morbidade e mortalidade em escala global. As manifestações clínicas e funcionais da DPOC resultam de danos pulmonares provocados por um conjunto de mecanismos, incluindo o estresse oxidativo, a inflamação, o desequilíbrio do sistema protease-antiprotease e a apoptose. O estresse oxidativo é central na gênese da DPOC, pois além de provocar dano direto às estruturas pulmonares, amplifica os demais mecanismos. Os eventos celulares e moleculares responsáveis pelo dano pulmonar antecedem em muito a expressão clínica e funcional da DPOC. Os broncodilatadores, principais drogas empregadas atualmente no tratamento da DPOC, não são eficazes em reduzir a progressão da doença. Avanços na compreensão da patogênese da DPOC aliados a esforços renovados na pesquisa básica e clínica deverão permitir sua detecção na fase pré-clínica e possibilitar um monitoramento mais adequado de sua atividade, além de permitir a introdução de novas modalidades de agentes terapêuticos capazes de impedir eficazmente sua progressão.

Worldwide, COPD is a major cause of morbidity and mortality. The clinical and functional manifestations of COPD result from lung injury occurring through various mechanisms, including oxidative stress, inflammation, protease-antiprotease imbalance and apoptosis. Oxidative stress is central to the pathogenesis of COPD, since it can directly damage lung structures and exacerbate the other mechanisms involved. The cellular and molecular events involved in such lung injury are believed to occur long before the clinical and functional expression of COPD. Although the use of bronchodilators is currently the principal treatment for COPD, bronchodilators have little or no effect on disease progression. A better understanding of the pathogenesis of COPD, together with renewed efforts in basic and clinical research, will allow the diagnosis of COPD at a pre-clinical stage and provide more appropriate monitoring of disease activity, as well as leading to the development of novel therapeutic agents that will effectively prevent the progression of the disease.

Fatores associados à diferença clinicamente significativa da qualidade de vida relacionada à saúde após condicionamento físico em pacientes com DPOC / Factors associated with the minimal clinically important difference for health-related quality of life after physical conditioning in patients with COPD

OBJETIVO: Investigar os fatores associados à diferença clinicamente significativa da qualidade de vida (DCSQV) após condicionamento físico em pacientes com DPOC. MÉTODOS: Trinta e cinco pacientes foram submetidos a 12 semanas de condicionamento físico, envolvendo treinamento de força e exercício aeróbio leve. Composição corporal, teste incremental e de endurance em esteira, teste de caminhada de seis minutos, força muscular periférica, PImáx, baseline dyspnea index (BDI) e Saint George's Respiratory Questionnaire (SGRQ) foram avaliados antes e após o treinamento, e suas alterações (Δ) foram calculadas. A DCSQV foi definida como a redução > 4 por cento no escore total do SGRQ. Os pacientes que responderam ao treinamento, apresentando DCSQV, foram alocados no grupo respondedores (R; n = 24), e os demais pacientes foram alocados no grupo não-respondedores (NR; n = 11). RESULTADOS: Os seguintes resultados foram significativamente maiores no grupo R que no grupo NR (p < 0,05): VEF1 (1,48 ± 0,54 L vs. 1,04 ± 0,34 L), VEF1/CVF (47,9 ± 11,7 por cento vs. 35,5 ± 10,7 por cento), PaO2 (74,1 ± 9,7 mmHg vs. 65,0 ± 8,9mmHg) e ΔBDI [mediana (interquartil); 2,0 (0,0-3,5) vs. 0,0 (0,0-1,0)]. Houve correlação significativa (p < 0,01) de ΔSGRQ-sintomas (r = 0,44), ΔSGRQ-atividade (r = 0,62) e ΔSGRQ-total (r = 0,60) com ΔBDI. Após regressão logística, apenas ΔBDI foi selecionado como determinante da DCSQV. CONCLUSÕES: A DCSQV após o condicionamento físico está associada principalmente à redução da dispneia nos pacientes com DPOC. Portanto, são necessárias estratégias de tratamento visando interromper o ciclo dispneia-sedentarismo-dispneia nesses pacientes.

OBJECTIVE: To identify factors associated with the minimal clinically important difference (MCID) for health-related quality of life (HRQoL) after physical conditioning in patients with COPD. METHODS: Thirty-five patients were submitted to a 12-week program of physical conditioning (strength training plus low-intensity aerobic exercise). Body composition, incremental treadmill test results, endurance treadmill test results, six-minute walk test results, peripheral muscle strength, MIP, baseline dyspnea index (BDI) and Saint George's Respiratory Questionnaire (SGRQ) scores were assessed at baseline and after the program, thus allowing the variations (Δ) to be calculated. The MCID for HRQoL was defined as a reduction of > 4 percent in the SGRQ total score. Subjects who responded to the program, achieving the MCID for HRQoL, were allocated to the responders (R) group (n = 24), and the remainder were allocated to the non-responders (NR) group (n = 11). RESULTS: The values obtained for the following variables were significantly higher in group R than in group NR (p < 0.05): FEV1 (1.48 ± 0.54 L vs. 1.04 ± 0.34 L); VEF1/FVC (47.9 ± 11.7 percent vs. 35.5 ± 10.7 percent); PaO2 (74.1 ± 9.7 mmHg vs. 65.0 ± 8.9 mmHg); and ΔBDI, expressed as median and interquartile range (2.0 [0.0-3.5] vs. 0.0 [0.0-1.0]). The ΔBDI correlated significantly with the ΔSGRQ symptoms domain score, activity domain score and total score (r = 0.44, 0.60 and 0.62, respectively, p < 0.01 for all). After logistic regression, only ΔBDI remained as a predictor of MCID for HRQoL. CONCLUSIONS: Achieving the MCID for HRQoL after physical conditioning is associated with dyspnea reduction in COPD patients. Therefore, there is a need to develop treatment strategies designed to interrupt the dyspnea-inactivity-dyspnea cycle in such patients.

Proton magnetic resonance spectroscopy of brain to study the cerebral metabolic abnormalities in COPD patients: a case control study in north India.

BACKGROUND: To investigate changes in the cerebral metabolism of nondiabetic and normolipidaemic patients with chronic obstructive pulmonary disease (COPD) using localised in vivo proton magnetic resonance spectroscopy (1H MRS), and to correlate these with the severity of disease. METHODS: Twenty-eight symptomatic COPD patients and 19 healthy controls underwent 1H MRS of brain, pulmonary function testing and respiratory muscle strength evaluation. The parieto-temporal and occipital regions were localised for 1H MRS. The metabolic ratios of N-acetyl aspartate to cretinine (NAA/Cr) and choline containing compound to creatinine (Cho/Cr) were calculated by integrating area under the each peak. RESULTS: The mean value of NAA/Cr and Cho/Cr in parieto-temporal area in COPD patients were (1.86 +/- 0.54) and (0.77 +/- 0.23), respectively. The mean values of NAA/Cr and Cho/Cr in occipital area in COPD patients were (1.75 +/- 0.44) and (0.61 +/- 0.25), respectively. Compared with healthy control subjects, the mean values of Cho/Cr in COPD patients were lower, both in parieto-temporal (0.77 +/- 0.23 vs. 0.89 +/- 0.35; p = 0.17) and occipital (0.61 +/- 0.25 +/- vs. 0.67 +/- 0.08; p = 0.36) areas of the brain. CONCLUSIONS: The cerebral metabolism, pulmonary function testing and respiratory muscle strength altered in symptomatic COPD patients. The clinical significance of cerebral metabolic changes in COPD patients needs to be further investigated.

Estudo imunohistoquímico do remodelamento pulmonar em camundongos expostos à fumaça de cigarro / Immunohistochemical study of lung remodeling in mice exposed to cigarette smoke

OBJETIVO: Muitos estudos sobre enfisema são realizados com exposição de animais à fumaça de cigarro durante um longo tempo, focando o tipo de célula envolvida no desequilíbrio protease/antiprotease e a degradação da matriz extracelular. A expressão aumentada de metaloproteinases no enfisema está associado com citocinas e evidências sugerem um papel importante da metaloproteinase de matriz-12 (MMP-12). Nosso objetivo foi estudar a detecção de inibidor tissular de metaloproteinase-2 (TIMP-2), fator de necrose tumoral alfa (TNF-α) e interleucina-6 (IL-6) por métodos imunohistoquímicos no pulmão de camundongos. MÉTODOS: Camundongos C57BL/6 machos foram expostos 3 vezes ao dia a fumaça de 3 cigarros por um período de 10, 20, 30 ou 60 dias através de uma câmara de inalação (grupos CS10, CS20, CS30 e CS60, respectivamente). O grupo controle foi exposto às mesmas condições ao ar ambiente. RESULTADOS: Nós observamos um aumento progressivo de macrófagos alveolares no lavado broncoalveolar dos grupos expostos. O diâmetro alveolar médio, um indicador de destruição alveolar, aumentou em todos os grupos expostos quando comparado ao grupo controle. O índice imunohistoquímico (II) para MMP-12 aumentou nos grupos CS10, CS20 e CS30 em paralelo a uma redução do II para TIMP-2 nos grupos CS10, CS20 e CS30. O II para as citocinas TNF-α e IL-6 aumentou em todos os grupos expostos quando comparado ao grupo controle. Enfisema foi observado no grupo CS60, com alterações na densidade de volume de fibras colágenas e elásticas. CONCLUSÕES: Estes achados sugerem que a fumaça de cigarro induz enfisema com uma participação importante do TNF-α e da IL-6 sem a participação de neutrófilos.

OBJECTIVE: Various studies of emphysema involve long-term exposure of animals to cigarette smoke, focusing on the cell type involved in the protease/antiprotease imbalance and on extracellular matrix degradation. In emphysema, increased expression of metalloproteinases is associated with cytokines, and evidence suggests that the matrix metalloproteinase-12 (MMP-12) plays an important role. Our objective was to investigate tissue inhibitor of metalloproteinase-2 (TIMP-2), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) detection by immunohistochemical methods in mouse lung. METHODS: Male C57BL/6 mice were exposed 3 times a day to smoke of 3 cigarettes over a period of 10, 20, 30 or 60 days in an inhalation chamber (groups CS10, CS20, CS30 and CS60, respectively). Controls were exposed to the same conditions in room air. RESULTS: A progressive increase in the number of alveolar macrophages was observed in the bronchoalveolar lavage fluid of the exposed mice. The mean linear intercept, an indicator of alveolar destruction, was greater in all exposed groups when compared to control group. In the CS10, CS20 and CS30 mice, the immunohistochemical index (II) for MMP-12 increased in parallel with a decrease in II for TIMP-2 in the CS10, CS20 and CS30 mice. The II for the cytokines TNF-α and IL-6 was greater in all exposed groups than in the control group. Emphysema, with changes in volume density of collagen and elastic fibers, was observed in the CS60 group. CONCLUSIONS: These findings suggest that cigarette smoke induces emphysema with major participation of TNF-α and IL-6 without participation of neutrophils.

Bases celulares e bioquímicas da doença pulmonar obstrutiva crônica / Cellular and biochemical bases of chronic obstructive pulmonary disease

A doença pulmonar obstrutiva crônica é uma doença inflamatória com participação ativa de macrófagos, neutrófilos e linfócitos CD8+ em sua patogênese, associada a estímulos oxidantes diretos das estruturas pulmonares, que desencadeiam reações bioquímicas, levando a progressiva desorganização das pequenas vias aéreas e ao remodelamento estrutural não reversível. A liberação de substâncias provenientes das células recrutadas e do estresse oxidativo leva ao desequilíbrio inicialmente temporário dos mecanismos de defesa pulmonar. A permanência desse desequilíbrio é uma das chaves da fisiopatogenia atual. Os autores descrevem as alterações celulares e bioquímicas da doença pulmonar obstrutiva crônica.

Chronic obstructive pulmonary disease is an inflammatory disease. Together with oxidant stimuli, which directly affect lung structures, macrophages, neutrophils and CD8+ lymphocytes actively participate in the pathogenesis of the disease and promote biochemical reactions that result in progressive alteration of the upper airways and irreversible lung remodeling. The release of substances promoted by inflammatory cell recruitment and by oxidative stress lead to a temporary imbalance in the pulmonary defense mechanisms. Understanding the long-term maintenance of this imbalance is key to understanding the current physiopathology of the disease. The present study explores the cellular and molecular alterations seen in chronic obstructive pulmonary disease.

Concentration of CCL11, CXCL8 and TNF-alpha in sputum and plasma of patients undergoing asthma or chronic obstructive pulmonary disease exacerbation

Asthma and chronic obstructive pulmonary disease (COPD) are common respiratory illnesses characterized by chronic inflammation of the airways. The characterization of induced or spontaneously produced sputum is a useful technique to assess airway inflammation. In the present study, we compared the concentrations of CCL2, CCL11, CXCL8, and tumor necrosis factor-alpha (TNF-alpha) in plasma and induced sputum of patients with severe asthma or COPD and correlated the levels of these mediators with inflammatory cells in sputum. Asthmatic patients had elevated levels of eosinophils (40.1 ± 6.24 percent) in sputum whereas neutrophils (63.3 ± 4.66 percent) predominated in COPD patients. The levels of the chemokine CCL11 were markedly increased in sputum (708.7 ± 330.7 pg/ml) and plasma (716.6 ± 162.2 pg/ml) of asthmatic patients and correlated with the percentage of eosinophils in induced sputum. The concentrations of CXCL8 (817.0 ± 105.2 pg/ml) and TNF-alpha (308.8 ± 96.1 pg/ml) were higher in sputum of COPD patients and correlated with the percentage of neutrophils in induced sputum. There was also an increase in the concentrations of CXCL8 (43.2 ± 6.8 pg/ml) in sputum of asthmatic patients. These results validate that sputum is a suitable method to assess chemokines and cytokines associated with asthma and COPD. Moreover, the mechanisms involved in the synthesis of CCL11 and CXCL8/TNF-alpha would be helpful to better understand the inflammatory profile associated with asthma and COPD, respectively.

Oxidative stress and protein glycation in patients with chronic obstructive pulmonary disease.

Several studies have indicated the presence of increased oxidative stress as a critical feature in the pathogenesis of chronic obstructive pulmonary disease (COPD). Another biochemical complication leading to pathogenesis is protein glycation. The nexus between oxidative stress and protein glycation in various pathological conditions is being unraveled. Increased oxidative stress can lead to enhanced protein glycation by a process of auto-oxidative glycation. No information is available in the literature regarding protein glycation among COPD patients. Eleven non-diabetic COPD patients were included in the study and equal number of age and sex-matched healthy individuals were enrolled as controls. The whole-blood reduced glutathione was found to be less among the patients while lipid peroxides and fructosamine were elevated in comparison to control. The present study confirmed oxidative stress and enhanced protein glycation among the COPD patients. Antioxidant therapy may be considered as part of the treatment regimen for COPD patients.

Expression of heat stress protein 70 mRNA in patients with chronic obstructive pulmonary disease and its significance / 华中科技大学学报（医学）（英德文版）

The effects of cigarette smoke extract (CSE) on the expression of heat stress protein 70 (Hsp70) in human bronchi smooth muscle cells were investigated in vitro, and the changes in Hsp70 mRNA in the patients with chronic obstructive pulmonary disease and their significance were explored. Human bronchi smooth muscle cells were cultured with CSE at the different concentrations. The expression of Hsp70 mRNA and Hsp70 was detected by reverse translation-polymerase chain reaction (RT-PCR) and Western blotting respectively. Levels of Hsp70 mRNA and Hsp70 in lymphocytes from 20 patients with COPD and 20 healthy smoking control subjects were measured by RT-PCR and Western blotting. The results showed the expression of both Hsp70 mRNA and Hsp70 was decreased conformably in human bronchi smooth muscle cells treated with CSE at certain concentration in vitro. The A values of the Hsp70 mRNA expression were 0.24 +/- 0.11 and 0. 42 +/- 0.13 respectively in COPD patients and healthy smoking controls with the difference being significant (P < 0.01). There was also significant difference in the A values of the Hsp70 expression between COPD patients and healthy smoking controls (20.9 +/- 9.9 vs 44.8 +/- 15.3, P < 0.01). The levels of Hsp70 mRNA had strongly positive correlation with Hsp70 protein (r = 0.85, P < 0.01). It was suggested that the expression of Hsp70 mRNA was in concordance with the expression of Hsp70, which could provide a basis on the study of Hsp70 gene regulation and Hsp70 gene in the development of COPD.