| BackgroudThe chronic airflow limitation characteristic of chronic obstructive pulmonary disease (COPD) is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema). Inhaled noxious substance leads to dysfunction of the epithelial cells and excessive secretion of mucus. Inflammation and fibrosis of the membranous bronchioles characterize the pathologic lesions that contribute to the small airway narrowing. The extent of inflammation, fibrosis and luminal exudates in small airways is correlated with the reduction with forced expiratory volume in one second(FEV1) and the ratio of FEV1 and forced vital capacity(FEV1/FVC), and probably with the accelerated decline in FEV1 characteristic of COPD. Several inflammatory cells and mediators interact with structural cells in airway and lung parenchyma and play an important role in the generation and aggravation of COPD. The tumor necrosis factor(TNF)-αand monocyte chemoattractant protein(MCP)-1 are two important inflammatory indictors which take part in the pathological process of COPD. TNF-a is a proinflammatory cytokine which is mainly produced by macrophages after stimulation of smoke, airborne contaminant, oxidative stress and so on. TNF-a lead to increased interleukin(IL)-8 release. IL-8 play a role in the recruitment of neutrophils which can active macrophages inversively and amplify the inflammatory effect. MCP-1 plays an important role in the migration of monocytes. Monocytes and the generated macrophages secrete active oxygen, intercellular matrix protein and lipid mediator such as leukotriene, prostaglandin, metalloprotease and several cytokine and chemokines. MCP-1 also takes part in the migration of lymphocytes and activation of monocytes and neutrophils.Systemic inflammation exists in COPD patients as well as airway inflammation. Myodystrophy, weight loss and exercise limitation which lead to decreased life quality and increased mortality may result from systemic inflammation. It is known that both airway and systemic inflammation exist in COPD patients and lead to severeal complications. However, the relationship between airway inflammation and systemic inflammation and the relationship between inflammation and quality of life still need to investigate. Since the goal of drug treatment for airflow limitation and pulmonary rehabilitation care is to improve quality of life in COPD patients, it is important to study the relationship between pathomechanism including inflammation of COPD and quality of life.The St' Georges respiratory questionnaire includes three parts:symptom, activity and impact. It is a specific questionnaire for health-related quality of life(HRQL) in patients with chronic airflow obstruction. SGRQ correlates strongly with symptoms, lung function and risk of exacerbation in COPD patients.The ratio of FEV1 and its predicted value (FEV1%), which is often used to grade the severity of COPD, can reflect the impairment of respiratory function and prognosis of this disease to some extent. However, FEV1% can not reflect the whole health status of COPD patients. BODE index which means body mass(B), degree airflow obstruction(O), dyspnea(D) and exercise capacity(E), includes body-mass index(BMI), FEV1%, the modified Medical Research Council(MMRC) dyspnea scale and 6-minutes walk distance(6MWD). It has been widely confirmed that BODE index correlates strongly with HRQL and that BODE index can better predict mortality in COPD patients than FEV1%.In this study, induced sputum and serum levels of TNF-a and MCP-1 were analysis, as well as the relationship between inflammation levels and lung function and quality of life in stable COPD patients.Objectives1. To investigate the induced sputum and serum levels of TNF-a and MCP-1 in stable COPD patients.2. To explore the relationship between inflammation levels and lung function and quality of life in stable COPD patients.Methods1. Subjects There were three study groups in this study:30 mild-moderate COPD patients,26 severe-very severe COPD patients and 28 healthy subjects. Informed consent was obtained from each participant.1.1 Mild-moderate COPD patients1.1.1 Enrollment Criteria: (1)Meeting the diagnosis criteria of COPD in Diagnosis and Management of Chronic Obstructive Pulmonary Disease 2007 (Chinese Society of Respiratory Disease). (2)The ratio of FEV1 and its predicted value (FEV1%)≥50%. (3)Symptoms including cough, sputum production and dyspnea slight or in stable status. (4)Normal hepatic function and renal function.1.1.2 Excluded criteria: (1) Other disease of respiratory system. (2) Malignant tumor, severe congestive heart failure, connective tissue disease, bone and joint disease or neuromuscular junction disease. (3) Reception of operation in the last 6 months. (4) Myocardial infarction or unstable angina pectoris attacks in the last 1 months. (5) Reception of glucocorticoid, inflammatory factor inhibitor, nutritional support or lowering lipoids therapy. (6) Exacerbations in the last 8 weeks. The COPD exacerbation was definined as: aggravation of cough, expectoration, short breath and(or) gasping; increased sputum production with purulence with or without phlegm; fever.1.2 Severe-very severe COPD patients1.2.1 Enrollment criteria (1)Meeting the diagnosis criteria of COPD in Diagnosis and Management of Chronic Obstructive Pulmonary Disease 2007 (Chinese Society of Respiratory Disease). (2)The ratio of FEV1 and its predicted value (FEV1%)<50%. (3)Symptoms including cough, sputum production and dyspnea slight or in stable status.(4)Normal hepatic function and renal function.1.2.2 Excluded criteria (1) Other disease of respiratory system. (2) Malignant tumor, severe congestive heart failure, connective tissue disease, bone and joint disease or neuromuscular junction disease. (3) Reception of operation in the last 6 months. (4) Myocardial infarction or unstable angina pectoris attacks in the last 1 monthes. (5) Reception of glucocorticoid, inflammatory factor inhibitor, nutritional support or lowering lipoids therapy. (6) Exacerbations in the last 8 weeks. The COPD exacerbation was defined as: aggravation of cough, expectoration, short breath and(or) gasping; increased sputum production with purulence with or without phlegm; fever.1.3 Healthy subjects1.3.1 Enrollment Criteria: (1)55 years old and above. (2)No abnormality in radiological examination on chest. (3)Normal hepatic function and renal function.1.3.2 Excluded criteria (1) Chronic disease of respiratory system. (2) Reception of operation in the last 6 months. (3) Myocardial infarction or unstable angina pectoris attacks in the last 1 monthes. (4) Reception of glucocorticoid, inflammatory factor inhibitor, nutritional support or lowering lipoids therapy. (5) Respiratory infection in the last 8 weeks.2. Study design2.1 Detection of induced sputum and serum levels of TNF-a and MCP-1. Serum and induced sputum were collected from all the subjects. TNF-a and MCP-1 in these samples were detected by used of enzyme linked immunosorbent sorbent assay. 2.2 Pulmonary function test Forced expiratory volume(FVC) and the ratio of FVC and predicted value(FVC%), FEV1, FEV1% and FEV1/FVC were detected in the pulmonary function test.2.3 BODE index2.3.1 BMI Height and weight of each participant were measured and BMI(kg/m2) was calculate from the following formula:BMI=W/H2.2.3.2 FEV1% FEV1% was detected in the pulmonary function test.2.3.3 MMRC dyspnea scale The MMRC dyspnea scale was detected.2.3.4 6MWT 6MWD was detected in the 6MWT, which was performed according to the ATS Statement:Guidelines for the Six-Minute Walk Test (American Thoracic Society).2.3.5 Values of BMI, FEV1%, MMRC dyspnea scale and 6MWD were totalled to final BODE index. Point values for the computation of BODE index: 0 BMI>21kg/m2, FEV1%>65%, MMRC dyspnea scale 0-1,6MWD>350m; 1 BMI≤21kg/m2, FEV1%50-64%, MMRC dyspnea scale 2,6MWD 250-349m; 2 FEV1%>36-49%, MMRC dyspnea scale 3,6MWD≥150-249m; 3 FEV1%≤35%, MMRC dyspnea scale 4,6MWD≤149m。;2.4. SGRQ St George's Respiratory Questionnaire Manual was performed in each COPD patients and each part and the total SGRQ score were detected.3. Statistical analysis SPSS 13.0 software package was used for statistical analysis. Variances of successive type were presented as mean±standard deviation.χ2-test was used for difference of gender among the three groups. One-way analysis of variance was used for difference of age, level of biomarkers, lung functions, BMI,6MWD and BODE index among the three groups. LSD-t tset was used for multiple comparison in variances with homogeneity and Dunnett's T3 test in variances without homogeneity. Kruskal-Wallis H was used for difference in MMRC dyspnea scale. Independent-T test was used for differences between mild-moderate COPD patients and severe-very severe COPD patients. Linear correlation analysis was performed to evaluate the relationship between the induced level and serum level of each biomarker. Linear regression was used for analyzing correlations between biomarker levels and lung function and quality of life in COPD patients. A value of P less than 0.05 was considered as statistical significance.Results1. Clinical characteristics Ages in mild-moderate COPD patients, severe-very severe COPD patients and healthy subjects were (67.36±8.82)years old, (70.30±7.94) years old and (69.73±8.66) years old respectively and there was no significant difference in the three groups. There were 30 mild-moderate COPD patients with 27 males and 3 females,26 severe-very severe COPD patients with 24 males and 2 females and 28 healthy subjects with 24 males and 4 females. There was no significant difference of age among the three groups.2. Induced sputum and serum levels of TNF-a and MCP-1 in the three groups Induced sputum levels of TNF-a in mild-moderate COPD patients, severe-very severe COPD patients and healthy subjects were (15.78±11.89)pg/ml, (21.91±19.31)pg/ml and (6.89±11.68)pg/ml respectively and there was significant difference in the three groups(F=7.325, P=0.001).The multiple comparison between mild-moderate COPD patients and healthy subjects(P=0.017) and the one between severe-very severe COPD patients and healthy subjects(P=0.004) were statistically significant. Induced sputum levels of MCP-1 in the three groups were (218.97±180.50)pg/ml, (352.18±289.36)pg/ml and (203.76±243.49)pg/ml respectively and there was significant difference in the three groups(F=6.795, P=0.049). The multiple comparison between mild-moderate COPD patients and severe-very severe COPD patients(P=0.044) and the one between severe-very severe COPD patients and healthy subjects(P=0.016) were statistically significant. Serum levels of TNF-αin the three groups were (4.00±5.58)pg/ml, (9.77±10.31)pg/m and (3.27±4.26)pg/ml respectively and there was significant difference in the three groups(F=7.325,P=0.002). The multiple comparison between mild-moderate COPD patients and severe-very severe COPD patients(P=0.017) and the one between severe-very severe COPD patients and healthy subjects(P=0.004) were statistically significant. Serum levels of MCP-1 in the three groups were (210.53±208.59)pg/ml, (373.55±304.17)pg/ml and (90.77±72.63)pg/ml respectively and there was significant difference in the three groups(F=11.801, P<0.001). The multiple comparison between mild-moderate COPD patients and healthy subjects (P=0.016), and the one between severe-very severe COPD patients and healthy subjects (P<0.001)were statistically significant.3. BODE index in the three groups BMI in the three groups were (22.16±2.86)kg/m2, (22.14±3.31)kg/m2 and (23.15±4.10)kg/m respectively and there was no significant difference in the three groups. FEV1% in the three groups were (69.47±17.74)%, (34.73±6.60)% and (105.71±18.65)% respectively and there was significant difference in the three groups(F=140.488P<0.001).The multiple comparison between each group were all statistically significant(P<0.001). The average rank of MMRC dyspnea scale in the three groups were 38.30,70.65 and 23.07 respectively,χ2=38.261, P<0.001. 6MWD in the three groups were (401.63±68.57)m, (373.88±69.44)m and (401.32±144.95)m respectively and there was no significant difference in the three groups.BODE index in the three groups were (3.56±1.94), (1.10±1.03) and (0.29±0.46) respectively and there was significant difference in the three groups(F=84.828, P< 0.001). The multiple comparison between mild-moderate COPD patients and healthy subjects(P<0.001), the one between severe-very severe COPD patients and healthy subjects(P<0.001) and the one between mild-moderate COPD patients and healthy subjects(P=0.001) were statistically significant.4. Clinical characteristics and SGRQ in mild-moderate COPD patients and severe-very severe COPD patients Course of disease in mild-moderate COPD patients and severe-very severe COPD patients were (6.46±8.92) and (16.88±15.22)years respectively and there was significant difference in the two groups(t=-3.065, P=0.004). Exacerbations in the two groups were (30.63±1.13) and (1.31±1.26) times respectively and there was significant difference in the two groups(t=-2.114, P=0.039). SGRQ total score in the two group were (25.45±16.55) and (37.97±18.69) respectively and there was significant difference in the two groups(t=-2.658, P=0.010). SGRQ symptom score in the two groups were (44.73±20.01) and (53.52±18.64) respectively and there was no significant difference in the two groups. SGRQ activity score in the two groups were (25.45±22.52) and (40.16±24.46) respectively and there was significant difference in the two groups(t=-2.343, P=0.023). SGRQ impact score in the two groups were (19.03±17.25) and (30.00±20.77) respectively and there was significant difference in the two groups(t=-2.160, P=0.035).5. Comparison and correlationship between induced sputum and serum levels of biomarkers In overall COPD patients, TNF-a level in induced sputum and serum were (18.62±15.92)pg/ml and (6.68±8.55)pg/ml respectively and there was significant difference between the levels of the two samples(t=4.947, P< 0.001), but there was no significant correlation between them. MCP-1 level in induced sputum and serum were (280.82±244.40)pg/ml and (286.22±267.82)pg/ml respectively and there was no significant difference between the levels of the two samples and there was no significant correlation between them. In mild-moderate COPD patients, TNF-a level in induced sputum and serum were (15.78±11.89)pg/ml and (4.00±5.58)pg/ml respectively and there was significant difference between the levels of the two samples (t=4.915, P<0.001), but there was no significant correlation between them. MCP-1 level in induced sputum and serum were (218.97±180.50)pg/ml and (210.53±208.59)pg/ml respectively and there was no significant difference between the levels of the two samples and there was no significant correlation between them.In severe-very severe COPD patients, TNF-a level in induced sputum and serum were (21.91±19.31)pg/ml and (9.77±10.31)pg/ml respectively and there was significant difference between the levels of the two samples (t=-2.828, P=0.007), but there was no significant correlation between them. MCP-1 level in induced sputum and serum were (352.18±289.36)pg/ml and (373.55±304.17)pg/ml respectively and there was no significant difference between the levels of the two samples and there was no significant correlation between them. 6. Multivariate models of linear regression between biomarker levels and lung function and quality of life in COPD patients In overall COPD patients, SGRQ impact score(β=0.280,t=2.144, P=0.037) was included in the multivariate model of induced sputum levels of TNF-a(R=0.280, adjusted R2=0.061, P=0.037). BODE index(β=0.318, t=2.461,P=0.017) was included in the multivariate model of induced sputum levels of MCP-1 (R=0.318, adjusted R2=0.084, P=0.017). FEV1/FVC (β=-0.489, t=-4.120, P<0.001) was included in the multivariate model of serum levels of TNF-a(R=0.280, adjusted R2=0.225, P<0.001). MMRC dyspnea scale (β=0.406,t=3.267, P=0.002) was included in the multivariate model of serum levels of MCP-1 (R=0.406, adjusted R2=0.150, P=0.002). In mild-moderate COPD patients, BMI (β=0.505,t=3.099, P=0.004) was included in the multivariate model of induced sputum levels of TNF-a(R=0.505, adjusted R2=0.229, P=0.004).6MWD (β=-0.396, t=-2.412, P=0.023) and MMRC dyspnea scale (β=0.258, t=-2.180, P=0.038) were included in the multivariate model of induced sputum levels of MCP-1(R=0.522, adjusted R2=0.218, P=0.014). The multivariate model of serum levels of TNF-a and serum levels of MCP-1 were not statistically significant.In severe-very severe COPD patients, FEV1/FVC(β=-0.532, t=-3.215,P=0.004) and SGRQ total core(β=0.344,t=2.079, P=0.049)were included in the multivariate model of serum levels of TNF-a(R=0.611, adjusted R2=0.319, P=0.005). FEV1/FVC(β=-0.377, t=-2.195, P=0.038) and MMRC dyspnea scale(β=0.535,t=3.121, P=0.005) were included in the multivariate model of serum levels of MCP-1 (R=0.591, adjusted R2=0.293, P=0.007). The multivariate model of induced sputum levels of TNF-a and induced sputum levels of MCP-1 were not statistically significant.Conclusions1. Both TNF-a and MCP-1 levels increased in airway and serum in stable COPD patients and especially in severe-very severe COPD patients.2. level of TNF-a in serum was lower than the one in induced sputum, while there was no difference between induced sputum and serum level of MCP-1. There was no correlation between induced sputum and serum level of both the two biomarkers..3. Quality of life was poor in stable COPD patients. BODE index increased in COPD patients as well as MMRC dyspnea scale. Poor FEV1% also happened in COPD patients. BODE index in severe-very severe COPD patients was higher than the one in mild-moderate COPD patients. However, there was no difference between COPD patients and healthy subjects in BMI and 6MWD. SGRQ total score was higher in severe-very severe COPD patients compared to mild-moderate COPD patients, as well as activity score and impact score.4. There were significant correlations of induced sputum levels of TNF-a and MCP-1 with lung function and quality of life, especially in mild-moderate COPD patients, but the correlation coefficient was relatively small. There were also correlations of serum levels of TNF-a and MCP-1 with lung function and quality of life, especially in severe-very severe COPD patients, and the correlation coefficient was relatively great. These correlations reflect the relationship between detectable biomaker levels in COPD patients and the disease status of them. It was also found that induced sputum levels of these two biomarkers were more valuable in mild-to moderate patients and the ones in serum were more valuable in severe-to very severe patients. |
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