| BackgroundChronic obstructive pulmonary disease (COPD for short) is a common respiratory disease with airflow limitation, its airflow limitation is usually progressing gradually, accompanied by chronic airway inflammation after inhalation of harmful gases or particles. The main clinical manifestations of COPD are dyspnea,chronic cough and sputum.With the aging of the world population, reduced mortality from other common causes of death(e.g. ischemic heart disease,infectious disease) and expanding epidemic of smoking, COPD mortality increased year by year. A data from World Health Organization showed that in 2012 a total of 310 million people died of COPD globally, accounting for 5.6% of total global deaths, chronic obstructive pulmonary disease in 2012 becoming the world’s third leading cause of death; according to the Global Burden of Disease project by 2020 COPD will continue to occupy the third causes of death worldwide. COPD is associated with significant economic burden as well as social burden according to its increased mortality. GOLD 2016 data showed that in the European Union,the direct costs of respiratory disease are estimated to be about 6% of the total health budget,with COPD accounting for 56% of this cost of respiratory disease. While in China COPD is also not popular.In 2007, A survey data showed that in Beijing, Tianjin, Shanghai, Guangzhou and other seven regions about 8.2% people old than 40 years were diagnosed with COPD,especially the prevalence among men even reached 12.4%.Inflammation plays an important role in the pathogenesis and progression of COPD. After long-term repeated inhalation of harmful gases or particles, chronic respiratory tract inflammation formed in patients with COPD, which may be associated with genetic susceptibility. Inflammatory cells involved in this inflammation are mainly CD8+T cells, neutrophils and macrophages. These cells may release large amounts of various inflammatory mediators and proteases after chronic irritation, causing local tissue damage, local tissue repeated injury and repair, finally airway remodeling, resulting in not fully reversible airflow limitation. At the same time, local inflammatory mediators spoiled into the pulmonary circulation through pulmonary circulation, with or without extra pulmonary complications. The levels of these inflammatory mediators in peripheral blood of patients were reported to associated with the severity of COPD, which were usually CRP, TNF-α,IL-6 and Fbg, but at the same time these inflammatory mediators present poor specificity or sensitivity. To this end, the present study attempts to investigate a biomarker with high sensitivity and specificity, even better performance of COPD inflammatory markers.Myeloid cells triggering receptors (TREMs) are a class of transmembrane immunoglobulin superfamily consisting of receptors expressed on myeloid cells, which’s expression levels in different tissues each are different. Recent studies showed that the TREMs mainly have TREM-1, TREM-2, TLT-1 and TLT-2 four subtypes, each subtype plays a unique role in the pathophysiology.The same kind of cells can express a variety of TREMs, of which TREM-1 is the focus of inflammation-related diseases research.In 2000 Bouchon et al discovered a novel cell receptor TREM-1, TREM-1 is mainly expressed on myeloid cells surface of monocytes, neutrophils e.g, the gene of which is located on chromosome 6p21. It’s reported that TREM-1 work synergistically with TLR, NLR and other pattern recognition receptors recognize and bind pathogen-associated molecular patterns (such as Gram-negative bacteria, Gram-positive bacteria, fungi components), switching on the body’s innate immune response, causing the neutrophils to release myeloperoxidase and nitric oxide accentuating neutrophils and monocytes to express adhesion molecules, TNF-a, IL-1, IL-6, IL-8, MCP-l,et al, local inflammatory reaction amplifies. At the same time studies showed that Gram-positive bacteria, Gram-negative bacteria and fungi cell components of LPS, CpG oligodeoxynucleotide, etc. can up-regulate the TREM-1 expression of myeloid cells such as neutrophils, monocytes.Matrix metalloproteinase is reported to cut TREM-1 on the cell membrane to form the soluble TREM-1 (sTREM-1), which is found in serum, pleural fluid, peritoneal fluid, cerebrospinal fluid, and other body fluid. Since the myeloid cell surface TREM-1 are always up-regulated by a pathogen component,early study of TREM-1 was mostly focused on sepsis, pneumonia, peritonitis, meningitis and other infectious diseases, and sTREM-1 was regarded as a marker of infection. Recent studies have found that, the expression of TREM-1 in psoriasis, rheumatoid arthritis, inflammatory bowel disease and some other non-infectious diseases also increased.More and more studies have found, TREM-1 has a close relationship with respiratory diseases. TREM-1 is also expressed on airway epithelial cells other than myeloid cells, working with TREM-2 and DAP-12 to regulate airway inflammation, airway hyperresponsiveness and airway permeability. Radsak found that sTREM-1 levels in patients with stable COPD were significantly higher than smokers and healthy population, and positively correlated with lung function in patients with COPD. Subsequent studies have found that serum sTREM-1 levels were even higher in patients with acute exacerbation of COPD, suggesting that TREM-1 may be involved in the development of COPD.This study attempts to determine the clinical value of sTREM-1 in COPD severity assessment and analyze the correlation betwwen sTREM-1 and other inflammatory factors to learn more about COPD pathogenesis and development,to provide new ideas for the assessment and treatment of chronic obstructive pulmonary disease.Part one:The detection and clinical value of serum sTREM-1 in patients with COPDObjective The aim of this study is to determine the value of sTREM-1 in COPD assessment and bacterial infection diagnosis.Materials and methods1. subjectsCOPD exacerbations group:from January 2015 to August 2015 randomly selected 60 patients with acute exacerbation of COPD from inpatients, including 48 men,12 women, mean age 63.45 ± 9.77 years old. ① diagnostic criteria according to "chronic obstructive pulmonary disease treatment guidelines (2013 Revision)"; ② unused glucocorticoid drugs before admission; ③ ruling out infection outside the lungs; ④ excluding tuberculosis; ⑤ ruling out cancer, rheumatism and autoimmune diseases etc; ⑥ excluding end-stage heart, lung, liver or kidney disease.Stable COPD group:Select 101 patients with COPD in the same period from inpatients and outpatients,77 cases were male,24 female, mean age 62.91 ± 8.96 years. Sex and age matched with acute exacerbation of COPD group. Inclusion and exclusion criteria consistent with acute exacerbation COPD group, and without acute attack within two months.The healthy control group:randomly selected 81 cases from the same period medical center healthy persons as a control group,61 cases were male and 10 female, mean age 62.25 ± 8.79 years. Exclusion of infectious, non-infectious systemic inflammatory diseases, cancer, autoimmune diseases and end-stage heart, lung, liver or kidney disease.2. Determination of clinical parameters(1) serological parameters were measured:three groups of subjects collected fasting blood after centrifugation supernatant. sTREM-1 enzyme-linked immunosorbent assay was measured, hs-CRP by immune turbidity measurement.(2) CAT score:All COPD patients were asked to fulfill the COPD Assessment Test (CAT), record their scores.(3) Other clinical parameters:record the results of lung function, arterial blood gas, blood, sputum culture,the frequency of exacerbations in the past year and other information.3. Statistical analysisAll data were analysed using SPSS20.0. Measurement data were presented as mean ± standard deviation. Two independent samples t-test were used for mean comparison between two groups;while ANOVA for comparison among three groups;Ratio comparison between the two groups were using the x2est. Correlation analysis was performed using Pearson test.Multiple linear regression were performed to analyse multiple assosiation. p<0.05 was considered statistically significant.Results1. Serum sTREM-1 levels of acute exacerbation of chronic obstructive pulmonary disease were significantly higher than stable COPD patients and healthy control group (165.96 ± 39.09pg/ml to 113.2 ± 31.5pg/ml to 83.8 ± 17.9pg/ml), among the three groups was statistically significant (F= 130.452, p= 0.000) difference between any two differences were statistically significant (p<0.05).2. Leukocyte count, hs-CRP concentrations of acute exacerbation of COPD group were (11.13 ± 2.59)× 109/L,14.72 ± 3.20mg/L1; white blood cell counts, hs-CRP concentrations of stable COPD group were (8.03 ± 1.70) × 109/L,3.12 ± 1.93mg/L; WBC counts, hs-CRP concentrations of healthy control group were (7.19 ± 1.40) × 109/L,2.01 ± 0.87mg/L. Patients with acute exacerbation have significantly higher white blood cell counts, hs-CRP than in stable COPD patients and healthy control group (p<0.05), and pairwise comparisons have statistically significant differences (p<0.05).3. Serum sTREM-1, hs-CRP levels in acute exacerbation of chronic obstructive pulmonary disease were significantly negatively correlated with FEV1% pred(r=-0.579, p= 0.000; r=-0.291, p= 0.003); Serum sTREM-1, hs-CRP levels in stable chronic obstructive pulmonary disease were significantly negatively correlated with FEV1% pred(r=-0.472, p= 0.000; r=-0.350, p= 0.006).4.Serum sTREM-1, hs-CRP levels in acute exacerbation of chronic obstructive pulmonary disease group were positively correlated with CAT scores(r= 0.629, p= 0.000; r= 0.513, p= 0.000); sTREM-1, hs-CRP levels with CAT scores stable chronic obstructive pulmonary disease serum also showed a significant correlation (r = 0.507, p= 0.000; r= 0.396, p= 0.000).5. In acute exacerbation of chronic obstructive pulmonary disease group,serum sTREM-l, hs-CRP levels were negatively correlated with PaO2 (r=-0.658, p= 0.000; r=-0.438, p= 0.000); In serum stable chronic obstructive pulmonary disease group,sTREM-1 with PaO2 also showed a significant negative correlation (r=-0.439, p= 0.000), hs-CRP and PaO2 was not significant correlated (r=-0.156, p= 0.120).6. In acute exacerbation of chronic obstructive pulmonary disease group, serum sTREM-l levels of sputum culture positive group were significantly higher than sputum culture-negative group (196.60 ± 34.1 lpg/ml to 144.07 ± 25.43pg/ml), the difference was statistically significant (t=-6.838, p<0.05). making ROC curve for sputum culture negative and positive groups, area under the ROC curve of sTREM-l, hs-CRP and WBC was 0.917 (95%CI:0.845-0.988, p<0.05),0.802 (95% CI:0.687-0.918, p＜0.05),0.895 (95% CI:0.819-0.972, p<0.05) respectively.Conclusions1.Serum sTREM-1 levels are generally higher in COPD patients, especially in patients with acute exacerbation.2.Serum sTREM-1 of COPD patients was significantly correlated with FEV1% pred, CAT score, suggesting sTREM-1 is of a potential value in assessing COPD.3. The serum sTREM-1 of COPD patients was significantly correlated with PaO2, suggesting that sTREM-1 may be used as a marker of hypoxia in COPD.4. sTREM-1 in patients with acute exacerbation COPD has a potential diagnostic value of of bacterial infection.Part two:The correlation of serum sTREM-1 with TNF-α and IL-6 in chronic obstructive pulmonary diseaseObjective The aim of this study is to analyse the relationship of sTREM-1 with TNF-a and IL-6 in patients with chronic obstructive pulmonary disease.Mateials and methods1. subjects (see part one)2.Determination of indicators:TNF-a, IL-6 were measured by enzyme-linked immunosorbent assay. Other assays, see part one.3. Statistical analysis All data were analysed using SPSS20.0. Measurement data were presented as mean ± standard deviation. Two independent samples t-test were used for mean comparison between two groups;while ANOVA for comparison among three groups;Ratio comparison between the two groups were using the x2est. Correlation analysis was performed using Pearson testMultiple linear regression were performed to analyse multiple assosiation. p<0.05 was considered statistically significant.Results1. Serum TNF-a, IL-6 concentrations of acute exacerbation of chronic obstructive pulmonary disease group were 131.17 ± 29.56pg/ml,72.74 ± 13.07pg/ml;serum TNF-a, IL-6 concentration in stable chronic obstructive pulmonary disease group were 46.91 ± 11.00pg/ml,31.55 ± 7.21pg/ml;Serum TNF-a, IL 6-concentrations of healthy control group were 22.66 ± 4.92pg/ml,10.77 ± 2.37pg/ml. serum levels of TNF-a, IL-6 in Acute exacerbation of patients were significantly higher than in stable COPD patients and healthy control group (p<0.05), and pairwise comparisons difference was statistically significant (p<0.05).2. Serum TNF-a, IL-6 levels in chronic obstructive pulmonary disease with acute exacerbationgroup were significant negatively correlated with FEV1% pred (r =-0.300, p= 0.002; r=-0.418, p= 0.000);ln stable COPD group,serum TNF-a, IL-6 levels with FEV1% pred also showed a significant negative correlation (r=-0.392, p = 0.002; r=-0.407, p= 0.001).3. Serum TNF-a, IL-6 levels in acute exacerbation of chronic obstructive pulmonary disease group with CAT scores were positively correlated (r= 0.370, p= 0.004; r= 0.358, p= 0.005); in stable chronic obstructive pulmonary disease group, serum TNF-a, IL-6 levels with CAT scores also showed a significant negative correlation (r= 0.327, p= 0.001; r= 0.398, p= 0.000).4. In acute exacerbation of chronic obstructive pulmonary disease group, serum TNF-a, IL-6 levels with PaO2 were negatively correlated (r=-0.414, p= 0.001; r=-0.275, p= 0.033); serum TNF-a, IL-6 levels in stable chronic obstructive pulmonary disease group with PaO2 also showed a significant negative correlation (r=-0.277, p = 0.005; r=-0.408, p= 0.000).5.Serum levels of COPD patients showed a significant positive correlation with TNF-a, IL-6 (r= 0.770, p= 0.000; r= 0.786, p= 0.000).6. Multiple linear regression analysis of serum sTREM-1 levels in patients with COPD showed that, TNF-a, IL-6, hs-CRP and WBC all had a positive correlation with sTREM-1 independently (0= 0.315, P<0.05; 0= 0.451, P<0.05; p= 0.250, P <0.05;P= 0.377, PO.05).Conclusions1. Serum TNF-a, IL-6 levels were generally higher in patients with chronic obstructive pulmonary disease, especially in patients with acute exacerbation.2.Serum TNF-a, IL-6 of COPD patients were significantly correlated with FEV1%pred and CAT scores, suggesting that the potential value of TNF-a, IL-6 to assess COPD.3.Serum sTREM-1,TNF-a and IL-6 in COPD patients were all increased and independently positively correlated, suggesting sTREM-1, TNF-a and IL-6 may participate in the same inflammatory pathway in COPD. |
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