Study On The Expression And Correlation Of Soluble Urokinase-type Plasminogen Activator Receptor And Biomarker Group In COPD

Objective: Chronic obstructive pulmonary disease(COPD)has the characteristics of high morbidity and high mortality in patients with acute exacerbations(AECOPD).At present,there is a lack of clinical biomarkers for the diagnosis of COPD,especially for the prediction of AECOPD,and studies on the clinical features and diagnosis and treatment strategies for COPD disease at high altitude,especially for areas above 3000 meters,are insufficient.In this thesis,COPD patients were divided according to the course of disease and lung function,and the expression differences of serum soluble urokinase-type plasminogen activator receptor(su PAR),C-reactive protein(CRP),procalcitonin(PCT),interleukin 6(IL-6)and plasma fibrinogen(FIB)between different COPD subgroups were analyzed.According to the results of difference analysis,the correlation of su PAR and other biomarkers with the severity of COPD and clinical indicators was explored,and the potential mechanism of su PAR involved in the occurrence and development of COPD was speculated and analyzed.Further diagnostic studies were conducted to evaluate the diagnostic and predictive effects of su PAR and other biomarkers and groups on COPD / AECOPD patients.In order to explore an objective,efficient and easy-to-promote diagnosis method for COPD in high altitude areas,this thesis further discusses the similarities and differences in clinical manifestations,detection indicators and diagnostic methods of COPD patients in high and low altitude areas through subgroup study,which provides support for chronic disease management in high altitude areas and Tibetan population.Methods: The thesis research is divided into two parts: evidence-based medicine research and clinical research.In the part of evidence-based medicine,we review articles about biomarkers used to diagnose and predict COPD through literature search,and discover candidate biomarkers;then we explore the clinical application effects of su PAR on COPD through systematic reviews and meta-analysis.In the clinical research part,patients admitted to the hospital with COPD or AECOPD as the main diagnosis from May to November 2020 in Lanzhou University First Hospital and Xiahe County People’s Hospital were included as the research objects,and the health checkups during the same period were included as controls.According to the clinical diagnosis,the subjects were divided into stable COPD group(s COPD)and acute exacerbation COPD group(AECOPD).For the included population,baseline data were collected and pulmonary function tests were performed.Serum samples of the observation group were collected on the day of admission,7 days after treatment,and on discharge.The enzyme-linked immunosorbent assay(ELISA)was used to detect the expression levels of serum su PAR,CRP,PCT,IL-6 and plasma FIB,and the expression characteristics of these five biomarkers in COPD/AECOPD patients were analyzed.Through the establishment of univariate and multivariate regression models,the correlation between biomarkers and lung function and clinical biochemical indicators was explored.The receiver operating characteristic(ROC)curve was used to evaluate and analyze the diagnostic and predictive effects of su PAR on COPD/AECOPD patients,and to further explore the better biomarker diagnostic groups.Finally,a subgroup analysis was performed on the included population based on altitude,and the similarities and differences between the clinical manifestations and clinical detection indicators of COPD patients in high and low altitude areas were analyzed.The recommended cutoff values of su PAR and other biomarkers for different clinical types of COPD patients were explored,and the diagnostic and predictive effects of biomarkers and their groups on COPD at different stages were given.Results: According to the results of systematic reviews and Meta analysis,compared with COPD patients with FEV1≥80%(WMD = 320.25;95% CI: 99.79-540.71),su PAR levels in patients with FEV1 <80%(WMD = 2950.74;95%CI:2647.06-3254.43)are higher.The sensitivity and specificity of su PAR in the diagnosis of COPD were 87% and 79%,respectively,and the AUC was 84%.Su PAR can effectively identify the acute exacerbation of COPD in healthy people(WMD=3114.77;95%CI: 2814.66-3414.88),and it has the potential to distinguish AECOPD from stable COPD(WMD=351.40;95%CI: 215.88-486.93).The level of su PAR decreased significantly after treatment [WMD=-1226.97;95%CI:-1380.91-(-1073.03)].The clinical study showed that there were significant differences in serum su PAR levels among the three groups(healthy control: 1.85 ± 0.48 ng / ml,s COPD: 2.43 ±0.50 ng / ml,AECOPD: 3.32 ± 0.58 ng / ml,P < 0.001),similar performances were also found in CRP and FIB,PCT and IL-6 levels were not statistically different between the s COPD group and the control group.In addition,serum su PAR levels are also statistically different among GOLD Ⅱ,Ⅲ,and Ⅳ groups.According to the correlation study,the five biomarkers are correlated in pairs.Among the clinical indicators,su PAR was mainly related to inflammatory cell indicators,and monocyte count was an independent influencing factor of su PAR level,and increased monocyte count indicated an increased risk of COPD(OR=1.82;95%CI:1.24-2.66).The sensitivity and specificity of su PAR in the diagnosis of COPD were 91% and 74%,respectively,and the AUC was 89%,which was higher than that of CRP,IL-6,PCT and FIB.su PAR combined with CRP showed the best performance,with sensitivity of 82%,specificity of 96% and AUC of 93%.Serum su PAR diagnosed s COPD with sensitivity of 0.852,specificity of 0.741,AUC of 0.805;the biomarker group of su PAR+CRP+FIB had a sensitivity of 0.722,specificity of 0.926,and AUC of 0.872.Serum su PAR diagnosed AECOPD with sensitivity of 0.672,specificity of 0.944,AUC of 0.872;the biomarker group of su PAR+CRP+PCT had the highest AUC value of 0.918,and sensitivity is0.862,and specificity is 0.833.The serum level of su PAR was 3.32 ± 0.58ng/ml at admission,and it decreased to 2.44 ± 0.62ng/ml after seven days of regular treatment(P < 0.01),indicating that the serum level of su PAR can timely reflect the therapeutic effect of AECOPD.Subgroup analysis based on altitude found that there were statistical differences in the following indicators between the two groups(P < 0.05): forced expiratory volume in one second(FEV1),FEV1%,forced vital capacity(FVC),total lung volume(TLV)and CRP,which were significantly higher in Xiahe area than in Lanzhou area,and the level of serum su PAR in Lanzhou area was significantly higher than that in Xiahe area.In the diagnostic study,it was found that the dual biomarker group of su PAR + CRP in Lanzhou area could achieve the similar effect of five biomarker group,with Sen of0.911,SPE of 0.904 and AUC of 0.963;the triple index of su PAR + PCT + CRP in Xiahe area could achieve the similar effect of five indexes,with sensitivity of 0.804,specificity of 0.941,and AUC of 0.896.Serum su PAR and CRP show good clinical application value in the diagnosis of COPD,stable COPD and prediction of acute exacerbation in populations in both high and low altitude areas.Conclusion: Serum su PAR levels are significantly correlated with lung function,disease severity,and inflammation in COPD patients.It has advantages over other commonly used biomarkers in identifying early(or mild)COPD patients,suggesting that the application of su PAR is conducive to the early diagnosis and treatment of COPD disease.In addition,su PAR may also participate in the inflammatory response process of COPD disease through the mutual interaction with monocytes.A single biomarker lacks reliability in disease diagnosis,and a group composed of multiple biomarkers can better reflect the complex state of COPD disease and effectively improve clinical applicability.The dual group of su PAR and CRP can make up for the lack of a single indicator,and has a stable and good performance in diagnosing COPD,identifying early(or mild)patients,and prompting acute exacerbations.The lung function and reserve capacity of people in high-altitude areas are better than those in low-altitude areas.Based on su PAR+CRP,biomarker groups should be adjusted accordingly based on the characteristics of the local population’s disease manifestations and medical conditions.This could be an objective,efficient and easily popularized method for the diagnosis of COPD diseases in high altitude areas.