Diagnosis And Mechanism Of TIMP-1 In Chronic Obstructive Pulmonary Disease With Pulmonary Hypertension

【Background】The latest epidemiological data show that the incidence of chronic obstructive pulmonary disease(COPD)among people over the age of 40 in China is as high as about 13.7%,of which,30%-70% of the patients with chronic obstructive pulmonary disease may suffer from pulmonary hypertension,and the incidence of COPD-related pulmonary hypertension(COPD-PH)is increasing with time going on.The mortality and disability rate of COPD-PH are extremely high,which has become a disease that seriously affects the quality of life and labor force of patients,endangers people’s health and brings a huge burden to the society.The golden standard method to diagnose COPD-PH is right heart catheterization,which is invasive.If the patient is extremely severe,this method this method has a certain risk.However,there is no perfect circulating biomarker for the detection of COPD-PH currently.Therefore,it is of great significance to uncover a non-invasive circulating biomarker for the diagnosis of COPD-PH.Angiogenesis and cytokines are involved in the pathological changes of pulmonary hypertension.However,it remains unclear whether these factors may contribute to the development of PH during the course of disease development of COPD patients and their underlying molecular mechanisms.【Objectives】To explore whether there are angiogenesis factors and /or cytokines that can serve as non-invasive circulating biomarkers for diagnosis or treatment of COPD-PH,to evaluate the diagnostic value of screened non-invasive markers,to investigate the specific mechanisms of the screened non-invasive markers in COPD-PH.【Methods】1.We screened the plasma target factors which can distinguish the recruited COPD and COPD-PH patients from 55 angiogenic factors and 36 inflammatory factor protein-related detection kits.2.We expanded the sample size to verify the selected target proteins by ELISA method.Then we analyzed the collected clinical data of the recruited patients,the correlation between various indicators of clinical examinations(Spirometry,Doppler echocardiography),pro-BNP and target factors were analyzed,the diagnostic value of target factors was evaluated.3.The proliferation of human pulmonary artery smooth muscle cells stimulated by different concentrations of cigarette smoke was observed under microscope to explore the concentration of cigarette smoke stimulation when the proliferation of human pulmonary artery smooth muscle cells was the most.At the same time,the expression of target factors in human pulmonary artery smooth muscle cells before and after cigarette smoke stimulation was studied by immunoblotting.【Results】1.In the primary screening cohort,the expression levels of matrix metalloproteinase inhibitor-1(TIMP-1)and thrombospondin-1(TSP-1)detected in plasma of COPD-PH patient are higher than those in COPD;2.TIMP-1 expression increased in plasma of COPD-PH patients in the verification cohort by ELISA verification,and its optimal cut-off value was 2.53 ng/m L.3.The increase of TIMP-1 has a strong correlation with changes in pulmonary arterial systolic pressure(PASP)and pulmonary vascular resistance(Pulmonary Vascular Resistance,PVR).4.The cell proliferation was observed most after 0.5% CSE stimulation of human PASMCs for 36 hours.5.0.5% CSE can up-regulate the protein expression level of TIMP-1 after stimulating human PASMCs for 36 hours.【Conclusion】Compared with chronic obstructive pulmonary disease,the plasma level of TIMP-1 is significantly increased in patients with COPD-PH,and the optimal cut-off value is2.53 ng/m L.The increasing TIMP-1 has a strong correlation with PASP and PVR,which suggesting that it may be related to abnormal changes of pulmonary hemodynamic and abnormal right heart function.The plasma level of TIMP-1 may serve as a non-invasive circulating biomarker to distinguish whether COPD patients are accompanied with PH or not.