Abstract
Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and induces increased mortality among COPD patients. However, there are no blood biomarkers to identify PH in COPD. Here, we investigated whether circulating angiogenic factors and cytokines could serve as (a) biomarker (s) for COPD-PH patients. Using Angiogenesis and Cytokine proteome profile array assay, we measured the level of 36 cytokines and 55 angiogenesis-associated proteins in plasma from four COPD patients with PH (COPD-PH) and four COPD patients without PH (COPD), respectively, tissue inhibitor of metalloproteinase 1 (TIMP-1) and thrombospondin 1(TSP-1) were significantly different between the two groups. Enzyme-linked immunosorbent assay (ELISA) was applied to measured TIMP-1 and TSP-1 in a validation cohort (COPD-PH, n = 28; COPD, n = 18), and TIMP-1 was the only factor that was significantly different between COPD-PH and COPD patients (P < 0.01). Logistic regression analysis demonstrated that elevated TIMP-1 was an independent risk factor for COPD-PH [odds ratio (OR) = 1.258, 95% CI: 1.005–1.574, P < 0.05). Next, we explored the expression level and function of TIMP-1 in human pulmonary arterial smooth muscle cells (hPASMCs) exposed to cigarette smoking extract (CSE, a major etiological factor of COPD). In cultured hPASMCs, CSE treatment increased both TIMP-1 protein level and cell proliferation, and exogenous TIMP-1 (25 ng/mL) treatment inhibited CSE-induced hPASMCs proliferation. Overall, our results indicated that TIMP-1 elevation could serve as a circulating biomarker to diagnose PH among COPD patients, and TIMP-1 elevation in COPD-PH could be adaptive.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by irreversible, progressive airflow obstruction
NT-pro-BNP, N-terminal pro-brain natriuretic peptide; predicted Forced expiratory volume in 1 s (FEV1), predicted forced expiratory volume in 1 s; EF, ejection fraction; RVD, the right ventricular diameter measured by Doppler Echocardiography, right atrium diameter (RAD), the transverse diameter of right atrium measured by Doppler Echocardiography; pulmonary arterial systolic pressure (PASP), systolic pulmonary arterial pressure measured by Doppler Echocardiography. *P < 0.05 vs. COPD group, **P < 0.01 vs. COPD group, absolute case numbers (% of cases in group)
Patients in the screening cohort were assessed by Doppler Echocardiography (ECHO), and those with PASP ≥ 35 mmHg were verified with Right Heart Catheterization (RHC, meam pulmonary arterial pressure (PAP) ≥ 20 mmHg) for Pulmonary hypertension (PH) diagnosis
Summary
Chronic obstructive pulmonary disease (COPD) is characterized by irreversible, progressive airflow obstruction. Pulmonary hypertension (PH) is a common complication of COPD and leads to cor pulmonale and even death [4, 5]. Plasma biomarkers can be efficiently measured in an non-invasive manner, serving as an ideal screening tool for diseases. Deranged angiogenic signaling and inflammation contribute to the pathogenesis of PH [11,12,13], and altered circulating angiogenic factors and cytokines have been reported in pulmonary arterial hypertension patients [14,15,16,17]. With an attempt to identify diagnostic blood biomarkers for PH in COPD, angiogenesis, and cytokines, proteome profile arrays were performed to screen the factors related to COPD-PH patients, and the identified biomarkers were further verified in a validation cohort
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