TIMP-1: A Circulating Biomarker for Pulmonary Hypertension Diagnosis Among Chronic Obstructive Pulmonary Disease Patients

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.

LRG1 promotes the apoptosis of pulmonary microvascular endothelial cells through KLK10 in chronic obstructive pulmonary disease

“…According to a previously described protocol with some modification, CSE was freshly prepared on the day of each experiment and used within half an hour in vitro experiments 24 . In this research, we tested the optical density (OD) values of 100% CSE to partly maintain the stability of CSE concentrations in in vitro experiments 27 . Firstly, one cigarette (Marlboro, Philip Morris, USA) was burned, and the smoke passed through 10 mL of phosphate-buffered saline (PBS) by connecting to a vacuum pump with a constant pressure of -0.1 Kpa.…”

Matrix Metalloproteinases in Chronic Obstructive Pulmonary Disease

“…Impaired protease–anti-protease imbalance in COPD patients is associated with the presence of airway injury [ 79 , 134 , 135 , 136 , 137 ]. In particular, TIMP-1 has the ability to moderate ECM degradation both in healthy tissues and under pathological conditions [ 40 , 42 , 138 , 139 ]. For example, the presence of circulating TIMP-1 has been shown to control proteolysis in the cardiovascular system [ 140 , 141 ].…”

“…Furthermore, TIMP-1 preferentially inhibits MMP-9, a key metalloproteinase in the pathogenesis of emphysema; therefore, TIMP-1 may exert protection, while the levels of MMP-9 and the MMP-9/TIMP-1 ratio are reliable predictors of emphysema [ 142 , 143 ]. On the other hand, TIMP-1 levels were found to be elevated in COPD patients, and plasma TIMP-1 levels were associated with disease severity [ 106 , 135 , 138 ]. Furthermore, TIMP-1 was found to be enhanced in PH, a very common and lethal comorbidity of COPD, compared to COPD patients, suggesting that TIMP-1 levels could be used as a biomarker to identify high-risk patients [ 138 ].…”

“…On the other hand, TIMP-1 levels were found to be elevated in COPD patients, and plasma TIMP-1 levels were associated with disease severity [ 106 , 135 , 138 ]. Furthermore, TIMP-1 was found to be enhanced in PH, a very common and lethal comorbidity of COPD, compared to COPD patients, suggesting that TIMP-1 levels could be used as a biomarker to identify high-risk patients [ 138 ].…”

Serum Biomarkers in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension

“…TIMP-4 may contribute to extracellular matrix deposition in SSc, and its serum levels have been shown to correlate with systolic pulmonary arterial pressure (sPAP) after echocardiography in both SSc-PAH and PH patients in general [ 63 , 64 ]. Other evidence has shown that serum MMPs levels are also increased in SSc patients with interstitial lung disease (ILD) [ 65 , 66 ], whereas TIMPs appear to be more specifically associated with vascular changes [ 64 , 67 ]; however, no studies to date have compared the serum levels of these molecules between patients with SSc-ILD and SSc-PAH.…”