Imbalance in the Expression of Genes Associated with Purinergic Signalling in the Lung and Systemic Arteries of COPD Patients

Abstract

Growing evidence indicates that purinergic signalling is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) and in the vascular remodelling that occurs in other disorders; however, its role in initial vascular changes of COPD is not entirely known. We hypothesised that expression of genes regulating extracellular ATP and adenosine levels would be altered in the lung and systemic arteries of COPD patients. Quantitative real-time PCR was performed to analyse the relative expression of 17 genes associated with purinergic signalling and inflammation in lungs and intercostal arteries of never smokers (NS) (n = 16), non-obstructed smokers (NOS) (n = 17) and COPD patients (n = 21). Gene expression of ATP-degrading enzymes was decreased in both tissues of NOS and COPD patients compared to NS. NT5E expression (gene transcribing for an AMP hydrolyzing ectonucleotidase) was increased in both tissues in NOS compared to the other groups. P1 and P2 receptors did not show changes in expression. Expression of genes associated with inflammation (interleukin-13) was upregulated only in lung tissues of COPD. These findings suggest that the expression of different extracellular ATP-degrading enzymes is altered in smokers (NOS and COPD patients), promoting inflammation. However, the high NT5E expression found only in NOS could compensate this inflammatory environment.

Extracellular adenosine triphosphate is associated with airflow limitation severity and symptoms burden in patients with chronic obstructive pulmonary disease

“…Cigarette smoking is the most common underlying mechanism of COPD development, and COPD patients are mostly current or former smokers, which was confirmed by our study. Previously, an increase in eATP was observed in BAL of a mouse model of smoke-induced acute lung inflammation and emphysema 12,33 as well as in BAL of COPD patients, even after smoking cessation 9,13 . In this study, control smokers had higher eATP concentrations in plasma from control non-smokers, although the levels were lower than in COPD patients, which might suggest some initial tissue changes ( e.g .…”

“…demonstrated that expression of P2X7R and P2Y2R were down-regulated in the lungs of non-obstructed smokers and COPD patients, but their study included patients in an early stage of COPD and a very few of them. Moreover, their study population had both lung cancer and COPD, so there might had been a bias regarding the observations associated with COPD 13 . Increased P2X7R expression in the lungs and BAL cells after LPS stimulation was reported 38 .…”

“…Afterwards, concentration of eATP was measured and it was increased in comparison to non-stimulated neutrophils 12 . It was also shown that higher eATP concentrations were present in BAL of COPD patients compared to healthy subjects, even after smoking cessation 9,13 . However, when ATP was measured in EBC, no differences between healthy non-smokers, healthy smokers and COPD patients were found 7 .…”

“…ATP is a ligand for some of the purinergic receptors (P2Rs) that are widely expressed in the lungs – trans-cell membrane cationic channels (P2XRs) and trans-membrane domain G protein-coupled receptors (P2YRs). When ATP binds to the P2Rs, macrophages and neutrophils secrete pro-inflammatory molecules and mediators of tissue degradation, all of which contribute to the chronic inflammation in COPD 13 . There are seven P2XRs (P2X 1–7 R) and eight P2YRs (P2Y 1/2/4/6/11/12/13/14 R).…”

Purinergic signaling and purine base metabolism at the crossroads between immunity, metabolism, and cancer: A review

“…Defects in purine signaling and metabolism have been wellcharacterized in several inflammatory diseases including lung disorders such as asthma [98][99][100][101][102] or chronic obstructive pulmonary disease (COPD), [103][104][105][106][107] graft-versus-host-disease (GVHD), [108][109][110][111] ischemiareperfusion injury, [112][113][114][115][116] gastrointestinal (GI) inflammation or inflammatory bowel disorder (IBD) [117][118][119][120][121][122] multiple sclerosis (MS), [123][124][125][126][127] and myasthenia gravis, 128,129 among others. Inflammatory disorders in the airway are mediated in part by both enhanced levels of adenosine in the bronchoalveolar lavage fluid and by enhanced hyperresponsiveness to adenosine challenge.…”