Is the purinergic pathway involved in the pathology of COPD? Decreased lung CD39 expression at initial stages of COPD

Abstract

BackgroundExtracellular adenosine triphosphate (ATP) is up-regulated in the airways of patients with chronic obstructive pulmonary disease (COPD), resulting in increased inflammation, bronchoconstriction, and cough. Although extracellular ATP levels are tightly controlled by nucleoside triphosphate diphosphohydrolase-1 (NTPDase1; also known as CD39) in the lungs, the role of CD39 in the pathology of COPD is unknown. We hypothesized that alterations in the expression and activity of CD39 could be part of the mechanisms for initiating and perpetuating the disease.MethodsWe analyzed CD39 gene and protein expression as well as ATPase enzyme activity in lung tissue samples of patients with COPD (n = 17), non-obstructed smokers (NOS) (n = 16), and never smokers (NS) (n = 13). Morphometry studies were performed to analyze pulmonary vascular remodeling.ResultsThere was significantly decreased CD39 gene expression in the lungs of the COPD group (1.17 [0.85–1.81]) compared with the NOS group (1.88 [1.35–4.41]) and NS group (3.32 [1.23–5.39]) (p = 0.037). This attenuation correlated with higher systemic inflammation and intimal thickening of muscular pulmonary arteries in the COPD group. Lung CD39 protein levels were also lower in the COPD group (0.34 [0.22–0.92]) compared with the NOS group (0.67 [0.32–1.06]) and NS group (0.95 [0.4–1.1) (p = 0.133). Immunohistochemistry showed that CD39 was downregulated in lung parenchyma, epithelial bronchial cells, and the endothelial cells of pulmonary muscular arteries in the COPD group. ATPase activity in human pulmonary structures was reduced in the lungs of patients with COPD.ConclusionAn attenuation of CD39 expression and activity is presented in lung tissue of stable COPD patients, which could lead to pulmonary ATP accumulation, favoring the development of pulmonary inflammation and emphysema. This may be a mechanism underlying the development of COPD.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0793-0) contains supplementary material, which is available to authorized users.

Purinergic Signaling in Pulmonary Inflammation

“…CD39 converts ATP and ADP to AMP. Correlating with increased ATP levels in the airways of COPD smokers, there was a significant decrease in CD39 gene and protein expression and ATPase activity in lung tissue acquired from COPD patients when compared with non-obstructive smokers and never-smokers (113). CD39 is decreased on T-cells in acute exacerbation of COPD (AECOPD) patients when compared to stable COPD.…”

The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

“…Although these findings hint that adenosine receptors may modulate the course of COPD, further studies will be necessary to precisely delineate the role of the various adenosine receptors in regulating the course of COPD in patients. Aliagas et al (2018) found decreased CD39 gene and protein expression as well as activity in the lungs of COPD patients in comparison with controls. This decrease in CD39 correlated with higher systemic inflammation and intimal thickening of muscular pulmonary arteries in the COPD group (Aliagas et al, 2018).…”

“…Aliagas et al (2018) found decreased CD39 gene and protein expression as well as activity in the lungs of COPD patients in comparison with controls. This decrease in CD39 correlated with higher systemic inflammation and intimal thickening of muscular pulmonary arteries in the COPD group (Aliagas et al, 2018). Immunohistochemical analysis showed that CD39 was downregulated mainly in lung parenchyma, in epithelial bronchial cells, and in the endothelial cells of pulmonary muscular arteries (Aliagas et al, 2018).…”

“…This decrease in CD39 correlated with higher systemic inflammation and intimal thickening of muscular pulmonary arteries in the COPD group (Aliagas et al, 2018). Immunohistochemical analysis showed that CD39 was downregulated mainly in lung parenchyma, in epithelial bronchial cells, and in the endothelial cells of pulmonary muscular arteries (Aliagas et al, 2018). In contrast, another study demonstrated that CD39 expression and activity were higher in sputa and BAL cells of COPD patients compared with controls (Lazar et al, 2016).…”

Host CD39 Deficiency Affects Radiation-Induced Tumor Growth Delay and Aggravates Radiation-Induced Normal Tissue Toxicity

“…Since our earlier work revealed a pathogenic role of the CD73/Adodependent arm of purinergic signaling in radiation-induced lung fibrosis (49,50), genetic loss of CD39 with assumed activation of the ATP-dependent proinflammatory arm of purinergic signaling and genetic loss of CD73 with assumed activation of the Ado-dependent anti-inflammatory, repair-promoting arm of purinergic signaling result in opposing outcomes in radiationinduced lung fibrosis. A pathology-promoting effect of low CD39 expression or high pulmonary ATP levels were already known for several lung pathologies, including pulmonary fibrosis (113)(114)(115). High extracellular ATP levels, for example, have been observed in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis, as well as in a murine model of bleomycin-induced lung fibrosis (116).…”