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

Elisabet Aliagas,Marta López-Sánchez,Salud Santos,Ester Cuevas,Jordi Dorca,Ignacio Escobar,Mariana Muñoz-Esquerre,Daniel Huertas,Oriol Careta

doi:10.1186/s12931-018-0793-0

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.

Highlights

Extracellular adenosine triphosphate (ATP) is up-regulated in the airways of patients with chronic obstructive pulmonary disease (COPD), resulting in increased inflammation, bronchoconstriction, and cough
There were no significant differences in baseline characteristics between groups, except for gender, tobacco exposure, and the presence of diabetes (Table 1), so these were included as covariates in all adjusted analyses
Gene expression in lung tissue samples The qRT-PCR analyses showed that CD39 was significantly downregulated in the COPD group compared with both the non-obstructed smokers (NOS) and never smokers (NS) groups (1.17 [0.85–1.81] vs 1.88 [1.35–4.41] and 3.32 [1.23–5.39], respectively, p = 0.037) (Fig. 1)

Summary

Introduction

Extracellular adenosine triphosphate (ATP) is up-regulated in the airways of patients with chronic obstructive pulmonary disease (COPD), resulting in increased inflammation, bronchoconstriction, and cough. Chronic obstructive pulmonary disease (COPD) is characterized by small airway inflammation that causes airway obstruction, parenchymal destruction, and emphysema [1]. Increased pulmonary ATP levels have been found in mice with acute lung inflammation. In patients with COPD it has been shown that ATP accumulation stimulates the recruitment and activation of lung neutrophils and macrophages, which in turn enhance the release of proinflammatory and tissuedegrading mediators [9]. It has been demonstrated that neutralizing intrapulmonary ATP levels or blocking airway specific ATP receptor subtypes can inhibit smoke-induced lung inflammation and confer protection from developing emphysema [7]

Objectives

Methods

Results

Discussion

Conclusion