Abstract
Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by an excessive activation of the adaptive immune system and, in particular, uncontrolled expansion of the B-cell pool. One of the key promoters of B cell expansion is A PRoliferation-Inducing Ligand (APRIL). APRIL has been strongly linked to non small cell lung cancer (NSCLC) onset and progression previously. However, little is known about the expression of APRIL in the lungs of COPD patients.
 Methods: Using immuno-fluorescence staining, the expression of APRIL was assessed in sections of lungs from 4 subjects with primary diagnosis of COPD (FEV1 33 ± 20 % predicted), 4 subjects with primary diagnosis of NSCLC, 4 subjects diagnosed with both COPD and NSCLC, smokers without COPD or NSCLC and 3 healthy never-smokers. The percentage of B cells, alveolar macrophages (AMs) and polymorphonuclear neutrophils (PMNs) in the lung and alveolar epithelial cells (AECs) that stained positively for APRIL was quantified using epi-fluorescence microscopy and image analysis software.
 Results: The percentage of APRIL-expressing B cells, AMs, PMNs and alveolar epithelial cells (AECs) was higher in patients having both COPD and NSCLC than in patients with either COPD or NSCLC alone, SC or NSC (p < 0.03 for all comparisons). The percentage of APRIL-expressing AMs and AECs (but not in B cells) was higher in patients with NSCLC alone than in patients with COPD alone. The percentage of APRIL-expressing AECs (but not B cells or AMs) was higher in COPD patients than in SC and NSC (p < 0.05 for all comparisons). The percentage of APRIL-expressing B cells, AMs and AECs cells was similar in NSC and SC.
 Conclusion: The percentage of APRIL-expressing B cells, AMs and AECs is higher in the lungs of patients with both COPD and NSCLC than in patients with COPD or NSCLC alone or control subjects. These findings suggest that APRIL may contribute to the pathogenesis of both COPD and NSCLC, and possibly to the development of NSCLC in patients with established COPD.
Highlights
Chronic Obstructive Pulmonary Disease (COPD) is characterized by an excessive activation of the adaptive immune system and, in particular, uncontrolled expansion of the B-cell pool
COPD was diagnosed on the basis of the presence of emphysema in high resolution computed tomography (HRCT) scans of the thorax and an FEV1/FVC ratio < 0.7, but the FEV1% predicted was not available from the electronic medical records
We report for the first time that there are increases in numbers of A PRoliferation-Inducing Ligand (APRIL)-expressing leukocytes and alveolar epithelial cells (AECs) in lungs of patients with either COPD or non small cell lung cancer (NSCLC) versus control subjects without these diseases
Summary
Chronic Obstructive Pulmonary Disease (COPD) is characterized by an excessive activation of the adaptive immune system and, in particular, uncontrolled expansion of the B-cell pool. APRIL has been strongly linked to non small cell lung cancer (NSCLC) onset and progression previously. COPD patients have an increased risk of developing non-small cell lung cancer (NSCLC) that is independent of smoking pack-year history [1, 2]. Increased lung oxidative stress levels can increase the susceptibility of COPD patients to recurrent respiratory tract infections, and drive chronic inflammation in the lungs, leading to further DNA damage and cellular injury by inducing the production of cytokines and proteinases in the lung [5]. Injury to the lungs that is induced by chronic inflammation triggers repair processes including cellular proliferation which, together with ROS and RNS-induced DNA damage, may promote tumorigenesis
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