Extracellular cadmium in the bronchoalveolar space of long-term tobacco smokers with and without COPD and its association with inflammation

Abstract

Tobacco contains cadmium, and this metal has been attributed a causative role in pulmonary emphysema among smokers, although extracellular cadmium has not to date been quantified in the bronchoalveolar space of tobacco smokers with or without COPD. We determined whether cadmium is enhanced in the bronchoalveolar space of long-term tobacco smokers with or without COPD in vivo, its association with inflammation, and its effect on chemokine release in macrophage-like cells in vitro. Bronchoalveolar lavage (BAL), sputum, and blood samples were collected from current, long-term smokers with and without COPD and from healthy nonsmokers. Cadmium concentrations were determined in cell-free BAL fluid using inductively coupled plasma mass spectrometry. Blood monocyte-derived macrophages were exposed to cadmium chloride in vitro. Depending upon the type of sample, molecular markers of inflammation were quantified either as protein (enzyme-linked immunosorbent assay) or as mRNA (real-time polymerase chain reaction). Cadmium concentrations were markedly increased in cell-free BAL fluid of smokers compared to that of nonsmokers (n=19–29; P<0.001), irrespective of COPD. In these smokers, the measured cadmium displayed positive correlations with macrophage TNF-α mRNA in BAL, neutrophil and CD8⁺ cell concentrations in blood, and finally with IL-6, IL-8, and MMP-9 protein in sputum (n=10–20; P<0.05). The cadmium chloride exposure caused a concentration-dependent increase in extracellular IL-8 protein in monocyte-derived macrophages in vitro. In conclusion, extracellular cadmium is enhanced in the bronchoalveolar space of long-term smokers and displays pro-inflammatory features. Its pathogenic role in tobacco-induced disease deserves further evaluation.

Keywords:

• cigarette
• metal
• obstruction
• macrophage
• neutrophil

Acknowledgments

We thank Karin Holm at Stockholm University for technical assistance with the analysis of metals in cell-free BAL fluid. We also thank Professor Carola Lidén and Doctor Hanna Karlsson, Institute of Environmental Medicine, Karolinska Institutet, for their invaluable support throughout this study. The authors gratefully acknowledge the expert technical advice from Doctor Karlhans Fru Che regarding the experiments on macrophage-like cells in vitro. Project funding was obtained from the Swedish Research Council (LP and AL), the Swedish Heart-Lung Foundation (KL, LP, and AL), the Foundation for Rehabilitation and Medical Research in Gothenburg (FRF-stiftelsen; AL), Stockholm County Council (ALF-medel; AL), King Gustav V’s and Queen Victoria’s Freemason Research Fund (AL), and federal funding from Karolinska Institutet (LP and AL). No funding was obtained from the tobacco industry.

Disclosure

The authors report no conflicts of interest in this work.