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Primary Human Alveolar Type II Epithelial Cell Chemokine Release

Effects of Cigarette Smoke and Neutrophil Elastase

Lung Cell Biology, National Heart and Lung Institute, Imperial College; and Department of Thoracic Surgery, Royal Brompton and Harefield NHS Trust, London, United Kingdom

Address correspondence to: Dr. T. D. Tetley, Lung Cell Biology, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, UK. E-mail: t.tetley{at}ic.ac.uk

An early response to cigarette smoke is an influx of leukocytes into the lung. Alveolar epithelial type II (ATII) cells may contribute by releasing chemokines in response to cigarette smoke and neutrophil elastase (NE). Human ATII cells were purified from normal regions of lungs resected for carcinoma (n = 14). In vitro, these cells exhibited ATII cell characteristics: lamellar bodies, apical microvilli, tight junctions, and expressed surfactant apoprotein C. Basal ATII cell release of five chemokines ranked as follows: monocyte chemotactic protein (MCP)-1 > interleukin (IL)-8 > growth-related oncogene (GRO)- > macrophage inflammatory protein (MIP)-1 > regulated on activation, normal T cell expressed and secreted (RANTES). MIP-1 and RANTES were often not detectable. After stimulation with a mixture of lipopolysaccharide/endotoxin (LPS), tumor necrosis factor-, IL-1ß, and IFN-, MCP-1 and IL-8 secretion rose 4–6-fold, whereas GRO- rose 25-fold. NE stimulated IL-8 mRNA expression, and 10nM NE stimulated IL-8 secretion; however, 100nM NE caused a decrease in extracellular IL-8, MCP-1, and GRO-, attributed to proteolysis. Cigarette smoke extract (CSE) inhibited IL-8 mRNA expression and release of all chemokines. Glutathione protected against the effects of CSE, suggesting oxidative mechanisms. GRO-, important in growth and repair, was sensitive to both stimulation, by LPS:cytokines, and inhibition, by CSE. Thus, contrary to the original hypothesis, high concentrations of NE and CSE resulted in reduced extracellular chemokine levels. We hypothesize that reduced ATII cell–derived chemokine levels compromise alveolar repair, contributing to cigarette smoke–induced alveolar damage and emphysema.

Abbreviations: alveolar type II cells, ATII • chronic obstructive pulmonary disease, COPD • cigarette smoke extract, CSE • growth-related oncogene-, GRO- • glutathione, GSH • interferon-, IFN- • interleukin, IL • low protein hybridoma media, LPHM • lipopolysaccharide and endotoxin, LPS • monocyte chemotactic protein-1, MCP-1 • macrophage inflammatory protein-1, MIP-1 • neutrophil elastase, NE • regulated on activation, normal T cell expressed and secreted, RANTES • surfactant protein, SP • tumor necrosis factor, TNF

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