Primary human alveolar type II epithelial cell chemokine release: effects of cigarette smoke and neutrophil elastase.
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)-alpha > macrophage inflammatory protein (MIP)-1alpha > regulated on activation, normal T cell expressed and secreted (RANTES). MIP-1alpha and RANTES were often not detectable. After stimulation with a mixture of lipopolysaccharide/endotoxin (LPS), tumor necrosis factor-alpha, IL-1beta, and IFN-gamma, MCP-1 and IL-8 secretion rose 4-6-fold, whereas GRO-alpha rose 25-fold. NE stimulated IL-8 mRNA expression, and 10nM NE stimulated IL-8 secretion; however, 100 nM NE caused a decrease in extracellular IL-8, MCP-1, and GRO-alpha, 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-alpha, 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.
Witherden
Ian R
IR
Lung Cell Biology, National Heart and Lung Institute, Imperial College of Science, London, United Kingdom.
Vanden Bon
Elizabeth J
EJ
Goldstraw
Peter
P
Ratcliffe
Cathy
C
Pastorino
Ugo
U
Tetley
Teresa D
TD
D000368:Aged; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D019272:Leukocyte Elastase / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D015854:Up-Regulation
D018925:Chemokines; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019272:Leukocyte Elastase