Nicotine and fibronectin expression in lung fibroblasts: implications for tobacco-related lung tissue remodeling.
Tobacco-related lung diseases are associated with alterations in tissue remodeling and are characterized by increased matrix deposition. Among the matrix molecules found to be highly expressed in tobacco-related lung diseases is fibronectin, a cell adhesive glycoprotein implicated in tissue injury and repair. We hypothesize that nicotine, a component of tobacco, stimulates the expression of fibronectin in lung fibroblasts via the activation of intracellular signals that lead to increased fibronectin gene transcription. In support of this, we found that nicotine stimulated the expression of fibronectin in lung fibroblasts and that its stimulatory effect was associated with activation of protein kinase C and mitogen-activated protein kinases, increased levels of intracellular cAMP, and phosphorylation and DNA binding of the transcription factor CREB. Increased transcription of the gene was dependent on cAMP-response elements (CREs) present on the 5' end of its gene promoter. The stimulatory effect of nicotine on fibronectin expression was abolished by alpha-bungarotoxin, an inhibitor of alpha7 nicotinic acetylcholine receptors (alpha7 AChRs). Of note, nicotine increased the expression of alpha7 nAChRs on fibroblasts. Our data suggest that nicotine induces lung fibroblasts to produce fibronectin by stimulating alpha7 nAChR-dependent signals that regulate the transcription of the fibronectin gene.
Roman
Jesse
J
Department of Medicine,Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michael St., Suite 205-M, Atlanta, GA 30322, USA. jroman@emory.edu
Ritzenthaler
Jeffrey D
JD
Gil-Acosta
Alcides
A
Rivera
Hilda N
HN
Roser-Page
Susanne
S
D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008168:Lung / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014028:Tobacco Smoke Pollution; D015854:Up-Regulation / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D005353:Fibronectins; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D014028:Tobacco Smoke Pollution; D009538:Nicotine; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases