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CELLULAR AND MOLECULAR

Smoke, Choline Acetyltransferase, Muscarinic Receptors, and Fibroblast Proliferation in Chronic Obstructive Pulmonary Disease

Institute of Biomedicine and Molecular Immunology, Italian National Research Council, Palermo, Italy (M.P., A.BO., L.S., A.Br., M.F., A.M.M., G.D.A., L.R., M.G.); and Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany (P.C., M.P.P.)

Acetylcholine (ACh), synthesized by choline acetyltransferase (ChAT), and muscarinic M₁, M₂, and M₃ receptors (MRs) are involved in fibroblast proliferation. We evaluated ChAT, MRs, and extracellular signal-regulated kinase (ERK) 1/2 and nuclear factor (NF) B activation in lung fibroblasts from patients with chronic obstructive pulmonary disease (COPD), control smokers, and controls. Human fetal lung fibroblasts (HFL-1) stimulated with interleukin (IL)-1β, tumor necrosis factor (TNF)-, and cigarette smoke extracts (CSEs) were evaluated for ChAT and MR expression. We tested the effects of ACh on fibroblast proliferation and its ability to bind fibroblasts from patients with COPD, control smokers, controls, and HFL-1 stimulated with IL-1β, TNF-, and CSE. ChAT, M₁, and M₃ expression and ERK1/2 and NFB activation were increased, whereas M₂ was reduced, in COPD and smoker subjects compared with controls. IL-1β increased the ChAT and M₃, TNF- down-regulated M₂, and CSE increased ChAT and M₃ expression while down-regulating the expression of M₂ in HFL-1 cells. ACh stimulation increased fibroblast proliferation in patients with COPD, control smokers, and controls, with higher effect in control smokers and patients with COPD and increased HFL-1 proliferation only in CSE-treated cells. The binding of ACh was higher in patients with COPD and in control smokers than in controls and in CSE-treated than in IL-1β- and TNF--stimulated HFL-1 cells. Tiotropium (Spiriva; [1,2β,4β,5,7β-7-hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatrcyclo[3.3.1.0²⁴], C₁₉H₂₂ NO₄S₂Br·H₂O), gallamine triethiodide (C₁₉H₂₂N₄O₂S·2HCl·H₂O), telenzepine [4,9-D-dihydro-3-methyl-4-[(4-methyl-1piperazinyl) acetyl]-10H-thieno [3,4-b][1,5]benzodiazepine-10-one dihydrobromide, C₃₀H₆₀I₃N₃O₃], 4-diphenylacetoxy-N-methylpiperidine, PD098059 [2-(2-amino-3methoxyphenyl)-4H-1benzopyran-4-one, C₁₆H₁₃NO₃], and BAY 11-7082 [(E)-3-(4-methylphenylsulfonyl)-2-propenetrile, C₁₀H₉NO₂C], down-regulated the ACh-induced fibroblast proliferation, promoting the MRs and ERK1/2 and NFB pathways involvement in this phenomenon. These results suggest that cigarette smoke might alter the expression of ChAT and MRs, promoting airway remodeling in COPD and that anticholinergic drugs, including tiotropium, might prevent these events.

Address correspondence to: Dr. Mirella Profita, Institute of Biomedicine and Molecular Immunology, Italian National Research Council, Via Ugo La Malfa 153, 90146 Palermo, Italy. E-mail: profita{at}ibim.cnr.it