MAPK pathway mediates muscarinic receptor-induced human lung fibroblast proliferation.
Airway remodelling is a pathological feature of chronic inflammatory and obstructive airway diseases like asthma and COPD wherein fibroblasts contribute to structural alteration processes. We recently reported expression of multiple muscarinic receptors in human lung fibroblasts and demonstrated muscarinic receptor-induced, G(i)-mediated proliferation in these cells. We now explore the underlying intracellular signalling pathways. As a measure of cell proliferation ((3)H)-thymidine incorporation in primary human lung fibroblasts and MRC-5 fibroblasts was increased by about 2 fold in presence of the muscarinic receptor agonist carbachol (10 microM) and this effect could be prevented by the MEK inhibitor PD 98059 (30 microM). Western blot analysis revealed a rapid (within 2 min) activation of p42/44 MAPK (ERK1, ERK2) following exposure to 10 microM carbachol or oxotremorine, effects blocked by tiotropium as well as atropine. In conclusion, the proliferative response of lung fibroblasts to muscarine receptor stimulation is mediated via activation of the classical MEK-ERK MAPK cascade. It is suggested that prevention of cholinergic driven fibroblast proliferation by prolonged blockade of airway muscarinic receptors may contribute to the reported long term beneficial effects of anticholinergics.
Matthiesen
Sonja
S
Institute of Pharmacology and Toxicology, University of Bonn, Reuterstr. 2b, D-53113 Bonn, Germany. s.matthiesen@uni-bonn.de
Bahulayan
Amit
A
Holz
Olaf
O
Racké
Kurt
K
D015153:Blotting, Western; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D018679:Cholinergic Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000502:physiology*; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D018679:Cholinergic Agonists; D005419:Flavonoids; D011976:Receptors, Muscarinic; D014316:Tritium; D002217:Carbachol; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D013936:Thymidine