title: Acetylcholine-induced proliferation of fibroblasts and myofibroblasts in vitro is inhibited by tiotropium bromide.
abstract: Acetylcholine (ACh) has been suggested to exert various pathophysiological activities in the airways in addition to vagally-induced bronchoconstriction. This archetypal neurotransmitter and other components of the cholinergic system are expressed in a number of non-neuronal cells in the airways. Non-neuronal ACh released from these cells may affect fibroblasts (Fb) as well as inflammatory cells in lung tissue. Tiotropium bromide is a once-a-day antimuscarinic drug, marketed under the brand name Spiriva, for the treatment of chronic obstructive pulmonary disease (COPD). Besides its proven direct bronchodilatory activity, recent evidence suggests that tiotropium may be able to reduce the frequency of exacerbations and attenuate the decline in lung function, thus improving the course of obstructive airway diseases. The aim of the present study was to investigate the effects of tiotropium on the ACh-induced proliferation of primary human Fb isolated from biopsies of lung fibrosis patients and myofibroblasts (MyFb) derived from these cells. A human lung Fb cell line acted as control. Expression of muscarinic receptor subtypes M1, M2 and M3 was demonstrated by RT-PCR in both cell types. Acetylcholine stimulated proliferation in all cells investigated. Tiotropium concentration-dependently inhibited the ACh-induced proliferation in both the Fb and MyFb with a maximum effect at 30 nM. These results suggest that cholinergic stimuli mediated by muscarinic receptors could contribute to remodeling processes in chronic airway disease. Tiotropium bromide may have a beneficial influence on airway remodeling processes in chronic airway diseases through antiproliferative effects on fibroblasts and myofibroblasts.
authors.affiliation: Department of Pulmonary Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany. michael.pieper@bc.boehringer-ingelheim.com
authors.forename: M P
authors.initials: MP
authors.lastname: Pieper
authors.forename: N I
authors.initials: NI
authors.lastname: Chaudhary
authors.forename: J E
authors.initials: JE
authors.lastname: Park
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000199:Actins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018678:Cholinergic Agents / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D043643:Receptor, Muscarinic M1 / Q000235:genetics; D043585:Receptor, Muscarinic M2 / Q000235:genetics; D043587:Receptor, Muscarinic M3 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012602:Scopolamine Derivatives / Q000494:pharmacology*; D000069447:Tiotropium Bromide
chemical_list: D000199:Actins; D018678:Cholinergic Agents; D018680:Cholinergic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D012602:Scopolamine Derivatives; D000109:Acetylcholine; D000069447:Tiotropium Bromide