title: Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD.
abstract: Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and remodelling using an animal model of COPD. To this aim, guinea pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits remodelling of the airways as well as pulmonary inflammation in a guinea pig model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease.
authors.affiliation: Department of Molecular Pharmacology, University Centre for Pharmacy, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. t.pera@rug.nl
authors.forename: T
authors.initials: T
authors.lastname: Pera
authors.forename: A
authors.initials: A
authors.lastname: Zuidhof
authors.forename: J
authors.initials: J
authors.lastname: Valadas
authors.forename: M
authors.initials: M
authors.lastname: Smit
authors.forename: R G
authors.initials: RG
authors.lastname: Schoemaker
authors.forename: R
authors.initials: R
authors.lastname: Gosens
authors.forename: H
authors.initials: H
authors.lastname: Maarsingh
authors.forename: J
authors.initials: J
authors.lastname: Zaagsma
authors.forename: H
authors.initials: H
authors.lastname: Meurs
mesh_terms: D000109:Acetylcholine / Q000502:physiology; D056151:Airway Remodeling / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D021461:Animals, Outbred Strains; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D004195:Disease Models, Animal; D004646:Emphysema / Q000188:drug therapy / Q000276:immunology; D020397:Goblet Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006168:Guinea Pigs; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000276:immunology; D008297:Male; D055271:Mucin 5AC / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000276:immunology; D012602:Scopolamine Derivatives / Q000494:pharmacology*; D000069447:Tiotropium Bromide
chemical_list: D018680:Cholinergic Antagonists; D008070:Lipopolysaccharides; D055271:Mucin 5AC; D018727:Muscarinic Antagonists; D012602:Scopolamine Derivatives; D000109:Acetylcholine; D000069447:Tiotropium Bromide