Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro.
The driving force in the progression of COPD is the development of exacerbations which are mostly the result of excessive inflammation. Bronchodilatators play an important role in the treatment of COPD. The reported reduction in exacerbation rates in COPD is due to the inhibition of vagal-mediated bronchoconstriction and mucus secretion. However, recent studies have highlighted the existence of muscarinic receptors on inflammatory cells and we have explored the possibility that tiotropium bromide might also inhibit neutrophil migration. We analysed the influence of tiotropium on the release of neutrophil chemotactic activity in response to acetylcholine (ACh) and the expression of muscarinic receptors on human alveolar macrophages (AM), A549 cells, MonoMac6 cells, and human lung fibroblasts. We found significant levels of all muscarinic receptor subtypes on all analysed cells except the fibroblasts. Fibroblasts expressed predominantly M2, receptors and did not release chemotactic activity. AM, A549 cells, and MonoMac6 cells released chemotactic active mediators after incubation with ACh. The secretion could be suppressed by more than 70% after coincubation with tiotropium. Tiotropium alone did not influence the granulocyte migration. Most of the chemotactic activity could be attributed to leukotriene B4 (LTB4). The release of interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) was not induced by ACh. From this, we suggest that the suppression of the Ach-mediated release of chemotactic substances like LTB4 modulates the inflammatory reaction. This may contribute to the decreased rate of exacerbations in COPD, which was observed in clinical trials.
Bühling
Frank
F
Institute of Immunology, Otto-von-Guericke-University-Magdeburg, Magdeburg, Leipziger-Str. 44, 39120 Magdeburg, Germany. frank@buehling.net
Lieder
Nadine
N
Kühlmann
Ulrike C
UC
Waldburg
Nadine
N
Welte
Tobias
T
D000109:Acetylcholine / Q000502:physiology; D000368:Aged; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors*; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000502:physiology; D016676:Macrophages, Alveolar / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011976:Receptors, Muscarinic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012602:Scopolamine Derivatives / Q000494:pharmacology*; D000069447:Tiotropium Bromide
D002630:Chemotactic Factors; D018680:Cholinergic Antagonists; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D007975:Leukotriene B4; D000109:Acetylcholine; D000069447:Tiotropium Bromide