title: Tiotropium sustains the anti-inflammatory action of olodaterol via the cyclic AMP pathway.
abstract: Mesenchymal cells (fibroblasts) of the airway wall respond to cholinergic stimulation by releasing pro-inflammatory and chemotactic cytokines and may thus contribute to chronic inflammation of the lung. Here, we studied the anti-inflammatory potential of olodaterol, a long acting β2-adrenergic receptor agonist, and tiotropium, a long-acting muscarinic receptor antagonist, and whether they interact at the level of the cyclic AMP dependent signaling pathway. Pulmonary fibroblasts of asthmatic (n = 9) and non-asthmatic (n = 8) subjects were stimulated with the muscarinic receptor agonist carbachol and interleukin-1β (IL-1 beta) in presence or absence of tiotropium or olodaterol alone, or their combination. We also measured cAMP levels and phosphorylation of the cAMP response element binding protein (CREB). As single components, carbachol, olodaterol and tiotropium did not affect IL-6 and IL-8 release. Carbachol concentration-dependently enhanced the production of IL-1β-induced IL-6 and IL-8, which was blocked by the simultaneous addition of tiotropium. The combination of olodaterol plus tiotropium further reduced IL-6 and IL-8 release. Olodaterol induced cAMP and the phosphorylation of CREB, an effect counteracted by carbachol, but rescued by tiotropium. We conclude that olodaterol plus tiotropium cooperate to decrease the inflammatory response in pulmonary fibroblasts in vitro.
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Costa
authors.affiliation: Pulmonology, Department of Internal medicine, University Hospital Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Miglino
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Keglowich
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Switzerland.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Thoracic Surgery, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.affiliation: Pulmonology, Department of Internal medicine, University Hospital Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.affiliation: Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Switzerland. Electronic address: pieter.borger@unibas.ch.
authors.forename: Pieter
authors.initials: P
authors.lastname: Borger
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002217:Carbachol / Q000008:administration & dosage / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000069447:Tiotropium Bromide
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000893:Anti-Inflammatory Agents; D048588:Benzoxazines; D001993:Bronchodilator Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D018727:Muscarinic Antagonists; D012602:Scopolamine Derivatives; D002217:Carbachol; D000242:Cyclic AMP; C549647:olodaterol; D000069447:Tiotropium Bromide
keywords: Airway biology; Airway pharmacology; Anticholinergics; Asthma therapy; Beta-2 agonists; Fibroblasts