title: β₂ long-acting and anticholinergic drugs control TGF-β1-mediated neutrophilic inflammation in COPD.
abstract: We quantified TGF-β1 and acetylcholine (ACh) concentrations in induced sputum supernatants (ISSs) from 18 healthy controls (HC), 22 healthy smokers (HS) and 21 COPDs. ISSs from HC, HS and COPD as well as rhTGF-β1 were also tested in neutrophil adhesion and in mAChR2, mAChR3 and ChAT expression experiments in human bronchial epithelial cells (16-HBE). Finally, we evaluated the effects of Olodaterol (a novel inhaled β(2)-adrenoceptor agonist) and Tiotropium Spiriva®, alone or in combination, on neutrophil adhesion and mAChRs and ChAT expression in stimulated 16-HBE. The results showed that 1) TGF-β1 and ACh concentrations are increased in ISSs from COPD in comparison to HC and HS, and TGF-β1 in HS is higher than in HC; 2) ISSs from COPD and HS caused increased neutrophil adhesion to 16-HBE when compared to ISSs from HC. The effect of ISSs from COPD was significantly reduced by TGF-β1 depletion or by the pretreatment with Olodaterol or Tiotropium alone or in combination, while the effect of ISSs from HS was significantly reduced by the pretreatment with Olodaterol alone; 3) mAChR2, mAChR3 and ChAT expression was increased in 16-HBE stimulated with ISSs from COPD and TGF-β1 depletion significantly reduced this effect on mAChR3 and ChAT expression; 4) rhTGF-β1 increased mAChR2, mAChR3 and ChAT expression in 16-HBE; 5) Olodaterol did not affect the expression of mAChRs and ChAT in 16-HBE. Our findings support the use of β₂ long-acting and anticholinergic drugs to control the bronchoconstriction and TGF-β1-mediated neutrophilic inflammation in COPD.
authors.affiliation: Institute of Biomedicine and Molecular Immunology, Italian National Research Council, Palermo, Italy. profita@ibim.cnr.it
authors.forename: Mirella
authors.initials: M
authors.lastname: Profita
authors.forename: Anna
authors.initials: A
authors.lastname: Bonanno
authors.forename: Angela Marina
authors.initials: AM
authors.lastname: Montalbano
authors.forename: Giusy Daniela
authors.initials: GD
authors.lastname: Albano
authors.forename: Loredana
authors.initials: L
authors.lastname: Riccobono
authors.forename: Liboria
authors.initials: L
authors.lastname: Siena
authors.forename: Maria
authors.initials: M
authors.lastname: Ferraro
authors.forename: Paola
authors.initials: P
authors.lastname: Casarosa
authors.forename: Michael Paul
authors.initials: MP
authors.lastname: Pieper
authors.forename: Mark
authors.initials: M
authors.lastname: Gjomarkaj
mesh_terms: D000109:Acetylcholine / Q000032:analysis / Q000378:metabolism*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000368:Aged; D000704:Analysis of Variance; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D002461:Cell Line, Transformed; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D018680:Cholinergic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000494:pharmacology / Q000627:therapeutic use; D012907:Smoking / Q000009:adverse effects; D013183:Sputum / Q000737:chemistry; D000069447:Tiotropium Bromide; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000378:metabolism*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; D001993:Bronchodilator Agents; D018680:Cholinergic Antagonists; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D012602:Scopolamine Derivatives; D053773:Transforming Growth Factor beta1; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine; C549647:olodaterol; D000069447:Tiotropium Bromide