title: Tiotropium Attenuates Virus-Induced Pulmonary Inflammation in Cigarette Smoke-Exposed Mice.
abstract: Viral infections trigger exacerbations in chronic obstructive pulmonary disease (COPD), and tiotropium, a M3 receptor antagonist, reduces exacerbations in patients by unknown mechanisms. In this report, we investigated whether tiotropium has anti-inflammatory effects in mice exposed to cigarette smoke (CS) and infected with influenza virus A/PR/8/34 (H1N1) or respiratory syncytial virus (RSV) and compared these effects with those of steroid fluticasone and PDE4-inhibitor roflumilast. Mice were exposed to CS; infected with H1N1 or RSV; and treated with tiotropium, fluticasone, or roflumilast. The amount of cells and cytokine levels in the airways, lung function, and viral load was determined. NCI-H292 cells were infected with H1N1 or RSV and treated with the drugs. In CS/H1N1-exposed mice, tiotropium reduced neutrophil and macrophage numbers and levels of interleukin-6 (IL-6) and interferon-γ (IFN-γ) in the airways and improved lung function. In contrast, fluticasone increased the loss of body weight; failed to reduce neutrophil or macrophage numbers; increased IL-6, KC, and tumor necrosis factor-α (TNF-α) in the lungs; and worsened lung function. Treatment with roflumilast reduced macrophage numbers, IL-6, and KC in the lungs but had no effect on neutrophil numbers or lung function. In CS/RSV-exposed mice, treatment with tiotropium, but not fluticasone or roflumilast, reduced neutrophil numbers and IL-6 and TNF-α levels in the lungs. Viral load of H1N1 and RSV was significantly elevated in CS/virus-exposed mice and NCI-H292 cells after fluticasone treatment, whereas tiotropium and roflumilast had no effect. In conclusion, tiotropium has anti-inflammatory effects on CS/virus-induced inflammation in mice that are superior to the effects of roflumilast and fluticasone. This finding might help to explain the observed reduction of exacerbation rates in COPD patients.
authors.affiliation: Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Bucher
authors.affiliation: Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Duechs
authors.affiliation: Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Tilp
authors.affiliation: Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Jung
authors.affiliation: Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany klaus.erb@boehringer-ingelheim.com.
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Erb
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D007652:Oxo-Acid-Lyases / Q000235:genetics; D011014:Pneumonia / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology / Q000821:virology*; D012136:Respiratory Syncytial Viruses / Q000502:physiology; D012906:Smoke / Q000009:adverse effects*; D000069447:Tiotropium Bromide / Q000494:pharmacology* / Q000627:therapeutic use; D014026:Nicotiana / Q000737:chemistry*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D012906:Smoke; D002795:Choline O-Acetyltransferase; C018730:N-acetylneuraminate synthase; D007652:Oxo-Acid-Lyases; D000069447:Tiotropium Bromide