Viral infections trigger COPD exacerbations 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 (H1N1) or respiratory syncytial virus (RSV) and compare effects with steroid fluticasone and PDE4-inhibitor roflumilast. Mice were exposed to CS, infected with H1N1 or RSV and treated with tiotropium, fluticasone or roflumilast. Amount of cells and cytokine levels in the airways, lung function and viral load were 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 IL-6 and IFN-γ in the airways and improved lung function. In contrast, fluticasone increased loss of body-weight, failed to reduce neutrophil or macrophage numbers, increased IL-6, KC and TNF-α in the lungs and worsened lung function. Treatment with roflumilast reduced macrophage numbers, IL-6 and KC in the lung but had no effect on neutrophil numbers or lung function. In CS/RSV-exposed mice tiotropium but not fluticasone or roflumilast treatment reduced neutrophil and IL-6 and TNF-α levels in the lung. Viral load of H1N1 and RSV was significantly elevated in virus/CS-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 being superior to roflumilast and fluticasone. This finding might help to explain the observed reduction of exacerbation rates in COPD patients.
Tiotropium attenuates virus-induced pulmonary inflammation in cigarette smoke-exposed mice.