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.

Tiotropium Is Predicted to Be a Promising Drug for COVID-19 Through Transcriptome-Based Comprehensive Molecular Pathway Analysis

“…It means that tiotropium may directly bind to some components of the replication complex and this most likely leads to the inhibition of SARS-CoV-2. Interestingly, tiotropium showed some antiviral effects on rhinovirus-infected human airway epithelial cells [ 40 ], RSV-infected human epithelial type 2 (HEp-2) cells [ 41 ] and lung tissues from cigarette smoke-exposed and RSV-infected mice [ 42 ]. Second, tiotropium has been shown to inhibit the TNF- and/or NFκB-signaling pathways, which were the most significantly upregulated pathways upon the infection of SARS-CoV-2 in NHBE cells.…”

Cigarette smoke up‐regulates PDE3 and PDE4 to decrease cAMP in airway cells

“…The PDE4 inhibitor roflumilast N‐oxide partly reverses CS‐induced epithelial dysfunction (Milara et al ., 2014, 2012; Schmid et al ., 2015; Tyrrell et al ., 2015), and the PDE4 inhibitors, GPD‐1116 and piclamilast can prevent the development of CS‐induced emphysema and pulmonary hypertension in mice (Mori et al ., 2008; Seimetz et al ., 2015, p. 4). Zl‐n‐91, a selective PDE4 inhibitor can also suppress CS‐induced lung inflammatory in rats (Wang et al ., 2010; Bucher et al ., 2016). The aim of the present study was to investigate whether CS may directly induce changes in PDE expression or activity, thus contributing to lung pathophysiology.…”

Protective effects of tiotropium alone or combined with budesonide against cadmium inhalation induced acute neutrophilic pulmonary inflammation in rats

“…Besides the blockage of M3 receptor which gives rise to the bronchodilation, more attention has been paid to the anti-inflammatory effects of muscarinic antagonists [ 4 – 6 ]. In several animal models tiotropium has been found to attenuate acute and chronic pulmonary inflammation [ 30 – 32 ]. Several studies in vitro also showed that tiotropium could suppress LPS-induced the release of neutrophil chemotactic mediators by human airway epithelial cells, lung fibroblasts and alveolar macrophages [ 5 , 6 ].…”