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Backgrounds: Smoking cessation is the most effective treatment in patient with chronic obstructive pulmonary disease (COPD) characterized by progressive and irreversible airflow limitation with emphysema and lung inflammation. Varenicline, which is a selective partial agonist of the α4β2 nicotinic acetylcholine receptor (nAChR) and full agonist of α7 nAChR, is a widely used and effective drug for smoking cessation. The aim of this study was to examine the effect of varenicline on the emphysema in mice intratracheally administrated porcine pancreatic elastase (PPE).
Methods: C57BL/6 mice (8 weeks old) were administrated 2U PPE by intratracheal instillation and subcutaneously injected with either saline (vehicle) or varenicline (0.5 mg kg-1 day-1) for 5 or 21 days. PPE-administrated mice were also injected intraperitoneally with 5mg kg-1 day-1 methyllycaconitine (MLA, α7 nAChR antagonist) for 21 days. At 5 days after PPE administration, the inflammatory cells including macrophages, neutrophils and T cells in the bronchoalveolar lavage (BAL) fluid were identified by immunofluorescence staining with anti-F4/80, anti-NIMP-R14 and anti-CD4 antibodies, respectively. To assess the effect of varenicline on the lung inflammation, the number of each positive cell was counted. In addition, the lung tissue sections were stained with hematoxylin and eosin. Air space enlargement was then quantified by the mean linear intercept values.
Results: The number of macrophages, neutrophils and T cells in BAL fluid was markedly increased by 2U PPE administration at 5 days after PPE administration. The number of inflammatory cells in BAL fluid was significantly decreased by varenicline compared with vehicle treatment. In addition, the administration of varenicline for 5 days significantly inhibited PPE-induced alveolar expansion; this marked inhibitory effect was also observed by its administration for 21 days after PPE instillation. This varenicline-induced protection against the alveolar expansion was markedly attenuated by MLA treatment in mice with PPE instillation.
Conclusions: In light of the present findings, varenicline likely have the anti-inflammatory property to protect PPE-induced alveolar expansion through α7 nAChR. Varenicline treatment could be useful for patients with COPD and acute-phase inflammatory response of the lung.
