bencycloquidium-bromide and Pneumonia

Bencycloquidium bromide (BCQB), a novel M3 receptor antagonist, alleviates airway hyperresponsiveness, inflammation, and airway remodeling in a murine model of asthma. The aim of this study was to investigate the anti-inflammatory activity of inhaled BCQB in a cigarette smoke (CS)-induced model of acute lung inflammation. Mice exposed to CS developed chronic obstructive pulmonary disease (COPD). Inhalation of BCQB suppressed the accumulation of neutrophils and macrophages in airways and lung and also inhibited the CS-induced increases in mRNA levels of keratinocyte-derived chemokine, monocyte chemotactic protein-1, tumor necrosis factor-alpha, and interleukin-1β in lung and protein expression levels in bronchoalveolar lavage fluid. Moreover, BCQB (300 μg/ml) inhibited the CS-induced changes in superoxide dismutase and myeloperoxidase activities in the lungs. Our study suggests that BCQB might be a potential therapy for inflammation in CS-induced pulmonary diseases, including COPD.

Topics: Administration, Inhalation; Animals; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Lung; Mice; Mice, Inbred ICR; Nicotiana; Pneumonia; Receptor, Muscarinic M3; Smoke; Smoking; Treatment Outcome

M(3) muscarinic receptors are localized on inflammatory cells, airway smooth muscle, and submucosal glands, known to mediate bronchoconstriction, mucus secretion, and airway remodeling. It is hypothesized bencycloquidium bromide (BCQB), a novel M(3) receptor antagonist, might have potential effects on airway hyperresponsiveness, inflammation and airway remodeling in a murine model of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was examined to determine the total and differential cell counts, and cytokine levels. Lung tissues were evaluated for cell infiltration, mucus hypersecretion, airway remodeling, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Inhalation administration of BCQB significantly not only reduced ovalbumin-induced airway hyperresponsiveness comparing to methacholine, and prevented the ovalbumin-induced increase in total cell counts and eosinophil counts. Reverse transcriptase polymerase chain reaction analysis of whole lung lysates revealed that BCQB markedly suppressed ovalbumin-induced mRNA expression of eotaxin, IL-5, IL-4 and MMP-9, and increased mRNA expression of IFN-γ and TIMP-1 in a dose-dependent manner. Substantial IFN-γ/IL-4 (Th1/Th2) levels were recovered in bronchoalveolar lavage fluid after BCQB treatment. In addition, histological studies showed that BCQB dramatically inhibited ovalbumin-induced lung tissue eosinophil infiltration, airway mucus production and collagen deposition in lung tissues. Results reported in current paper suggest that M(3) receptors antagonist may provide a novel therapeutic approach to treat airway inflammation, hyperresponsiveness and remodeling.

Topics: Airway Remodeling; Animals; Bridged Bicyclo Compounds, Heterocyclic; Bronchoalveolar Lavage Fluid; Chemokines; Eosinophilia; Female; Gene Expression Regulation; Hypersensitivity; Inflammation; Lung; Matrix Metalloproteinases; Methacholine Chloride; Mice; Pneumonia; Receptor, Muscarinic M3; Respiratory System; RNA, Messenger