title: M(3) muscarinic receptor antagonist bencycloquidium bromide attenuates allergic airway inflammation, hyperresponsiveness and remodeling in mice.
abstract: 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.
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Cao
authors.forename: Xin-Wei
authors.initials: XW
authors.lastname: Dong
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Jiang
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yan
authors.forename: Jun-Shan
authors.initials: JS
authors.lastname: He
authors.forename: Yang-Mei
authors.initials: YM
authors.lastname: Deng
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Li
authors.forename: Meng-Jing
authors.initials: MJ
authors.lastname: Bao
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Xie
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
authors.forename: Qiang-Min
authors.initials: QM
authors.lastname: Xie
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000235:genetics; D004802:Eosinophilia / Q000188:drug therapy; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006967:Hypersensitivity / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D011014:Pneumonia / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018925:Chemokines; D012333:RNA, Messenger; D043587:Receptor, Muscarinic M3; C518439:bencycloquidium bromide; D016210:Methacholine Chloride; D020782:Matrix Metalloproteinases