title: Kinin B1 receptor antagonist BI113823 reduces allergen-induced airway inflammation and mucus secretion in mice.
abstract: Kinin B1 receptors are implicated in asthmatic airway inflammation. Here we tested this hypothesis by examining the anti-inflammatory effects of BI113823, a novel non-peptide orally active kinin B1 receptor antagonist in mice sensitized to ovalbumin (OVA). Male Balb-c mice were randomly assigned to four study groups: (1) control, (2) OVA+vehicle, (3) OVA+BI113823, (4) OVA+dexamethasone. Mice were sensitized intraperitoneally with 75μg ovalbumin on days 1 and 8. On days 15-17, mice were challenged intranasally with 50μg of ovalbumin. Mice received vehicle, BI113823, or dexamethasone (positive control) on days 16-18. On day 19, bronchoalveolar lavage (BAL) and lung tissue were collected for biochemical and immuno-histological analysis. Compared to controls treatment with BI113823 significantly reduced the numbers of BAL eosinophils, macrophages, neutrophils and lymphocytes by 58.3%, 61.1%, 66.4% and 56.0%, respectively. Mice treated with dexamethasone showed similar reductions in BAL cells. Treatment with BI113823 and dexamethasone also significantly reduced total protein content, IgE, TNF-α and IL-1β in lavage fluid, reduced myeloperoxidase activity, mucus secretion in lung tissues, and reduced the expression of B1 receptors, matrix metalloproteinase (MMP)-2 and cyclooxygenase (COX)-2 compared to vehicle-treated mice. Only BI113823 reduced MMP-9 and inducible nitric oxide synthase (iNOS). BI113823 effectively reduced OVA-induced inflammatory cell, mediator and signaling pathways equal to or greater than that seen with steroids in a mouse asthma model. BI113823 might be useful in modulating inflammation in asthma.
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, South Korea.
authors.forename: Malarvizhi
authors.initials: M
authors.lastname: Gurusamy
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, South Korea.
authors.forename: Saeed
authors.initials: S
authors.lastname: Nasseri
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, South Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Lee
authors.affiliation: Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Jung
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, South Korea.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, South Korea.
authors.forename: Gilson
authors.initials: G
authors.lastname: Khang
authors.affiliation: Department of Research Mount Sinai Medical Center, Miami Beach, FL, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.affiliation: Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Henri
authors.initials: H
authors.lastname: Doods
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, South Korea; Department of Research Mount Sinai Medical Center, Miami Beach, FL, USA. Electronic address: dongmeiwu@bellsouth.net.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
mesh_terms: D000485:Allergens; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D065169:Bradykinin B1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D051546:Cyclooxygenase 2 / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology; D007073:Immunoglobulin E / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000276:immunology; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D010047:Ovalbumin; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000485:Allergens; D000893:Anti-Inflammatory Agents; D065169:Bradykinin B1 Receptor Antagonists; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; D003907:Dexamethasone; D010047:Ovalbumin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: Airway inflammation; Cyclooxygenase-2; Inducible nitric oxide synthase; Kinin B1 receptors; Matrix metalloproteinase; Mucus