title: Adrenomedullin insufficiency increases allergen-induced airway hyperresponsiveness in mice.
abstract: Adrenomedullin (ADM), a newly identified vasodilating peptide, is reported to be expressed in lungs and have a bronchodilating effect. We hypothesized whether ADM could be involved in the pathogenesis of bronchial asthma. We examined the role of ADM in airway responsiveness using heterozygous ADM-deficient mice (AM+/-) and their littermate control (AM+/+). Here, we show that airway responsiveness is enhanced in ADM mutant mice after sensitization and challenge with ovalbumin (OVA). The immunoreactive ADM level in the lung tissue after methacholine challenge was significantly greater in the wild-type mice than that in the mutant. However, the impairment of ADM gene function did not affect immunoglobulins (OVA-specific IgE and IgG1), T helper 1 and 2 cytokines, and leukotrenes. Thus the conventional mechanism of allergen-induced airway responsiveness is not relevant to this model. Furthermore, morphometric analysis revealed that eosinophilia and airway hypersecretion were similarly found in both the OVA-treated ADM mutant mice and the OVA-treated wild-type mice. On the other hand, the area of the airway smooth muscle layer of the OVA-treated mutant mice was significantly greater than that of the OVA-treated wild-type mice. These results suggest that ADM gene disruption may be associated with airway smooth muscle hyperplasia as well as enhanced airway hyperresponsiveness. ADM mutant mice might provide novel insights to study the pathophysiological role of ADM in vivo.
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-8655. hyamamot-tky@umin.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Takahide
authors.initials: T
authors.lastname: Nagase
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shindo
authors.forename: Shinji
authors.initials: S
authors.lastname: Teramoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Aoki-Nagase
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hanaoka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ouchi
mesh_terms: D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000485:Allergens; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D001985:Bronchial Provocation Tests / Q000379:methods*; D006967:Hypersensitivity / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin
chemical_list: D000485:Allergens; D053607:Adrenomedullin; D010047:Ovalbumin