Submitted on June 2, 2006
Accepted on February 25, 2007
Adrenomedullin insufficiency increases allergen induced airway hyperresponsiveness in mice
Hiroshi Yamamoto1*, Takahide Nagase2, Takayuki Shindo3, Shinji Teramoto4, Tomoko Aoki-Nagase1, Yasuhiro Yamaguchi1, Yoko Hanaoka1, Hiroki Kurihara5, and Yasuyoshi Ouchi6
1 Department of Geriatric Medicine, University of Tokyo, Graduate School of Medicine, Tokyo, Japan
2 Department of Respiratory Medicine, University of Tokyo, Graduate School of Medicine, Tokyo, Japan
3 Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Nagano, Japan
4 Department of Geriatric Medicine, University of Tokyo, Graduate School of Medicine, Tokyo, Tokyo, Japan
5 Department of Physiological Chemistry and Metabolism, University of Tokyo, Graduate School of Medicine, Tokyo, Japan
6 Department of Geriatric Medicine, University of Tokyo, Graduate School of Medicine, Tokyo, Japan; Tokyo, Japan
* To whom correspondence should be addressed. E-mail: hyamamot-tky{at}umin.ac.jp.
Adrenomedullin (ADM), a newly identified vasodilating peptide, is reported to be expressed in lungs and have 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 unaffected immunoglobulins (OVA-specific IgE and IgG1), Th1 and Th2 cytokines, and leukotrienes. Thus, the conventional mechanism of allergen induced airway responsiveness is not relevant to this model. Further, 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.
