title: Disruption of ET-1 gene enhances pulmonary responses to methacholine via functional mechanism in knockout mice.
abstract: Endothelin (ET)-1 has been shown to have various pathophysiological roles in the lung. Recently, it has been reported that ET-1 and a gene encoding ET-1 (Edn1) might be involved in airway hyperresponsiveness, which is a major feature of bronchial asthma. Meanwhile, it remains unclear whether ET-1 might be involved in airway remodeling in vivo. In the present study, we hypothesized whether ET-1 might play a role in airway remodeling, leading to altered responsiveness. To test this hypothesis, we investigated airway function in vivo and airway wall structure in Edn1(+/-) heterozygous knockout mice, which genetically produce lower levels of ET-1, and Edn1(+/+) wild-type mice. In the physiological study, enhanced responses in lung elastance and resistance to methacholine administration were observed in Edn1(+/-) mice, whereas there was no difference in serotonin responsiveness. In the morphometric study, there were no differences in either lamina propria or airway smooth muscle thickness between Edn1(+/-) mice and Edn1(+/+) mice. These findings suggest that ET-1 gene disruption is involved in methacholine pulmonary hyperresponsiveness via functional mechanism, but not airway remodeling, in mice. The ET-1 knockout mice may provide appropriate models to study diseases related to ET-1 metabolism.
authors.affiliation: Department of Geriatric Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan. takahide-tky@umin.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Nagase
authors.forename: H
authors.initials: H
authors.lastname: Kurihara
authors.forename: Y
authors.initials: Y
authors.lastname: Kurihara
authors.forename: T
authors.initials: T
authors.lastname: Aoki-Nagase
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: Y
authors.initials: Y
authors.lastname: Ouchi
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D004548:Elasticity; D019332:Endothelin-1 / Q000819:agonists / Q000235:genetics*; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D016210:Methacholine Chloride / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology
chemical_list: D016085:Bronchoconstrictor Agents; D019332:Endothelin-1; D016210:Methacholine Chloride; D012701:Serotonin