Disruption of ET-1 gene enhances pulmonary responses to methacholine via functional mechanism in knockout mice

Takahide Nagase, Hiroki Kurihara, Yukiko Kurihara, Tomoko Aoki-Nagase, Ryozo Nagai, Yasuyoshi Ouchi
1999 Journal of applied physiology  
Disruption of ET-1 gene enhances pulmonary responses to methacholine via functional mechanism in knockout mice. J. Appl. Physiol. 87(6): 2020-2024, 1999.-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.
more » ... 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 ϩ/Ϫ heterozygous knockout mice, which genetically produce lower levels of ET-1, and Edn1 ϩ/ϩ wild-type mice. In the physiological study, enhanced responses in lung elastance and resistance to methacholine administration were observed in Edn1 ϩ/Ϫ 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 ϩ/Ϫ mice and Edn1 ϩ/ϩ 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. knockout mouse; bronchial asthma; airway smooth muscle; bronchial hyperreactivity; asthma gene 8750-7587/99 $5.00
doi:10.1152/jappl.1999.87.6.2020 pmid:10601144 fatcat:tpvlq5ptnndrdlf5ealbpsmcou