Funada Yasuhiro, Nishimura Yoshihiro, Yokoyama Mitsuhiro
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Kobe J Med Sci. 2004;50(3-4):59-67.
Klotho mice, which exhibit multiple phenotypes resembling human aging, develop pulmonary emphysema. In this study, to clarify the mechanism of their emphysematous change through development, we evaluated the expression of matrix metalloproteinase (MMP)-2, 9 and the tissue inhibitors of matrix metalloproteinase (TIMP)-1, 2 in the lungs of Klotho mice and wild type mice. Klotho mice showed obvious air space enlargement at 5 weeks of age, but not at 2 weeks of age. Immunohistochemical analysis revealed that expression of MMP-9 was increased in Klotho mice compared with wild type at 5 weeks of age. Western blot analysis and gelatin zymography also revealed that the expression and the gelatinolytic activity of MMP-9 were increased in the lungs of Klotho mice. The expression of TIMP-1 decreased in the lungs of Klotho mice. MMP-2 and TIMP-2 showed no significant differences at 5 weeks of age. At 2 weeks of age, there were no significant differences in the expressions of MMP-9 and TIMP-1 between Klotho and wild type mice. These findings suggest that imbalance of MMP-9 and TIMP-1 is associated with the development of pulmonary emphysema in Klotho mice.
表现出多种类似人类衰老表型的klotho小鼠会发展为肺气肿。在本研究中，为了阐明其肺气肿变化在发育过程中的机制，我们评估了klotho小鼠和野生型小鼠肺中基质金属蛋白酶（MMP）-2、9以及基质金属蛋白酶组织抑制剂（TIMP）-1、2的表达。klotho小鼠在5周龄时出现明显的气腔扩大，但在2周龄时未出现。免疫组织化学分析显示，与野生型相比，5周龄的klotho小鼠中MMP-9的表达增加。蛋白质免疫印迹分析和明胶酶谱分析也显示，klotho小鼠肺中MMP-9的表达和明胶酶解活性增加。klotho小鼠肺中TIMP-1的表达降低。5周龄时，MMP-2和TIMP-2无显著差异。在2周龄时，klotho小鼠和野生型小鼠之间MMP-9和TIMP-1的表达无显著差异。这些发现表明，MMP-9和TIMP-1的失衡与klotho小鼠肺气肿的发展有关。
