Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3)
Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3)
复制标题
DOI：
10.1172/jci12067
复制
发表时间：
2001-09-01
影响因子：
15.9
通讯作者：
Khokha, R
中科院分区：
文献类型：
--
作者：
Leco, KJ;Waterhouse, P;Khokha, R
金属蛋白酶组织抑制剂通过基质金属蛋白酶（MMPs）调节ECM降解。我们已经开发了一种缺乏金属蛋白酶组织抑制剂-3（TIMP-3）的小鼠品系，TIMP-3是已知存在于ECM中的唯一TIMP。纯合Timp-3缺失动物在肺中发展自发的气隙扩大，这在出生后2周时是明显的，并且随着动物的年龄而进展。早在13个月大的时候，动物就变得奄奄一息。肺功能，测量一氧化碳摄取，是受损的老年无效动物。与对照组相比，老年无效动物的肺胶原蛋白丰度降低，支气管周围间隙胶原蛋白降解增强，肺泡上皮胶原纤维解体，但炎性细胞浸润或纤维化证据未增加。使用原位酶谱，我们发现，从老年无效动物肺MMP活性提高野生型和杂合子动物。最后，TIMP-3无效的成纤维细胞培养物证明了体外ECM分子的破坏增强。我们认为，TIMP-3的缺失导致肺中TIMP/MMP平衡的转变，有利于ECM降解，最终导致失能性疾病和较短的寿命。
Tissue inhibitors of metalloproteinases regulate ECM degradation by matrix metalloproteinases (MMPs). We have developed a mouse line deficient for tissue inhibitor of metalloproteinases-3 (TIMP-3), the only TIMP known to reside within the ECM. Homozygous Timp-3-null animals develop spontaneous air space enlargement in the lung that is evident at 2 weeks after birth and progresses with age of the animal. As early as 13 months of age animals become moribund. Lung function, measured by carbon monoxide uptake, is impaired in aged null animals. Lungs from aged null animals have reduced abundance of collagen, enhanced degradation of collagen in the peribronchiolar space, and disorganization of collagen fibrils in the alveolar interstitium, but no increase in inflammatory cell infiltration or evidence of fibrosis in comparison with controls. Using in situ zymography, we show that lungs from aged null animals have heightened MMP activity over wild-type and heterozygotic animals. Finally, TIMP-3-null fibroblast cultures demonstrate enhanced destruction of ECM molecules in vitro. We propose that the deletion of TIMP-3 results in a shift of the TIMP/MMP balance in the lung to favor ECM degradation, culminating in incapacitating illness and a shorter life span.