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Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3)
Kevin J. Leco, … , Tak W. Mak, Rama Khokha
Kevin J. Leco, … , Tak W. Mak, Rama Khokha
Published September 15, 2001
Citation Information: J Clin Invest. 2001;108(6):817-829. https://doi.org/10.1172/JCI12067.
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Article

Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3)

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Abstract

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.

Authors

Kevin J. Leco, Paul Waterhouse, Otto H. Sanchez, Katrina L.M. Gowing, A. Robin Poole, Andrew Wakeham, Tak W. Mak, Rama Khokha

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Figure 2

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Survival of TIMP-3–null mice is compromised. (a) Beginning at 56 weeks o...
Survival of TIMP-3–null mice is compromised. (a) Beginning at 56 weeks of age, individual TIMP-3–null mice became overtly sick, and by 83 weeks of age all animals in this study were sacrificed. This compared with heterozygote controls (Hets), which lived illness free for at least 120 weeks. Shown is pooled data for both males and females. (b) Sex-specific differences in survival (TIMP-3–/– males, n = 10; TIMP-3–/– females, n = 10; TIMP-3+/– males, n = 3).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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