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

Tissue inhibitors of metalloproteinases regulate ECM degradation by matrix metalloproteinases (MMPs). We have developed a mouse line deficient for tis sue inhibitor of metalloproteinases-3 (TIMP-3), the only TIMP known to resi de within the ECM. Homozygous Timp-3-null animals develop spontaneous air s pace enlargement in the lung that is evident at 2 weeks after birth and pro gresses with age of the animal. As early as 13 months of age animals become moribund. Lung function, measured by carbon monoxide uptake, is impaired i n aged null animals. Lungs from aged null animals have reduced abundance of collagen, enhanced degradation of collagen in the peribronchiolar space, a nd disorganization of collagen fibrils in the alveolar interstitium, but no increase in inflammatory cell infiltration or evidence of fibrosis in comp arison with controls. Using in situ zymography, we show that lungs from age d null animals have heightened MMP activity over wild-type and heterozygoti c animals. Finally, TIMP-3-null fibroblast cultures demonstrate enhanced de struction 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 degrad ation, culminating in incapacitating illness and a shorter life span.