EMPHYSEMATOUS CHANGES ARE CAUSED BY DEGRADATION OF TYPE III COLLAGEN IN TRANSGENIC MICE EXPRESSING MMP-1

Abstract

Disruption of the extracellular matrix is believed to play an important role in the pathogenesis of emphysema. Prior studies have demonstrated that transgenic mice expressing the human tissue collagenase, matrix metalloproteinase 1 (MMP-1), develop emphysema. MMP-1 is a protease with substrate specificity for fibrillar collagen. Type I and III collagens, which are the most abundant proteins within the lungs, are the primary substrates for MMP-1. To assess if type I collagen was indeed the site of action for MMP-1 in these transgenic mice, hybrid mice were generated by crossing the MMP-1 transgenic mice with mice that had degradation-resistant type I collagen. The hybrid mice demonstrated an identical emphysematous phenotype as the MMP-1 transgenic mice, indicating that the degradation of type I collagen was not essential to the development of emphysema in these mice. Immunohistochemical studies in control mice demonstrated that collagen fibers in the alveolar walls and ducts of the normal mouse lungs consist mainly of type III collagen. In the transgenic and hybrid mice, the emphysematous changes, which developed, were associated with a marked decrease in type III collagen in these alveolar structures. These results indicate that MMP-1 generated the emphysematous phenotype via the degradative effect on type III collagen, which is a vital structural element of the alveolar walls. This is the first study to show that a matrix metalloproteinase may cause emphysema via its effects on a specific collagen subtype. As such, it should provide important insight into the mechanisms of this disease in humans.