Progressive adult-onset emphysema in transgenic mice expressing human MMP-1 in the lung.
Mice with lung-specific expression of human matrix metalloproteinase-1 (MMP-1) develop emphysematous changes similar to those seen in smoking-induced emphysema in humans. Morphometric analyses of three transgenic lines [homozygous colony (Col) 34, Col 50, and Col 64] with varying temporal expression of MMP-1 were undertaken to determine the validity of this animal as a model of adult-onset emphysema. Line 50 mice, which have early expression of MMP-1 (14 days postconception), exhibited morphometric changes by 5 days of age. In contrast, homozygous line 34 and 64 with delayed expression (birth and 2 wk of age) were normal up until 4 wk of age when progressive changes in their mean linear intercept were first noted. In contrast, heterozygous mice from line 34 with lower transgene expression did not develop emphysema until 1 yr of age. The changes in mean linear intercept coincided with an increase in lung compliance. Emphysema in these mice was associated with decreased immunostaining for type III collagen within the alveolar septa. This study provides evidence that MMP-1 induces progressive adult-onset emphysema by the selective degradation of type III collagen within the alveolar wall.
Foronjy
Robert F
RF
Department of Medicine, Division of Molecular Medicine and Pulmonary Medicine, Columbia University, New York, New York 10032, USA.
Okada
Yasunori
Y
Cole
Randolph
R
D'Armiento
Jeanine
J
D000208:Acute Disease; D017668:Age of Onset; D000596:Amino Acids / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D024042:Collagen Type I / Q000032:analysis / Q000378:metabolism; D024061:Collagen Type III / Q000032:analysis / Q000378:metabolism; D004549:Elastin / Q000032:analysis / Q000378:metabolism; D004646:Emphysema / Q000378:metabolism*; D005109:Extracellular Matrix / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis / Q000378:metabolism; D007150:Immunohistochemistry; D007958:Leukocyte Count; D008168:Lung / Q000737:chemistry / Q000201:enzymology; D008170:Lung Compliance / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D019076:Transgenes / Q000502:physiology
D000596:Amino Acids; D024042:Collagen Type I; D024061:Collagen Type III; C015484:pyridinoline; D004549:Elastin; D020781:Matrix Metalloproteinase 1; D006909:Hydroxyproline