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Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis

¹Instituto Nacional de Enfermedades Respiratorias, Mexico City, CP14080, ²Hospital General de Mexico, SSA, Mexico City, CP06720, and ³Facultad de Ciencias, Universidad Nacional Autónoma de Mexico, Mexico City, CP04510, Mexico; and ⁴Department of Physiology, Michigan State University, Lansing, Michigan 48824

Submitted 9 June 2003 ; accepted in final form 20 July 2003

In this study, we examined the sequential expression of several matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and growth factors as well as the presence of apoptosis in a model of pulmonary fibrosis induced in rats with paraquat and hyperoxia. Animals showing neither clinical nor morphological changes with this double aggression were classified as "resistant". Rats were killed at 1, 2, 3, and 6 wk, and lungs were used for collagen content, gene expression by real-time PCR, gelatinolytic activity by zymography, apoptosis by in situ DNA fragmentation, and protein localization by immunohistochemistry. Our results showed a significant decrease of collagenases MMP-8 and MMP-13, with an increase of TIMP-1 and transforming growth factor-. Immunoreactive TIMP-1 was increased in experimental rats and primarily localized in alveolar macrophages. Expression of gelatinases MMP-2 and MMP-9 mRNAs was not affected, but lung zymography revealed an increase in progelatinase B, progelatinase A, and its active form. Epithelial apoptosis was evident from the first week, whereas at later periods, interstitial cell apoptosis was also noticed. Resistant animals behave as controls. These findings suggest that an imbalance between collagenases and TIMPs, excessive gelatinolytic activity, and epithelial apoptosis participate in the fibrotic response in this experimental model.

gelatinases; tissue inhibitor of metalloproteinases-1

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