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1 Instituto Nacional de Enfermedades Respiratorias, Mexico DF, Mexico
2 Hospital General de Mexico, SSA, Mexico DF, Mexico
3 Facultad de Ciencias, Universidad Nacional Autonoma de Mexico, Mexico DF, Mexico
4 Department of Physiology, Michigan State University, East Lansing, Michigan, USA
* To whom correspondence should be addressed. E-mail: mselman{at}sni.conacyt.mx.
In this study we examined the sequential expression of several matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP), 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 sacrificed at 1, 2, 3, and 6 weeks 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 beta. 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 zimography revealed an increase in progelatinase B, progelatinase A and its active form. Epithelial apoptosis was evident from the first week, while 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.
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