Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis.
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-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 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.
Ruiz
Victor
V
Instituto Nacional de Enfermedades Respiratorias, México City, DF, CP 14080, México.
Ordóñez
Rosa Ma
RM
Berumen
Jaime
J
Ramírez
Remedios
R
Uhal
Bruce
B
Becerril
Carina
C
Pardo
Annie
A
Selman
Moisés
M
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015415:Biomarkers / Q000032:analysis; D015152:Blotting, Northern; D017364:Collagenases / Q000235:genetics*; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006909:Hydroxyproline / Q000032:analysis; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020545:Respiratory Mucosa / Q000473:pathology*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000032:analysis
D015415:Biomarkers; D017931:DNA Primers; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D017364:Collagenases; D006909:Hydroxyproline