Resistance to bleomycin-induced lung fibrosis in MMP-8 deficient mice is mediated by interleukin-10.
BACKGROUND
Matrix metalloproteinases (MMPs) may have pro and antifibrotic roles within the lungs, due to its ability to modulate collagen turnover and immune mediators. MMP-8 is a collagenase that also cleaves a number of cytokines and chemokines.


RESULTS
To evaluate its relevance in lung fibrosis, wildtype and Mmp8(-/-) mice were treated with either intratracheal bleomycin or saline, and lungs were harvested at different time points. Fibrosis, collagen, collagenases, gelatinases, TGFβ and IL-10 were measured in lung tissue. Mmp8(-/-) mice developed less fibrosis than their wildtype counterparts. This was related to an increase in lung inflammatory cells, MMP-9 and IL-10 levels in these mutant animals. In vitro experiments showed that MMP-8 cleaves murine and human IL-10, and tissue from knockout animals showed decreased IL-10 processing. Additionally, lung fibroblasts from these mice were cultured in the presence of bleomycin and collagen, IL-10 and STAT3 activation (downstream signal in response to IL-10) measured by western blotting. In cell cultures, bleomycin increased collagen synthesis only in wildtype mice. Fibroblasts from knockout mice did not show increased collagen synthesis, but increased levels of unprocessed IL-10 and STAT3 phosphorylation. Blockade of IL-10 reverted this phenotype, increasing collagen in cultures.


CONCLUSIONS
According to these results, we conclude that the absence of MMP-8 has an antifibrotic effect by increasing IL-10 and propose that this metalloprotease could be a relevant modulator of IL-10 metabolism in vivo.
García-Prieto
Emilio
E
Department of Biología Funcional, Universidad de Oviedo, Instituto Universitario de Oncología (IUOPA), Oviedo, Spain.
González-López
Adrián
A
Cabrera
Sandra
S
Astudillo
Aurora
A
Gutiérrez-Fernández
Ana
A
Fanjul-Fernandez
Miriam
M
Batalla-Solís
Estefanía
E
Puente
Xose S
XS
Fueyo
Antonio
A
López-Otín
Carlos
C
Albaiceta
Guillermo M
GM
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D005780:Gelatin / Q000378:metabolism; D016753:Interleukin-10 / Q000502:physiology*; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
D016207:Cytokines; D001761:Bleomycin; D016753:Interleukin-10; D005780:Gelatin; D003094:Collagen; D020784:Matrix Metalloproteinase 8