Meprin ß contributes to collagen deposition in lung fibrosis.

ABSTRACT

Lung fibrosis is a severe disease characterized by epithelial cell injury, inflammation and collagen deposition. The metalloproteases meprinα and meprinß have been shown to enhance collagen maturation and inflammatory cell infiltration via cleavage of cell-cell contact molecules; therefore we hypothesized that meprins could play a role in lung fibrosis. An exhaustive characterization of bleomycin-treated meprinα, meprinß and the double meprinsαß knock-out (KO) with respective wt-littermates was performed by using several different methods. We observed no difference in lung function parameters and no change in inflammatory cells infiltrating the lung between wt and all meprins KO mice after 14 days bleomycin. No difference in epithelial integrity as assessed by e-cadherin protein level was detected in bleomycin-treated lungs. However, morphological analysis in the bleomycin-treated mice revealed decrease collagen deposition and tissue density in meprinß KO, but not in meprinα and meprinαß KO mice. This finding was accompanied by localization of meprinß to epithelial cells in regions with immature collagen in mice. Similarly, in human IPF lungs meprinß was mostly localized in epithelium. These findings suggest that local environment triggers meprinß expression to support collagen maturation. In conclusion, our data demonstrate the in vivo relevance of meprinß in collagen deposition in lung fibrosis.