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Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis

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Abstract

Elastin has been linked to maturity of liver fibrosis. To date, the regulation of elastin secretion and its degradation in liver fibrosis has not been characterised. The aim of this work was to define elastin accumulation and the role of the paradigm elastase macrophage metalloelastase (MMP-12) in its turnover during fibrosis. Liver fibrosis was induced by either IP injections of CCl(4) for up to 12 weeks (rat and mouse) or oral administration of thioacetamide (TAA) for one year (mouse). Elastin synthesis, deposition and degradation were investigated by immunohistochemistry, qPCR and western blotting and casein zymography. The regulation of MMP-12 elastin degradation was defined mechanistically using CD11b-DTR and MMP-12 knockout mice. In a CCl(4) model of fibrosis in rat, elastin deposition was significantly increased only in advanced fibrosis. Tropoelastin expression increased with duration of injury. MMP-12 protein levels were only modestly changed and in co-immunoprecipitation experiments MMP-12 was bound in greater quantities to its inhibitor TIMP-1 in advanced vs. early fibrosis. Immunohistochemistry and macrophage depletion experiments indicated that macrophages were the sole source of MMP-12. Exposure of CCl(4) in MMP-12(-/-) mice lead to similar degree of overall fibrosis compared to wild-type but increased perisinusoidal elastin. Conversely, oral administration of TAA caused both higher elastin accumulation and higher fibrosis in MMP-12(-/-) mice compared to WT. CONCLUSIONS: Elastin is regulated at the level of degradation during liver fibrosis. Macrophage derived MMP-12 regulates elastin degradation even in progressive experimental liver fibrosis. These observations have important implications for the design of antifibrotic therapies. (HEPATOLOGY 2011.).

ID: 2026789