11, 12 Elastin is an insoluble nonpolar protein, formed by polymerization of the soluble monomer tropoelastin.13 The tropoelastin molecule is rich in alanine and lysine residues, which are principal sites for crosslinking reactions. Such reactions are potentially catalyzed by either lysyl-oxidase

(LOX) or tissue transglutaminase (tTG)14, 15; in addition, in mature scars a nonenzymatic reaction EGFR inhibitor is possible.11 Thus, intermolecular crosslinks increase the insolubility of the elastic fibers and render matrix resistant to degradation, in turn limiting the reversibility of fibrosis. Elastic fibers are present in the normal liver in the capsule and portal tracts and their number increases in fibrosis and cirrhosis.16, 17 Furthermore, the ratio between elastin and collagen

increases as liver fibrosis check details progresses.18 In parallel, an increase in crosslinking is observed.19 Despite this clear contribution of elastin to liver fibrosis and progression of liver disease, the regulation of elastin secretion and turnover has not been investigated in liver fibrosis. Two main cell types are responsible for elastin degradation, neutrophils, secreting neutrophil elastase (NE), and macrophages through macrophage metalloelastase (MMP-12).20 Like other MMPs, MMP-12 is transcriptionally regulated,21 secreted as a proenzyme, and subsequently activated by (self)-cleavage in selleck screening library the extracellular space. Macrophage depletion during spontaneous recovery from fibrosis leads to a failure of matrix degradation, associated with an increase in scar elastin relative to control22 (see below). This suggests that macrophages serve a discrete function mediating degradation of elastin. Furthermore, Fallowfield et al.23 have shown expression of MMP-13 (collagenase 3) by scar-associated macrophages, suggesting that these cells may be critically important in mediating matrix remodeling during fibrosis. We therefore deployed targeted gene mutation and conditional macrophage depletion studies to define

the role of macrophages and MMP-12 in mediating elastin turnover during progressive fibrosis. Our data provide evidence that elastin is regulated at the level of degradation during experimental liver fibrosis. Specifically, macrophage-derived MMP-12 appears to be critical for regulating elastin degradation in progressive experimental liver fibrosis. CCl4, carbon tetrachloride; HSC, hepatic stellate cell; LOX, lysyl-oxidase; MMP, macrophage metalloelastase; NE, neutrophil elastase; TAA, thioacetamide; TIMP, tissue inhibitors of metalloproteinase; tTG, tissue transglutaminase; WT, wildtype. Animals were housed in standard sterile conditions with free access to chow and water. All procedures were undertaken in accordance with the local ethical committee.