Moreover, western-blot analyses revealed expression of MMP13 prot

Moreover, western-blot analyses revealed expression of MMP13 protein in the group administered HA/PEI/pMMP13, but not in other groups (Figure 7e). Figure 7 Expression of MMP13 proteins in liver tissues of fibrotic mice. Expression of EGFP and MMP13 proteins in liver tissues was visualized by fluorescent microscopy and immunoblotting, respectively. (a,c) Representative phase-contrast and selleck products (b,d) fluorescence … Figure 8 Hepatic collagen deposition and serum AST after pMMP13 gene therapy. Collagen deposition was tested for the (a) liver tissues from normal mice, (b) fibrotic mice treated with saline, (c) HA/PEI/pVector, or (d) HA/PEI/pMMP13. Bar = 400 mm. The … Antifibrotic effect of pMMP13 administered in HA/PEI complexes Intravenous administration of pMMP13 in HA/PEI complexes ameliorated liver fibrosis in mice.

Sirius red staining of liver sections showed the presence of collagen deposition in the liver tissues of CCl4-treated mice administered saline (Figure 8b). Collagen was deposited to a similar extent in liver tissues of CCl4-treated mice administered pVector in HA/PEI complexes (Figure 8c). In contrast, injections of pMMP13/HA/PEI complexes significantly decreased the deposition of collagen in CCl4-treated mice (Figure 8d), reducing collagen to levels similar to those in untreated normal mouse livers (Figure 8a). The administration of pMMP13 in HA/PEI complexes also promoted recovery from liver damage in the liver fibrosis model, significantly decreasing the plasma levels of aspartate aminotransferase (AST) compared with those in animals administered pVector in HA/PEI complexes.

Consistent with the collagen-deposition histology data, there was no significant difference in serum AST levels between the untreated normal group and the liver fibrosis group treated with pMMP13 in HA/PEI complexes (Figure 8e). Discussion In this study, we demonstrated the antifibrotic effects of pMMP13 administered in HA-shielded complexes in a murine liver fibrosis model. Treatment of mice with liver fibrosis by administering HA/PEI/pMMP13 increased MMP13 mRNA and protein levels in liver tissue. Moreover, HA/PEI/pMMP13 treatment reduced collagen I deposition in liver tissue and restored plasma AST levels to values similar to those in untreated normal mice. The shielding of PEI/pMMP13 with HA provided protection against PEI cytotoxicity.

The mechanism underlying this cytoprotective effect remains to be elucidated. However, Moghimi et al.23 reported that PEI cytotoxicity was associated with activation of caspase-2 and changes in the mitochondrial GSK-3 membrane potential. Thus, it is possible that neutralization of the cationic charges of PEI by HA reduces the mitochondrial damage caused by PEI. Moreover, in vivo, the shielding of PEI/pMMP13 with HA may prevent the interaction of PEI with plasma proteins of the circulatory system.

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