3A), whereas in CoPP-treated mice, only mild fibrosis was observe

3A), whereas in CoPP-treated mice, only mild fibrosis was observed, which was limited to the portal tracts (Fig.

3A). The equilibrium of assembly and disassembly of the extracellular matrix (ECM) is regulated by the activity of MMPs.27 We observed that activity of MMP-9 was significantly up-regulated in Mdr2ko mice upon HO-1 induction, whereas activity of MMP-2 was not altered (Fig. 3B,C). The fibrosis marker, hydroxyproline, was also found to be significantly reduced in livers of CoPP-treated Mdr2ko mice (Fig. 4A). Fibrogenesis is characterized by high expression levels of collagens I and III,28 which we found to be reduced upon HO-1 induction (Fig. 4B). Because activated HSCs play a crucial role in fibrosis, we stained for the HSC marker, desmin, and found

those cells increased in Mdr2ko mice, whereas HSCs were reduced after Selleck BAY 80-6946 CoPP-treatment (Fig. 4C). Staining for α-SMA revealed a large number of activated HSCs in Mdr2ko mice, which was significantly reduced MLN0128 in livers of CoPP-treated animals (Fig. 4D). To specifically investigate the effect of HO-1 induction on HSC activation, we isolated HSCs from wild-type mice, activated those cells by incubation with TGF-β1 and induced HO-1 in vitro. Our results showed that HO-1 induction significantly reduced the expression of the HSC activation marker, α-SMA, TNFRs, as well as expression of TGF-β1 (Fig. 4E), whereas it enhanced the expression of HO-1, TIMP-1, MMP-9, and MMP-13 (Fig. 4F). To investigate the effects of HO-1 induction on established fibrosis, we started treatment of Mdr2ko mice at the

age of 12 weeks. Measurement of plasma ALT levels after 7 weeks of CoPP treatment revealed that induction of HO-1 significantly decreased hepatocyte damage (Supporting Fig. 3A). Similar to our observations during early medchemexpress fibrosis (Fig. 4B), CoPP treatment decreased the expression of collagens I and III (Supporting Fig. 3B) and elevated MMP-9 activity significantly (data not shown). Inflammation (Supporting Fig. 3C) and fibrosis (Supporting Fig. 3D) were significantly decreased upon HO-1 induction. Quantitative evaluation and comparison of histological staining revealed that HO-1 induction, at late time points, improved inflammation and fibrosis to better scores than observed at the age of 12 weeks. This observation was statistically significant for portal inflammation (Fig. 5A) and lobular fibrosis (Fig. 5B). HCC frequency is increased in patients after years of chronic inflammation.29 Mdr2ko mice, which suffer from chronic hepatic inflammation, have been shown to develop HCC from the age of 12-15 month onward.12 To analyze effects of HO-1 induction on early signs of progression to HCC, we first investigated expression levels of growth factors and proliferation markers. TGF-β2 was significantly down-regulated in livers of Mdr2ko mice upon HO-1 induction during early (Fig. 6A) and established fibrosis (Fig.

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