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. 2012 May 8:12:45.
doi: 10.1186/1471-230X-12-45.

High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity

Runkuan Yang  1 , Shutian Zhang, Antonella Cotoia, Niku Oksala, Shengtao Zhu, Jyrki Tenhunen
Affiliations

High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity

"V体育平台登录" Runkuan Yang et al. BMC Gastroenterol. .

Abstract (VSports在线直播)

Background: Acetaminophen (APAP) overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1), and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI) at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration VSports手机版. This study aims to test whether blockade of HMGB1 improves hepatocyte regeneration after APAP overdose. .

Methods: Male C57BL/6 mice were treated with a single dose of APAP (350 mg/kg) V体育安卓版. 2 hrs after APAP administration, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose) or non-immune (sham) IgG every 24 hours for a total of 2 doses. .

Results: 24 hrs after APAP injection, anti-HMGB1 therapy instead of sham IgG therapy significantly improved hepatocyte regeneration microscopically; 48 hrs after APAP challenge, the sham IgG treated mice showed 14. 6% hepatic necrosis; in contrast, blockade of HMGB1 significantly decreased serum transaminases (ALT and AST), markedly reduced the number of hepatic inflammatory cells infiltration and restored liver structure to nearly normal; this beneficial effect was associated with enhanced hepatic NF-κB DNA binding and increased the expression of cyclin D1, two important factors related to hepatocyte regeneration V体育ios版. .

Conclusion: HMGB1 impairs hepatocyte regeneration after APAP overdose; Blockade of HMGB1 enhances liver recovery and may present a novel therapy to treat APAP overdose. VSports最新版本.

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Figures

Figure 1
Figure 1
Serum HMGB1 in APAP-induced ALI model. ALI was induced in C57Bl/6 male mice with a single dose of APAP by intraperitoneal (i.p.) injection (300 mg/kg dissolved in 1 mL saline), each control animal was injected with 1 mL saline not containing APAP (n = 5 animals for each group). Western blot was performed by using serum obtained 24 hours after APAP injection. Results from 5 representative assays are shown (n = 5, each band stands for one serum sample from the control or APAP injected animals). Typical gels are depicted.
Figure 2
Figure 2
Effect of treatment with anti-HMGB1 antibody or sham IgG on serum ALT/AST in acetaminophen (APAP)-induced acute liver injury (ALI). ALI was induced in C57 BL/6 male mice with a single dose of APAP (350 mg/kg) by i.p. injection. 2 hours after APAP administration, the first dose of 400 μg of anti-HMGB1 antibody in 0.5 mL saline was i.p. injected into mice in the anti-HMGB1 group, the same amount of sham IgG or saline solution was given to the sham IgG and the control animals at the equivalent time points. The same dose was repeated 24 hrs after the first dose. Figure 2A, 2B: Serum ALT/AST was assessed 24 hrs after APAP injection from the anti-HMGB1 group, the sham IgG and the control group (n = 6 for each group). Figure 2C and 2D: 3 separate groups of mice were used. Serum ALT and AST were assessed at 48 h time point from the anti-HMGB1 group (n = 10), the sham IgG group (n = 9) and the control group (n = 6). Results are means ± SEM. * indicates p < 0.05 vs. control; † indicates p < 0.05 vs. sham IgG.
Figure 3
Figure 3
Effect of treatment with anti-HMGB1 antibody or sham IgG on pathology in mice with ALI. Hematoxylin-eosin staining was assessed 24 and 48 h after induction of ALI (or sham procedure). Method and treatment were the same as described in Figure 2 (n = 6 for each group at 24 h time point; at 48 h time point, n = 9 for the sham IgG group, n = 10 for the anti-HMGB1 group and n = 6 for the control group). Typical picture is shown. [A=sham IgG at 24 h (200x), B=anti-HMGB1 at 24 h (200x), C=sham IgG at 48 h (200x), D=anti-HMGB1 at 48 h (200x), E=sham IgG at 48 h (100x), F=anti-HMGB1 at 48 h (100x)].
Figure 4
Figure 4
Effect of treatment with anti-HMGB1 antibody or sham IgG on NF-кB DNA binding in nuclear extracts prepared from hepatic tissue samples from mice with ALI. NF-кB DNA binding was assessed 48 h h after induction of ALI (or sham procedure). The figure depicts results from six representative assays. Typical gels are depicted.
Figure 5
Figure 5
Effect of treatment with anti-HMGB1 or sham IgG on the expression of cyclin D1 in the hepatic tissue. Western blot was performed using hepatic extracts prepared from tissues obtained 48 hrs after APAP injection. The figure depicts results from six representative assays. Typical gels are depicted.
Figure 6
Figure 6
Effect of treatment with sham or anti-HMGB1 antibodies on hepatocyte regeneration in acetaminophen (APAP)-injected mice. 5-bromo-2-deoxyuridine (BrdU) staining was assessed at 48 hours after induction of acute liver injury (ALI) (or sham procedure, n = 6 for each group). A typical picture is shown. BrdU-positive nuclei are indicated by arrows. (A = 48 h Control, B = 48 h Sham IgG, C = 48 h anti-HMGB1).
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