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Hepatocyte apoptosis is enhanced after ischemia/reperfusion in the steatotic liver.

Suzuki T, Yoshidome H, Kimura F, Shimizu H, Ohtsuka M, Takeuchi D, Kato A, Furukawa K, Yoshitomi H, Iida A, Dochi T, Miyazaki M - J Clin Biochem Nutr (2011)

Bottom Line: Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury.In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline.Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-0856, Japan.

ABSTRACT
Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury. The aim of the current study was to determine the precise mechanism leading to hepatocyte apoptosis after steatotic liver ischemia/reperfusion. Using a murine model of partial hepatic ischemia for 90 min, we examined the levels and pathway of apoptosis, and the peroxynitrite expression, serum alanine aminotransferase levels, and liver histology 1 and 4 h after reperfusion. In the steatotic liver, the peroxynitrite expression increased after ischemia/reperfusion. Significant hepatocyte apoptosis in the steatotic liver was seen after reperfusion, caused by upregulation of cleaved caspases 9 and 3, but not caspase 8. Serum alanine aminotransferase levels were elevated and histological examination revealed severe liver injury in the steatotic liver 4 h after reperfusion. In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline. Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine. Our data suggested that the steatotic liver is vulnerable to hepatic ischemia/reperfusion, leading to significant hepatocyte apoptosis by the mitochondrial permeability transition, and thereby resulting in organ dysfunction.

No MeSH data available.


Related in: MedlinePlus

Hepatocyte apoptosis induced by ischemia/reperfusion assessed by the TUNEL method. To assess the effect of the iNOS inhibitor on hepatocyte apoptosis, samples from mice treated with PBS or aminoguanidine (AG) prior to ischemia for 90 min were examined. Samples were obtained from (A) sham operated WT, (B) sham operated FL, and (C) FL mice undergoing 90 min ischemia and 4 h reperfusion (I/R) with PBS treatment, (D) WT mice undergoing I/R with PBS treatment, (E) FL mice undergoing I/R with AG treatment. (F) WT mice undergoing I/R with AG treatment. Original magnification ×200. Arrows indicate hepatocyte apoptosis. The apoptotic index was also calculated in mice 4 h after reperfusion (G). The data represent the mean ± SEM with n = 6 per group. *p<0.05 compared to mice treated with PBS.
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Figure 5: Hepatocyte apoptosis induced by ischemia/reperfusion assessed by the TUNEL method. To assess the effect of the iNOS inhibitor on hepatocyte apoptosis, samples from mice treated with PBS or aminoguanidine (AG) prior to ischemia for 90 min were examined. Samples were obtained from (A) sham operated WT, (B) sham operated FL, and (C) FL mice undergoing 90 min ischemia and 4 h reperfusion (I/R) with PBS treatment, (D) WT mice undergoing I/R with PBS treatment, (E) FL mice undergoing I/R with AG treatment. (F) WT mice undergoing I/R with AG treatment. Original magnification ×200. Arrows indicate hepatocyte apoptosis. The apoptotic index was also calculated in mice 4 h after reperfusion (G). The data represent the mean ± SEM with n = 6 per group. *p<0.05 compared to mice treated with PBS.

Mentions: To determine whether iNOS was involved in liver apoptosis during hepatic ischemia/reperfusion, we performed TUNEL staining. The number of TUNEL positive cells, quantified by calculating the apoptotic index, was significantly upregulated 4 h after reperfusion in WT and FL mice relative to sham-operated controls (n = 6, respectively; Fig. 5). There was significant difference in apoptotic index of WT mice administered AG as an iNOS specific inhibitor. Treatment with AG significantly reduced the number of apoptotic cells in FL mice relative to treatment with PBS (Fig. 5). To determine whether iNOS was involved in hepatic ischemia/reperfusion injury, we examined the serum alanine aminotransferase (ALT) levels following the administration of AG. In sham-operated controls, there were no differences in serum ALT levels among WT and FL mice treated with PBS or AG. One hour after reperfusion, serum ALT levels were significantly decreased by administration of AG (56% decrease, p = 0.002) in the WT mice. In the FL mice, administration of AG also attenuated serum ALT levels (20% decrease, p = 0.025) compared with the FL mice treated with PBS 1 and 4 h after reperfusion (Fig. 6).


Hepatocyte apoptosis is enhanced after ischemia/reperfusion in the steatotic liver.

Suzuki T, Yoshidome H, Kimura F, Shimizu H, Ohtsuka M, Takeuchi D, Kato A, Furukawa K, Yoshitomi H, Iida A, Dochi T, Miyazaki M - J Clin Biochem Nutr (2011)

Hepatocyte apoptosis induced by ischemia/reperfusion assessed by the TUNEL method. To assess the effect of the iNOS inhibitor on hepatocyte apoptosis, samples from mice treated with PBS or aminoguanidine (AG) prior to ischemia for 90 min were examined. Samples were obtained from (A) sham operated WT, (B) sham operated FL, and (C) FL mice undergoing 90 min ischemia and 4 h reperfusion (I/R) with PBS treatment, (D) WT mice undergoing I/R with PBS treatment, (E) FL mice undergoing I/R with AG treatment. (F) WT mice undergoing I/R with AG treatment. Original magnification ×200. Arrows indicate hepatocyte apoptosis. The apoptotic index was also calculated in mice 4 h after reperfusion (G). The data represent the mean ± SEM with n = 6 per group. *p<0.05 compared to mice treated with PBS.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: Hepatocyte apoptosis induced by ischemia/reperfusion assessed by the TUNEL method. To assess the effect of the iNOS inhibitor on hepatocyte apoptosis, samples from mice treated with PBS or aminoguanidine (AG) prior to ischemia for 90 min were examined. Samples were obtained from (A) sham operated WT, (B) sham operated FL, and (C) FL mice undergoing 90 min ischemia and 4 h reperfusion (I/R) with PBS treatment, (D) WT mice undergoing I/R with PBS treatment, (E) FL mice undergoing I/R with AG treatment. (F) WT mice undergoing I/R with AG treatment. Original magnification ×200. Arrows indicate hepatocyte apoptosis. The apoptotic index was also calculated in mice 4 h after reperfusion (G). The data represent the mean ± SEM with n = 6 per group. *p<0.05 compared to mice treated with PBS.
Mentions: To determine whether iNOS was involved in liver apoptosis during hepatic ischemia/reperfusion, we performed TUNEL staining. The number of TUNEL positive cells, quantified by calculating the apoptotic index, was significantly upregulated 4 h after reperfusion in WT and FL mice relative to sham-operated controls (n = 6, respectively; Fig. 5). There was significant difference in apoptotic index of WT mice administered AG as an iNOS specific inhibitor. Treatment with AG significantly reduced the number of apoptotic cells in FL mice relative to treatment with PBS (Fig. 5). To determine whether iNOS was involved in hepatic ischemia/reperfusion injury, we examined the serum alanine aminotransferase (ALT) levels following the administration of AG. In sham-operated controls, there were no differences in serum ALT levels among WT and FL mice treated with PBS or AG. One hour after reperfusion, serum ALT levels were significantly decreased by administration of AG (56% decrease, p = 0.002) in the WT mice. In the FL mice, administration of AG also attenuated serum ALT levels (20% decrease, p = 0.025) compared with the FL mice treated with PBS 1 and 4 h after reperfusion (Fig. 6).

Bottom Line: Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury.In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline.Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-0856, Japan.

ABSTRACT
Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury. The aim of the current study was to determine the precise mechanism leading to hepatocyte apoptosis after steatotic liver ischemia/reperfusion. Using a murine model of partial hepatic ischemia for 90 min, we examined the levels and pathway of apoptosis, and the peroxynitrite expression, serum alanine aminotransferase levels, and liver histology 1 and 4 h after reperfusion. In the steatotic liver, the peroxynitrite expression increased after ischemia/reperfusion. Significant hepatocyte apoptosis in the steatotic liver was seen after reperfusion, caused by upregulation of cleaved caspases 9 and 3, but not caspase 8. Serum alanine aminotransferase levels were elevated and histological examination revealed severe liver injury in the steatotic liver 4 h after reperfusion. In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline. Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine. Our data suggested that the steatotic liver is vulnerable to hepatic ischemia/reperfusion, leading to significant hepatocyte apoptosis by the mitochondrial permeability transition, and thereby resulting in organ dysfunction.

No MeSH data available.


Related in: MedlinePlus