Intrahepatic microcirculatory disorder, parenchymal hypoxia and NOX4 upregulation result in zonal differences in hepatocyte apoptosis following lipopolysaccharide- and D-galactosamine-induced acute liver failure in rats

Masatake Tanaka, Kosuke Tanaka, Yuko Masaki, Masayuki Miyazaki, Masaki Kato, Kazuhiro Kotoh, Munechika Enjoji, Makoto Nakamuta, Ryoichi Takayanagi

研究成果: ジャーナルへの寄稿記事

6 引用 (Scopus)

抄録

Although the mechanisms responsible for acute liver failure (ALF) have not yet been fully elucidated, studies have indicated that intrahepatic macrophage activation plays an important role in the pathogenesis of ALF through intrahepatic microcirculatory disorder and consequent parenchymal cell death. Intrahepatic microcirculatory disorder has been demonstrated in animal models using intravital microscopy; however, the limitations of this method include simultaneously evaluating blood flow and the surrounding pathological changes. Therefore, in this study, we devised a novel method involving tetramethylrhodamine isothiocyanate (TRITC)-dextran administration for the pathological assessment of hepatic microcirculation. In addition, we aimed to elucidate the mechanisms through which intrahepatic microcirculatory disorder progresses with relation to activated macrophages. ALF was induced in Wistar rats by exposure to lipopolysaccharide and D-galactosamine. Intrahepatic microcirculation and microcirculatory disorder in zone 3 (pericentral zone) of the livers of rats with ALF was observed. Immunohistochemical examinations in conjunction with TRITC-dextran images revealed that the macrophages were mainly distributed in zone 2 (intermediate zone), while cleaved caspase-3-positive hepatocytes, pimonidazole and hypoxia-inducible factor 1-a were abundant in zone 3. We also found that 4-hydroxy-2-nonenal and nicotinamide adenine dinucleotide phosphate oxidase (NOX)4-positive cells were predominantly located in the zone 3 parenchyma. The majority of apoptotic hepatocytes in zone 3 were co-localized with NOX4. Our results revealed that the apoptotic cells in zone 3 were a result of hypoxic conditions induced by intrahepatic microcirculatory disorder, and were not induced by activated macrophages. The increased levels of oxidative stress in zone 3 may contribute to the progression of hepatocyte apoptosis.

元の言語英語
ページ(範囲)254-262
ページ数9
ジャーナルInternational journal of molecular medicine
33
発行部数2
DOI
出版物ステータス出版済み - 2 1 2014

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Galactosamine
Acute Liver Failure
Lipopolysaccharides
Hepatocytes
Up-Regulation
Apoptosis
Macrophages
Microcirculation
Hypoxia-Inducible Factor 1
Macrophage Activation
Liver
NADP
Caspase 3
Wistar Rats
Oxidoreductases
Oxidative Stress
Cell Death
Animal Models
Hypoxia
tetramethylrhodamine isothiocyanate

All Science Journal Classification (ASJC) codes

  • Genetics

これを引用

Intrahepatic microcirculatory disorder, parenchymal hypoxia and NOX4 upregulation result in zonal differences in hepatocyte apoptosis following lipopolysaccharide- and D-galactosamine-induced acute liver failure in rats. / Tanaka, Masatake; Tanaka, Kosuke; Masaki, Yuko; Miyazaki, Masayuki; Kato, Masaki; Kotoh, Kazuhiro; Enjoji, Munechika; Nakamuta, Makoto; Takayanagi, Ryoichi.

:: International journal of molecular medicine, 巻 33, 番号 2, 01.02.2014, p. 254-262.

研究成果: ジャーナルへの寄稿記事

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abstract = "Although the mechanisms responsible for acute liver failure (ALF) have not yet been fully elucidated, studies have indicated that intrahepatic macrophage activation plays an important role in the pathogenesis of ALF through intrahepatic microcirculatory disorder and consequent parenchymal cell death. Intrahepatic microcirculatory disorder has been demonstrated in animal models using intravital microscopy; however, the limitations of this method include simultaneously evaluating blood flow and the surrounding pathological changes. Therefore, in this study, we devised a novel method involving tetramethylrhodamine isothiocyanate (TRITC)-dextran administration for the pathological assessment of hepatic microcirculation. In addition, we aimed to elucidate the mechanisms through which intrahepatic microcirculatory disorder progresses with relation to activated macrophages. ALF was induced in Wistar rats by exposure to lipopolysaccharide and D-galactosamine. Intrahepatic microcirculation and microcirculatory disorder in zone 3 (pericentral zone) of the livers of rats with ALF was observed. Immunohistochemical examinations in conjunction with TRITC-dextran images revealed that the macrophages were mainly distributed in zone 2 (intermediate zone), while cleaved caspase-3-positive hepatocytes, pimonidazole and hypoxia-inducible factor 1-a were abundant in zone 3. We also found that 4-hydroxy-2-nonenal and nicotinamide adenine dinucleotide phosphate oxidase (NOX)4-positive cells were predominantly located in the zone 3 parenchyma. The majority of apoptotic hepatocytes in zone 3 were co-localized with NOX4. Our results revealed that the apoptotic cells in zone 3 were a result of hypoxic conditions induced by intrahepatic microcirculatory disorder, and were not induced by activated macrophages. The increased levels of oxidative stress in zone 3 may contribute to the progression of hepatocyte apoptosis.",
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AU - Tanaka, Masatake

AU - Tanaka, Kosuke

AU - Masaki, Yuko

AU - Miyazaki, Masayuki

AU - Kato, Masaki

AU - Kotoh, Kazuhiro

AU - Enjoji, Munechika

AU - Nakamuta, Makoto

AU - Takayanagi, Ryoichi

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