Ischemic preconditioning protects hepatocytes via reactive oxygen species derived from Kupffer cells in rats

Tejima, Kazuaki; Arai, Masahiro; Ikeda, Hitoshi; Tomiya, Tomoaki; Yanase, Mikio; Inoue, Yukiko; Nagashima, Kōzō; Nishikawa, Tatsuya; Watanabe, Naoko; Omata, Masao; Fujiwara, Kenji

doi:10.1053/j.gastro.2004.07.023

Cited by 57 publications

(57 citation statements)

References 46 publications

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“…The importance of redox state is further supported by our findings that a brief treatment of DMNQ, a redox-cycling agent [15], to normal hepatocytes reversed the sensitivity to TGFβ-induced apoptosis. Similar findings were noted by Tejima et al [29] who used H 2 O 2 as a preconditioning molecule and demonstrated the hepatotoxicity could be reduced by low-dose H 2 O 2 . Likewise, hepatocytes treated with nontoxic doses of menadione, a superoxide generator, resisted oxidant-induced cell death through an ERK-dependent pathway while the JNK pathway was pro-apoptotic [30].…”

Section: Discussionsupporting

confidence: 87%

Basal reactive oxygen species determine the susceptibility to apoptosis in cirrhotic hepatocytes

Raval

Lyman

Nitta

et al. 2006

Free Radical Biology and Medicine

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Hepatocytes from cirrhotic murine livers exhibit increased basal ROS activity and resistance to TGFβ-induced apoptosis, yet when ROS levels are decreased by antioxidant pretreatment, these cells recover susceptibility to apoptotic stimuli. To further study these redox events, hepatocytes from cirrhotic murine livers were pretreated with various antioxidants prior to TGFβ treatment and the ROS activity, apoptotic response, and mitochondrial ROS generation were assessed. In addition, normal hepatocytes were treated with low-dose H 2 O 2 and ROS and apoptotic responses determined. Treatment of cirrhotic hepatocytes with various antioxidants decreased basal ROS and rendered them susceptible to apoptosis. Examination of normal hepatocytes by confocal microscopy demonstrated co-localization of ROS activity and respiring mitochondria. Basal assessment of cirrhotic hepatocytes showed non-focal ROS activity that was abolished by antioxidants. After pretreatment with an adenovirus expressing MnSOD, basal cirrhotic hepatocyte ROS was decreased and TGFβ-induced co-localization of ROS and mitochondrial respiration was present. Treatment of normal hepatocytes with H 2 O 2 resulted in a sustained increase in ROS and resistance to TGFβ apoptosis that was reversed when these cells were pretreated with an antioxidant. In conclusion, cirrhotic hepatocytes have a non-focal distribution of ROS. However, normal and cirrhotic hepatocytes exhibit mitochondrial localization of ROS that is necessary for apoptosis.

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Section: Discussionsupporting

confidence: 87%

Basal reactive oxygen species determine the susceptibility to apoptosis in cirrhotic hepatocytes

Raval

Lyman

Nitta

et al. 2006

Free Radical Biology and Medicine

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“…GdCl 3 has been used in different studies to block KCs. [25][26][27] The KC-dependent and long-lasting increase in portal perfusion pressure subsequent to LPS pretreatment was in accordance with earlier studies. 5 In this previous study, the basal, maximal and long-lasting portal perfusion pressures were increased by additional LPS pretreatment for 6 h in prefibrotic rats 1 week after BDL.…”

Section: Kc-dependent Effects Of Intraperitoneal Lpssupporting

confidence: 91%

Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis

Steib¹,

Hartmann²,

Hesler³

et al. 2010

Laboratory Investigation

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Recent studies have shown that the risk of variceal bleeding in patients with liver cirrhosis increases with infections such as spontaneous bacterial peritonitis (SBP). In this study, we hypothesized that pretreatment with intraperitoneal LPS may escalate portal hypertension. In fibrotic livers (4 weeks after bile duct ligation, BDL), the activation of Kupffer cells (KCs) by zymosan (150 mg/ml) in the isolated non-recirculating liver perfusion system resulted in a transient increase in portal perfusion pressure. Pretreatment with intraperitoneal LPS (1 mg/kg body weight (b.w.) for 3 h) increased basal portal perfusion pressure, and prolonged the zymosan-induced increase from transient to a long-lasting increase that was sustained until the end of the experiments in BDL but not in sham-operated animals. Pretreatment with gadolinium chloride (10 mg/kg b.w.), MK-886 (0.6 mg/kg b.w.), Ly171883 (20 mM) or BM 13.177 (20 mM) reduced the maximal and long-lasting pressure increase in BDL animals by approximately 50-60%. The change in portal perfusion pressure was paralleled by a long-lasting production of cysteinyl leukotriene (Cys-LT) and thromboxane (TX) after LPS pretreatment. However, the response to vasoconstrictors was not altered by intraperitoneal LPS. Western blot analyses showed an increased Toll-like receptor (TLR)4 and MyD88 expression after LPS pretreatment. In vivo experiments confirmed that intraperitoneal LPS increased basal portal pressure, and extended the portal pressure increase produced by intraportal zymosan or by LPS infusion. In conclusion, upregulation of TLR4 and MyD88 expression in fibrotic livers confers hypersensitivity to LPS. This may lead to escalation of portal hypertension by production of TX and Cys-LT after endotoxin-induced KC activation. Therefore, LT inhibitors may represent a promising treatment option in addition to early administration of antibiotics in SBP.

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“…Cold storage of the liver was carried out as described previously [21,27]. Mice were anesthetized by intraperitoneal injection of pentobarbital sodium (50 mg/kg).…”

Section: Cold Storage Of the Livermentioning

confidence: 99%

Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver

et al. 2010

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Donor organ damage caused by cold preservation is a major problem affecting liver transplantation. Cold preservation most easily damages liver sinusoidal endothelial cells (LSECs), and information about the molecules modulating LSECs function can provide the basis for new therapeutic strategies. Adrenomedullin (AM) is a peptide known to possess anti-apoptotic and anti-inflammatory properties. AM is abundant in vascular endothelial cells, but levels are comparatively low in liver, and little is known about its function there. In this study, we demonstrated both AM and its receptors are expressed in LSECs. AM treatment reduced LSECs loss and apoptosis under cold treatment. AM also downregulated cold-induced expression of TNF, IL1, IL6, ICAM1 and VCAM1. AM reduced apoptosis and expression of ICAM1 and VCAM1 in an in vivo liver model subjected to cold storage. Conversely, apoptosis was exacerbated in livers from AM and RAMP2 (AM receptor activity-modifying protein) knockout mice. These results suggest that AM expressed in LSECs exerts a protective effect against cold-organ damage through modulation of apoptosis and inflammation.

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Ischemic preconditioning protects hepatocytes via reactive oxygen species derived from Kupffer cells in rats

Cited by 57 publications

References 46 publications

Basal reactive oxygen species determine the susceptibility to apoptosis in cirrhotic hepatocytes

Basal reactive oxygen species determine the susceptibility to apoptosis in cirrhotic hepatocytes

Intraperitoneal LPS amplifies portal hypertension in rat liver fibrosis

Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver

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