Role of the perforin/granzyme cell death pathway in<scp>d</scp>-Gal/LPS-induced inflammatory liver injury

Kuhla, Angela; Eipel, Christian; Abshagen, Kerstin; Siebert, Nikolai; Menger, Michael D.; Vollmar, Brigitte

doi:10.1152/ajpgi.90689.2008

Cited by 40 publications

(25 citation statements)

References 42 publications

(47 reference statements)

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“…LPS/D-GalN-treated mouse models are frequently used to study the pathogenesis of liver injury [8], [9], [10]. In this study, the data from the mouse model with FHF induced by LPS/D-GalN demonstrated that liver injury was associated with elevated serum C3a levels, extensive hepatic deposition of C3 and increased hepatic expression of C3aR mRNA and C5aR mRNA, along with elevated serum levels of proinflammatory cytokines and ALT.…”

Section: Discussionmentioning

confidence: 73%

Complement and the Alternative Pathway Play an Important Role in LPS/D-GalN-Induced Fulminant Hepatic Failure

et al. 2011

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Fulminant hepatic failure (FHF) is a clinically severe type of liver injury with an extremely high mortality rate. Although the pathological mechanisms of FHF are not well understood, evidence suggests that the complement system is involved in the pathogenesis of a variety of liver disorders. In the present study, to investigate the role of complement in FHF, we examined groups of mice following intraperitoneal injection of LPS/D-GalN: wild-type C57BL/6 mice, wild-type mice treated with a C3aR antagonist, C5aR monoclonal antibody (C5aRmAb) or CR2-Factor H (CR2-fH, an inhibitor of the alternative pathway), and C3 deficient mice (C3−/− mice). The animals were euthanized and samples analyzed at specific times after LPS/D-GalN injection. The results show that intraperitoneal administration of LPS/D-GalN activated the complement pathway, as evidenced by the hepatic deposition of C3 and C5b-9 and elevated serum levels of the complement activation product C3a, the level of which was associated with the severity of the liver damage. C3a receptor (C3aR) and C5a receptor (C5aR) expression was also upregulated. Compared with wild-type mice, C3−/− mice survived significantly longer and displayed reduced liver inflammation and attenuated pathological damage following LPS/D-GalN injection. Similar levels of protection were seen in mice treated with C3aR antagonist,C5aRmAb or CR2-fH. These data indicate an important role for the C3a and C5a generated by the alternative pathway in LPS/D-GalN-induced FHF. The data further suggest that complement inhibition may be an effective strategy for the adjunctive treatment of fulminant hepatic failure.

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Section: Discussionmentioning

confidence: 73%

Complement and the Alternative Pathway Play an Important Role in LPS/D-GalN-Induced Fulminant Hepatic Failure

et al. 2011

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“…The pathophysiological background of ACLF remains poorly understood, necessitating the development of optimal experimental ACLF models with features resembling those of the human disorder. The most widely used ACLF model is induced in rats 5 and mice (Pko and Pwt mice) 6 by human serum albumin (HSA) and d -galactosamine ( d -gal)/lipopolysaccharide (LPS), which serve as reliable mimics for the pathophysiological processes and histological characteristics of ACLF, while the HSA-induced model shows relatively high mortality with fibrosis. Balasubramaniyan et al 7 developed an ACLF model using a bile-duct ligation (BDL) method.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a new acute-on-chronic liver failure model

Miao

Sun

et al. 2017

Acta Pharmaceutica Sinica B

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To establish an animal model of acute-on-chronic liver failure (ACLF) that would replicate the pathological process of ACLF in humans, rats were administered porcine serum (PS) for 11 weeks. Liver fibrosis was determined by pathological and biochemical assessments. The animals then were injected with d-galactosamine (d-gal) and lipopolysaccharide (LPS). The survival times of animals with cirrhosis and ACLF were determined over 48 h. Other animals were killed at 0, 4, 8 and 12 h after administration of d-gal/LPS. Liver injury was assessed by histopathological analysis and biochemical indices, and apoptosis was detected by Western blot and TUNEL analysis. After PS administration for 11 weeks the serum levels of hyaluronic acid and N-procollagen type III peptide increased significantly, and serious fibrosis and cirrhosis was observed at weeks 10 and 11. Cirrhotic rats were injected with d-gal/LPS to induced ACLF; the rate of mortality over 48 h was 80%. ALT and AST levels increased markedly at 4 h, but decreased significantly at 8 and 12 h post-treatment. The total bilirubin, direct bilirubin, and total bile acids levels increased markedly at 8 and 12 h. Clotting times, TNF-α and IL-6 levels increased significantly, except for 12 h post-treatment. Apoptosis, inflammation and necrosis were elevated as determined by hematoxylin-eosin staining and TUNEL assays. BCL-2 levels decreased significantly, While BAX levels increased significantly. Cytochrome c expression peaked at 8 h post-d-gal/LPS treatment. In conclusion, an ACLF model induced by PS and d-gal/LPS was established and the underlying mechanisms of ACLF development were explored.

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“…15,16 Therefore, LPS/D-GalN-induced hepatitis is a wellestablished model to mimic liver injury induced by intestinal endotoxemia in a clinical setting. [17][18][19] The present study aims to examine the in vivo role of PDCD4 in LPS/D-GalN-induced liver injury using PDCD4-deficient mice and wild-type (WT) mice. We first demonstrated that PDCD4 deficiency exacerbated LPS/DGalN-induced hepatocyte apoptosis and necrosis, and enhanced liver injury in PDCD4-deficient mice was due to an increased release of inflammatory factors induced by excessive activation of the MAPK and NF-kB pathways.…”

mentioning

confidence: 99%

The inhibitory action of PDCD4 in lipopolysaccharide/D-galactosamine-induced acute liver injury

Wang

Zhang

Wei

et al. 2013

Laboratory Investigation

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Programmed cell death 4 (PDCD4) acts as a tumor suppressor gene, which suppresses tumor growth, infiltration and metastasis. Our previous studies demonstrated that PDCD4 had an important role in the development of ovarian cancer and glioma. Recent studies show that PDCD4 is also involved in various inflammatory diseases. However, its exact effect on inflammation remains unclear. In our current study, we explored the role of PDCD4 in acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) using wild-type (WT) mice and PDCD4-deficient mice. Our results showed that liver-to-body weight ratios, as well as serum aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly increased in PDCD4-deficient mice than WT mice. Histological examination, immunohistochemical and TUNEL analysis revealed PDCD4-deficient mice had more necrotic and apoptotic hepatocytes, inflammatory cells infiltration and liver internal hemorrhage than WT mice. In addition, some inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) in the serum and liver tissues were also significantly increased in PDCD4-deficient mice. More importantly, we found that the aggravation of liver tissue injury in PDCD4-deficient mice was due to excessive mitogen-activated protein kinase and NF-kB activation, which induced the release of more inflammatory factors, and consequently resulted in higher levels of hepatocyte necrosis and apoptosis. These results indicate that PDCD4 has a protective role in LPS/D-GalN-induced acute liver injury. This finding may present new opportunities for PDCD4 to be explored as a therapeutic target in acute liver injury.

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Role of the perforin/granzyme cell death pathway ind-Gal/LPS-induced inflammatory liver injury

Cited by 40 publications

References 42 publications

Complement and the Alternative Pathway Play an Important Role in LPS/D-GalN-Induced Fulminant Hepatic Failure

Complement and the Alternative Pathway Play an Important Role in LPS/D-GalN-Induced Fulminant Hepatic Failure

Establishment of a new acute-on-chronic liver failure model

The inhibitory action of PDCD4 in lipopolysaccharide/D-galactosamine-induced acute liver injury

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