Effect of age and carbon tetrachloride on cytokine concentrations in rat liver

Rikans, Lora E.; DeCicco, Lacinda A.; Hornbrook, K. R.; Yamano, Tetsuo

doi:10.1016/s0047-6374(99)00012-3

Cited by 23 publications

(17 citation statements)

References 40 publications

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“…The induction of the AR gene expression by IL-1␤ in cultured cells is consistent with the early production of this cytokine in different experimental models of liver injury and regeneration in which we observed AR up-regulation. 17,28 In contrast, IL-6, TNF-␣, and HGF failed to activate AR gene expression in isolated hepatocytes. It is interesting to note that TNF-␣ 29 and HGF, 30 but not IL-1␤ (unpublished data), are able to induce the expression of other EGF-R ligands, such as TGF-␣, in hepatocytes.…”

Section: Discussionmentioning

confidence: 96%

Amphiregulin: An early trigger of liver regeneration in mice

et al. 2005

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See editorial on page 504. Background & Aims:Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. Methods: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of amphiregulin were studied in isolated hepatocytes. The in vivo role of amphiregulin in liver regeneration after partial hepatectomy was analyzed in amphiregulin-null mice. Results: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1␤ and prostaglandin E 2 , but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor ␣. We show that amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, amphiregulin-null mice display impaired proliferative responses after partial liver resection. Conclusions: Our findings indicate that amphiregulin is an earlyresponse growth factor that may contribute to the initial phases of liver regeneration.

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Section: Discussionmentioning

confidence: 96%

Amphiregulin: An early trigger of liver regeneration in mice

et al. 2005

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“…10 An increase in CCl 4 hepatotoxicity occurs in old animals, 15 indicating genetic compounds are potential causes of age-dependent changes in chemically induced liver damage. Age-dependent changes in the circadian gene expression in laboratory rodents and humans have been described extensively.…”

Section: Discussionmentioning

confidence: 99%

“…14 Hepatotoxicity induced by CCl 4 increases with age. 15 Circadian functions are also impaired in old animals, 16 in parallel to increase in drug-induced hepatic injury. That provoked us to investigate whether there is molecular relationship between circadian gene and CCl 4 -induced hepatotoxicity.…”

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confidence: 99%

The Protective Role of Per2 Against Carbon Tetrachloride-Induced Hepatotoxicity

Chen

Pang

et al. 2009

The American Journal of Pathology

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Period 2 (Per2) is a key component of the core clock oscillator and is involved in regulating a number of different biological processes and pathways. Here we report that Per2 plays a protective role in carbon tetrachloride (CCl 4 )-induced hepatotoxicity via the modulation of uncoupling protein-2 (Ucp2) gene expression in mice. Hepatic injury after acute CCl 4 injection was monitored in both wild-type and Per2-null mice. At the 12-hour time point after CCl 4 treatment, many more vacuolations were observed in the liver tissues of Per2-null mice whereas fatty tissue degeneration primarily occurred in the liver tissues of wide-type mice. Serum alanine and aspartate aminotransferase activities were elevated in Per2-null mice compared with wide-type mice at 24 hours after CCl 4 treatment, which was in agreement with the observation of significantly larger areas of centrilobular necrosis in the livers of Per2-null mice. A deficit of the Per2 gene enhanced Ucp2 gene expression levels in the liver. As a consequence, intracellular levels of ATP markedly decreased in the liver, allowing increased production of toxic CCl 4 derivatives. The absence of Per2 expression caused a dramatic elevation of Clock expression and influenced Ucp2 through a mechanism that involved a Clock-controlled PPAR-␣ signal transduction pathway. Our studies suggest that the Per2 gene functions in hepatocyte protection from chemical toxicants via the regulation of hepatic

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“…Many studies have noted that subject age is a critical factor in many experimental models of liver disease, such as acetaminophen, carbon tetrachloride, lipopolysaccharide (LPS), α-galactosylceramide, and cadmium-induced liver injury [5,9,15,22,23,26]. In these model systems, mature adults exhibit greater susceptibility than young adults to injury by xenotic substances that induce various cytokines released from Kupffer cells (KCs) and T-cells.…”

mentioning

confidence: 99%

Influence of Age on Susceptibility to Pseudomonas aeruginosa Exotoxin A-induced Hepatotoxicity in Long-Evans Rats

Chuang

Huang

Chiu

et al. 2009

The Journal of Veterinary Medical Science

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ABSTRACT. Epidemiological investigations suggest that increased age is associated with susceptibility to infection. Pseudomonas aeruginosa (P. aeruginosa) infection and associated exotoxin A (PEA) toxicity have been reported in hospitalized elderly patients and young children with cystic fibrosis. The present study investigated age-related differences in PEA-induced hepatotoxicity in post weaning (PW, 3 weeks), young adult (YA, 12 weeks), and mature adult (MA, 60-64 weeks) rats. PEA (20 µg/kg) was injected intraveneously and mortality, clinical chemistry, hepatic histopathology, TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling) and PCNA (Proliferating cell nuclear antigen) staining, and serum cytokine levels were assessed at specific time points, up to 72 hr post-exposure (HPE). Mortality in MA rats was 100% at less than 48 HPE. Serum ALT levels in MA rats were approximately 5-fold greater than levels in PW and YA rats at 36 HPE. MA rat liver histological sections showed diffuse hepatocellular necrosis. In contrast, hepatocellular apoptosis, demonstrable by the TUNEL method, was noted simply in the periportal and midzonal regions from 36 to 48 HPE. Increased morphological mitoses and PCNA-positive hepatocytes were seen in PW and YA rats at 72 HPE. These parameters were correlated with age-dependent significant increases in TNF-α, IL-2, IL-6, and IL-18 levels. These data suggest that inflammatory cytokines play an important role in age-related differences in PEA-induced hepatotoxicity. Moreover, these cytokines might correlate with different patterns histopathologic features at various ages.

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Effect of age and carbon tetrachloride on cytokine concentrations in rat liver

Cited by 23 publications

References 40 publications

Amphiregulin: An early trigger of liver regeneration in mice

Amphiregulin: An early trigger of liver regeneration in mice

The Protective Role of Per2 Against Carbon Tetrachloride-Induced Hepatotoxicity

Influence of Age on Susceptibility to Pseudomonas aeruginosa Exotoxin A-induced Hepatotoxicity in Long-Evans Rats

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