Downregulation of Hepatic Cytochrome P-450 Isoforms and PPAR-γ: Their Role in Hepatic Injury and Proinflammatory Responses in a Double-Hit Model of Hemorrhage and Sepsis

Higuchi, Shinya; Wu, Rongqian; Zhou, Mian; Ravikumar, Thanjavur S.; Wang, Haichao

doi:10.1016/j.jss.2006.04.019

Cited by 18 publications

(9 citation statements)

References 36 publications

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“…PPAR␥ expression and DNA binding are also markedly reduced in lungs of mice subjected to endotoxic shock and are associated with massive lung injury and neutrophil infiltration (17,34). In support of our findings, it has been reported that PPAR␥ expression is also downregulated in the liver of rats subjected to sepsis by cecal ligation and puncture (30) or double-hit hemorrhage and sepsis (14). Recently, we have reported that age may also influence PPAR␥ expression and may represent an enhancing risk factor for lung injury in rats subjected to severe hemorrhage (39).…”

supporting

confidence: 89%

“…We have previously demonstrated that the onset of systemic inflammation and lung injury is preceded by lung downregulation of PPAR␥ expression in septic rats (37) and endotoxemic mice (17,34). Other laboratories also support the findings that PPAR␥ is downregulated in the liver in rats subjected to sepsis by cecal ligation and puncture (30) or double-hit hemorrhage and sepsis (14). Inflam- matory cytokines also downregulate the expression of PPAR␥ and other coactivators in human hepatoma cell lines (18).…”

Section: Discussionmentioning

confidence: 61%

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Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-γ in hemorrhagic shock

Zingarelli

Chima

O’Connor

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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supporting

confidence: 89%

Section: Discussionmentioning

confidence: 61%

Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-γ in hemorrhagic shock

Zingarelli

Chima

O’Connor

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Trauma-hemorrhage induces hepatic damage and it has been found that even after fluid resuscitation following trauma-hemorrhage, the hepatic damage is still progressive [16,24]. Associated with a sustained disturbance in hepatic circulation and elevated levels of circulating α-GST levels, hepatocellular apoptosis has also been reported [9,24].…”

Section: Discussionmentioning

confidence: 99%

Activation of endoplasmic reticulum stress response following trauma-hemorrhage

Jian

Hsieh

Chen

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Summary Hemorrhagic trauma leads to organ dysfunction, sepsis and death. There is abnormal production of proinflammatory cytokines by Kupffer cells, tissue hypoxia and liver injury following trauma-hemorrhage. The physiological conditions consequent to trauma-hemorrhage are consistent with factors necessary to initiate endoplasmic reticulum (ER) stress and unfolded protein response. However, the contribution of ER stress to apoptosis and liver injury after trauma-hemorrhage is not known. In the present study ER stress was investigated in mice that underwent trauma-hemorrhage or sham operation. Expression of endoplasmic reticulum stress proteins Bip, ATF6, PERK, IRE1α, and PDI were significantly elevated in the liver after trauma-hemorrhage compared to the controls. The ER stress associated proapoptotic transcription factor CHOP protein expression was also significantly elevated in trauma-hemorrhage group. Consistent with this, enhanced DNA fragmentation was observed, confirming apoptosis, in the liver following trauma-hemorrhage. These results demonstrate the initiation of ER stress and its role in apoptosis and liver injury, subsequent to hemorrhagic trauma.

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“…IL-1, IL-6, TNFμ) that induce the expression of acute phase proteins while causing the down-regulation of genes involved in the metabolism and clearance of xenobiotics (Hoebe et al, 2001). Proinflammatory cytokines produced by KC can cause a potent and complete suppression of cytochrome P450, Uridine 5'-diphospho (UDP)-glucuronosyl transferase systems and uptake and efflux transporter expression (Sunman et al, 2004; Wu et al, 2006; Higuchi et al, 2007; Morgan, 2009). In this context, KC are an important component in the development of hepatocyte culture systems intended to mimic liver injury caused by bioactivation of xenobiotics and their resultant inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

Organotypic liver culture models: Meeting current challenges in toxicity testing

LeCluyse

Witek²,

Andersen

et al. 2012

Critical Reviews in Toxicology

304

301

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Prediction of chemical-induced hepatotoxicity in humans from in vitro data continues to be a significant challenge for the pharmaceutical and chemical industries. Generally, conventional in vitro hepatic model systems (i.e. 2-D static monocultures of primary or immortalized hepatocytes) are limited by their inability to maintain histotypic and phenotypic characteristics over time in culture, including stable expression of clearance and bioactivation pathways, as well as complex adaptive responses to chemical exposure. These systems are less than ideal for longer-term toxicity evaluations and elucidation of key cellular and molecular events involved in primary and secondary adaptation to chemical exposure, or for identification of important mediators of inflammation, proliferation and apoptosis. Progress in implementing a more effective strategy for in vitro-in vivo extrapolation and human risk assessment depends on significant advances in tissue culture technology and increasing their level of biological complexity. This article describes the current and ongoing need for more relevant, organotypic in vitro surrogate systems of human liver and recent efforts to recreate the multicellular architecture and hemodynamic properties of the liver using novel culture platforms. As these systems become more widely used for chemical and drug toxicity testing, there will be a corresponding need to establish standardized testing conditions, endpoint analyses and acceptance criteria. In the future, a balanced approach between sample throughput and biological relevance should provide better in vitro tools that are complementary with animal testing and assist in conducting more predictive human risk assessment.

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Downregulation of Hepatic Cytochrome P-450 Isoforms and PPAR-γ: Their Role in Hepatic Injury and Proinflammatory Responses in a Double-Hit Model of Hemorrhage and Sepsis

Cited by 18 publications

References 36 publications

Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-γ in hemorrhagic shock

Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-γ in hemorrhagic shock

Activation of endoplasmic reticulum stress response following trauma-hemorrhage

Organotypic liver culture models: Meeting current challenges in toxicity testing

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