Liver Regeneration And Inflammatory Mediators

Liver regeneration requires the activity of multiple signaling pathways, assuring the synchronized proliferation of liver cells, protection from apoptotic signals, remodeling of extracellular matrix (ECM), and restoration of lobular architec-ture7. The initiation of regeneration through PHx is associated with minimal injury; therefore, an obvious inflammatory reaction that includes a significant inflammatory infiltrate is not seen in the liver parenchyma under these circumstances. However, elevated levels of acute-phase proteins in the blood, activation of liver macrophages, and release of cytokines that are involved in regulation of inflammatory responses to various pathogens suggest that PHx does initiate an inflammatory reaction4. Unlike PHx, injection of CCl4 results in an inflammatory infiltrate in the liver in response to necrosis. In this model, regeneration is associated with significant tissue injury and an inflammatory response not seen after PHx. Though cell death and the inflammatory reaction may interfere with attempts to clearly elucidate the molecular background of regeneration in the CCl4 model, it can be seen as a better reflection of liver diseases that trigger the regenerative response, such as viral hepatitis and toxic- or drug-induced injury, and of the regeneration of liver parenchyma that occurs after surgical resection carried out in response to various pathologies, including primary or metastatic tumors .

2.1. Cytokines and Transcription Factors

Lipopolysaccharde (LPS), a strong activator of innate immunity, may be present in increased concentration in the portal blood flow after PHx8,9. This factor is known to be necessary for proper liver regeneration, as both germ-free athymic and LPS-resistant mice show impaired regeneration after PHx10. LPS is thought to be one of the earliest signals that starts the regenerative process, likely arriving from the gut to engage receptors on Kupffer cells, the resident macrophages of the liver4. Activation of Kupffer cells results in production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-a) and interleukin (IL)-6. TNF-a activates the nuclear factor-kappa B (NF-kB) transcription factor in macrophages and hepatocytes.11 This response leads to secretion of IL-6, mainly from Kupffer cells, which in turn activates the transcription factor signal transducer and activator of transcription (STAT) 3 in hepatocytes12-14. Studies using mice deficient in TNF receptor 1 (TNFR1)14-16 or IL-613,17 have shown that these cytokines are necessary for liver regeneration. The ability of IL-6 administration to correct the defect in hepatocyte DNA synthesis seen in TNFR1-deficient mice (TNFR1-'-) after PHx suggests that the role of TNF-a in liver regeneration is mediated by IL-614.

NF-kB and STAT3 participate in the induction of immediate-early genes important for liver cell growth and hepatoprotection13,18. NF-kB regulates the cell cycle regulator cyclin D119,20. Stimulation of the IL-6 receptor (IL-6R'gp130) by IL-6 promotes cell growth not only through STAT3 activation21, but also through activation of the mitogen-activated protein kinase (MAPK) signaling cascade22. There is some debate that IL-6 may be more important as a hepatoprotective factor rather than as a mitogen17,23,24. IL-6 activates the pro-survival proteins phosphoinositol 3 kinase (PI3K) and Akt in addition to STAT3, which is also involved in hepatoprotection25,26. NF-kB has also been shown to be an anti-apoptotic factor during liver regeneration. When NF-kB activation is inhibited, such as through the action of a superrepressor transgene of the NF-kB inhibitor, IKBa, or by treatment with gliotoxin, liver regeneration after PHx is impaired and apoptosis of hepatocytes occurs instead of proliferation27,28. NF-kB regulates genes for anti-apoptotic proteins29-35 and prevents TNF-a-induced hepatocyte

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