Dataset Information

Cirrhosis-Based Acute-on-Chronic Liver Failure Is Marked by Inflammation and Impaired Liver Regeneration Despite Stat3 Activation.

ABSTRACT:

Background and aims

Acute-on-chronic liver failure (ACLF) is associated with excessive systemic inflammation, cell death, and organ failures. Yet, little is known about the hepatic histopathology of ACLF. Here, we assessed the histopathology and regenerative capacity of the liver in ACLF with or without cirrhosis.

Methods

Liver specimens of patients with compensated cirrhosis (N = 37), acute decompensation (N = 40), and ACLF with (N = 18) or without (N = 10) cirrhosis were assessed for morphological features and the pro-regenerative Stat3 pathway.

Results

ACLF was associated with high levels of lobular inflammation, tissue necrosis, and apoptosis. In patients with cirrhosis, the percentage of pStat3-positive hepatocytes was increasing with disease severity (3.5%/10.4%/21% for compensated cirrhosis/acute decompensation/cirrhosis-ACLF; P < .001), but lower in noncirrhotic ACLF vs cirrhosis-ACLF (21% vs 13%; P = .02). A distinct pattern of the expression of the proliferation marker Ki-67, a downstream effector marker of pStat3, was observed. Ki-67-positive hepatocytes were more frequent in patients with cirrhosis-ACLF compared to compensated cirrhosis or acute decompensation (4.9% vs 1.3% vs 1.8%; P < .05), but much lower in cirrhosis-ACLF vs noncirrhotic ACLF (4.9% vs 13.5%; P = .01). The ratio of Ki-67-positive to pStat3-positive hepatocytes was lowest in cirrhosis-ACLF and predicted 3-month transplant-free survival accurately (area under the curve = 0.95, P < .00001).

Conclusion

Our study identifies hepatic inflammation and Stat3 activation as hallmarks of ACLF. In cirrhosis-ACLF, Stat3 activation does not appear to translate in effective liver regeneration, which is distinct from noncirrhotic ACLF.

SUBMITTER: Lange CM

PROVIDER: S-EPMC11308700 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Cirrhosis-Based Acute-on-Chronic Liver Failure Is Marked by Inflammation and Impaired Liver Regeneration Despite Stat3 Activation.

Lange Christian M CM Al-Juboori Kawther K Rawitzer Josefine J Moellmann Dorothe D Schlattjan Martin M Guckenbiehl Sabrina S Willuweit Katharina K Canbay Ali A Baba Hideo A HA

Gastro hep advances 20220429 4

<h4>Background and aims</h4>Acute-on-chronic liver failure (ACLF) is associated with excessive systemic inflammation, cell death, and organ failures. Yet, little is known about the hepatic histopathology of ACLF. Here, we assessed the histopathology and regenerative capacity of the liver in ACLF with or without cirrhosis.<h4>Methods</h4>Liver specimens of patients with compensated cirrhosis (N = 37), acute decompensation (N = 40), and ACLF with (N = 18) or without (N = 10) cirrhosis were assesse ...[more]

PMID: 39132076

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Project description:Background & aimsAcute-on-chronic liver failure (ACLF) is a clinical syndrome defined by liver failure on pre-existing chronic liver disease. It is often associated with bacterial infection and high short-term mortality. Experimental models that fully reproduce ACLF are lacking, so too are effective pharmacological therapies for this condition.MethodsTo mimic ACLF conditions, we developed a severe liver injury model by combining chronic injury (chronic carbon tetrachloride [CCl4] injection), acute hepatic insult (injection of a double dose of CCl4), and bacterial infection (intraperitoneal injection of bacteria). Serum and liver samples from patients with ACLF or acute drug-induced liver injury (DILI) were used. Liver injury and regeneration were assessed to ascertain the potential benefits of interleukin-22 (IL-22Fc) administration.ResultsThis severe liver injury model recapitulated some of the key features of clinical ACLF, including acute-on-chronic liver injury, bacterial infection, multi-organ injury, and high mortality. Liver regeneration in this model was severely impaired because of a shift from the activation of the pro-regenerative IL-6/STAT3 pathway to the anti-regenerative IFN-γ/STAT1 pathway. The impaired IL-6/STAT3 activation was due to the inability of Kupffer cells to produce IL-6; whereas the enhanced STAT1 activation was due to a strong innate immune response and subsequent production of IFN-γ. Compared to patients with DILI, patients with ACLF had higher levels of IFN-γ but lower liver regeneration. IL-22Fc treatment improved survival in ACLF mice by reversing the STAT1/STAT3 pathway imbalance and enhancing expression of many antibacterial genes in a manner involving the anti-apoptotic protein BCL2.ConclusionsAcute-on-chronic liver injury or bacterial infection is associated with impaired liver regeneration due to a shift from a pro-regenerative to an anti-regenerative pathway. IL-22Fc therapy reverses this shift and attenuates bacterial infection, thus IL-22Fc may have therapeutic potential for ACLF treatment.Lay summaryA mouse model combining chronic liver injury, acute hepatic insult, and bacterial infection recapitulates some of the key features of acute-on-chronic liver failure (ACLF) in patients. Both fibrosis and bacterial infection contribute to the impaired regenerative capacity of the liver in patients with ACLF. Herein, we show that IL-22Fc therapy improves ACLF by reprogramming impaired regenerative pathways and attenuating bacterial infection. Thus, it may have therapeutic potential for patients with ACLF.

Project description:Cold‑inducible RNA‑binding protein (CIRP) is a cold shock protein implicated in the regulation of multiple biological processes depending on its cellular localization. However, to the best of our knowledge, the role of CIRP in liver regeneration and injury after hepatectomy has not been investigated. The present study was therefore designed to explore whether CIRP is involved in liver regeneration after hepatectomy and its specific role and underlying molecular mechanism. The overall involvement of CIRP in liver regeneration and injury after hepatectomy was evaluated in CIRP‑deficient mice. C23, an antagonist of extracellular CIRP, was used to assess the effect of extracellular CIRP on liver regeneration and injury after hepatectomy. CIRP overexpression and short hairpin RNA plasmids were transfected into HepG2 cells to study the effect of intracellular CIRP on cell proliferation. The effects of extracellular CIRP on cell proliferation and injury were determined via the use of recombinant CIRP protein to stimulate HepG2 cells in vitro. The results indicated that both hepatic and serum CIRP levels significantly increased after partial hepatectomy. Additionally, CIRP deficiency impaired liver regeneration but alleviated liver injury after partial hepatectomy in mice. C23 administration attenuated liver injury and suppressed endoplasmic reticulum (ER) stress and oxidative stress. Loss‑ and gain‑of‑function analyses in HepG2 cells indicated that an increase in intracellular CIRP promoted cell proliferation via signal transducers and activation of transcription 3 (STAT3) signaling pathway activation. Moreover, recombinant CIRP had no effect on cell proliferation or STAT3 phosphorylation but induced ER stress, which was blocked by TAK242, an inhibitor of Toll‑like receptor 4 (TLR4), in HepG2 cells. Taken together, the results of the present study demonstrated that intracellular CIRP promotes liver regeneration by activating the STAT3 pathway, whereas extracellular CIRP induces ER stress possibly via the TLR4 signaling pathway after hepatectomy.

Project description:Hepatic S-adenosylmethionine (SAMe) is maintained constant by the action of methionine adenosyltransferase I/III (MATI/III), which converts methionine into SAMe and glycine N-methyltransferase (GNMT), which eliminates excess SAMe to avoid aberrant methylation reactions. During liver regeneration after partial hepatectomy (PH) MATI/III activity is inhibited leading to a decrease in SAMe. This injury-related reduction in SAMe promotes hepatocyte proliferation because SAMe inhibits hepatocyte DNA synthesis. In MATI/III-deficient mice, hepatic SAMe is reduced, resulting in uncontrolled hepatocyte growth and impaired liver regeneration. These observations suggest that a reduction in SAMe is crucial for successful liver regeneration. In support of this hypothesis we report that liver regeneration is impaired in GNMT knockout (GNMT-KO) mice. Liver SAMe is 50-fold higher in GNMT-KO mice than in control animals and is maintained constant following PH. Mortality after PH was higher in GNMT-KO mice than in control animals. In GNMT-KO mice, nuclear factor kappaB (NFkappaB), signal transducer and activator of transcription-3 (STAT3), inducible nitric oxide synthase (iNOS), cyclin D1, cyclin A, and poly (ADP-ribose) polymerase were activated at baseline. PH in GNMT-KO mice was followed by the inactivation of STAT3 phosphorylation and iNOS expression. NFkappaB, cyclin D1 and cyclin A were not further activated after PH. The LKB1/AMP-activated protein kinase/endothelial nitric oxide synthase cascade was inhibited, and cytoplasmic HuR translocation was blocked despite preserved induction of DNA synthesis in GNMT-KO after PH. Furthermore, a previously unexpected relationship between AMPK phosphorylation and NFkappaB activation was uncovered.These results indicate that multiple signaling pathways are impaired during the liver regenerative response in GNMT-KO mice, suggesting that GNMT plays a critical role during liver regeneration, promoting hepatocyte viability and normal proliferation.

Dataset Information

Cirrhosis-Based Acute-on-Chronic Liver Failure Is Marked by Inflammation and Impaired Liver Regeneration Despite Stat3 Activation.

Background and aims

Methods

Results

Conclusion

Publications

Cirrhosis-Based Acute-on-Chronic Liver Failure Is Marked by Inflammation and Impaired Liver Regeneration Despite Stat3 Activation.

Similar Datasets

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