Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation

Journal of Hepatology, Год журнала: 2024, Номер 81(5), С. 895 - 910

Опубликована: Июнь 20, 2024

Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting fibrosis, cirrhosis, portal hypertension failure. Thus, an improved understanding of inflammasomes - as key molecular drivers may result the development novel diagnostic or prognostic biomarkers effective therapeutics. In disease, innate immune cells respond insults by activating cell-intrinsic via toll-like receptors NF-κB, releasing cytokines (such IL-1β, IL-18, TNF-α IL-6). Subsequently, adaptive system are recruited fuel inflammation undergo gasdermin D-mediated programmed death, termed pyroptosis. With progression, there is shift towards type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation occur at extrahepatic sites, such white adipose MASH (metabolic dysfunction-associated steatohepatitis). end-stage flares (e.g., severe alcohol-related hepatitis) spark on dysfunctional system, contribute inflammasome-mediated potentially organ dysfunction/failure, seen ACLF (acute-on-chronic failure). This review provides overview current concepts regarding inflammasome with focus related therapeutic approaches being developed for patients disease.

Язык: Английский

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Liver transplantation for acute-on-chronic liver failure

˜The œLancet. Gastroenterology & hepatology, Год журнала: 2024, Номер 9(6), С. 564 - 576

Опубликована: Фев. 1, 2024

Язык: Английский

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Infections in cirrhosis

˜The œLancet. Gastroenterology & hepatology, Год журнала: 2024, Номер 9(8), С. 745 - 757

Опубликована: Май 13, 2024

Язык: Английский

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Gut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases

Seminars in Immunology, Год журнала: 2024, Номер 71, С. 101859 - 101859

Опубликована: Янв. 21, 2024

Язык: Английский

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Autologous macrophage therapy for liver cirrhosis: a phase 2 open-label randomized controlled trial

Nature Medicine, Год журнала: 2025, Номер unknown

Опубликована: Янв. 10, 2025

Abstract Cirrhosis is a major cause of morbidity and mortality; however, there are no approved therapies except orthotopic liver transplantation. Preclinical studies showed that bone-marrow-derived macrophage injections reduce inflammation, resolve fibrosis stimulate regeneration. In multicenter, open-label, parallel-group, phase 2 randomized controlled trial ( ISRCTN10368050 ) in n = 51 adult patients with compensated cirrhosis Model for End-Stage Liver Disease (MELD) score ≥10 ≤17, we evaluated the efficacy autologous monocyte-derived therapy 27) compared to standard medical care 24). The primary endpoint was difference baseline day 90 change MELD (ΔMELD) between treatment control groups (ΔΔMELD). Secondary endpoints included adverse clinical outcomes, non-invasive biomarkers health-related quality life (HRQoL) at d, 180 d 360 d. ΔΔMELD 0 group controls −0.87 (95% confidence interval: −1.79, 0.0; P 0.06); therefore, not met. During 360-d follow-up, five 24 participants developed total 10 severe events, four which were related, three deaths (two related), whereas liver-related events or occurred group. Although differences observed HRQoL, exploratory analysis anti-inflammatory serum cytokine profiles after infusion. This study reinforces safety potential cirrhosis, supporting further investigation.

Язык: Английский

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Immune Checkpoints and the Immunology of Liver Fibrosis

Livers, Год журнала: 2025, Номер 5(1), С. 5 - 5

Опубликована: Янв. 27, 2025

Liver fibrosis is a very complicated dynamic process where several immune cells are involved. Both innate and adaptive immunity implicated, their interplay always present. Multi-directional interactions between liver macrophages, hepatic stellate (HSCs), cells, cytokines important for the induction perpetuation of fibrosis. Detailed studies proteomics transcriptomics have produced new evidence role individual in cirrhosis. Most these controlled by various checkpoints whose main function to maintain homeostasis implicated cells. Recent indicates that involved In particular, programmed cell death protein 1 (PD-1), death-ligand (PD-L1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) been investigated, particularly after availability checkpoint inhibitors. Their activation leads exhaustion CD4+ve CD8+ve promotion this review, current pathogenesis immunological abnormalities discussed. The recent data on involvement identified as possible targets future interventions.

Язык: Английский

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Monocytes subsets altered distribution and dysregulated plasma hsa-miR-21-5p and hsa-miR-155-5p in HCV-linked liver cirrhosis progression to hepatocellular carcinoma

Journal of Cancer Research and Clinical Oncology, Год журнала: 2023, Номер 149(17), С. 15349 - 15364

Опубликована: Авг. 28, 2023

Abstract Purpose The authors aim to investigate the altered monocytes subsets distribution in liver cirrhosis (LC) and subsequent hepatocellular carcinoma (HCC) association with expression level of plasma Homo sapiens (has)-miR-21-5p hsa-miR-155-5p. A step toward non-protein coding (nc) RNA precision medicine based on immune perturbation manifested as distribution, top LC HCC. Methods Seventy-nine patients diagnosed chronic hepatitis C virus (CHCV) infection were enrolled current study. Patients sub-classified into group without HCC ( n = 40), 39), 15 apparently healthy controls. Monocyte frequencies assessed by flow cytometry. Real-time quantitative PCR was used measure hsa-miR-21-5p hsa-miR-155-5p expression. Results Hsa-miR-21-5p correlated intermediate r 0.30, p 0.007), while negatively non-classical − 0.316, 0.005). ROC curve analysis revealed that combining frequency hsa-miR-21 yielded sensitivity 79.5%, specificity 75%, AUC 0.84. In comparison, AFP a lower 69% 100% 0.85. Logistic regression proved up-regulation independent risk factors for progression HCC, after adjustment co-founders. Conclusion differentiation linked Combined could be considered sensitive indicator Circulating evolution, clinically silico proved. Graphical abstract

Язык: Английский

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AASLD Practice Guidance on Acute-on-chronic liver failure and the management of critically ill patients with cirrhosis

Hepatology, Год журнала: 2023, Номер 79(6), С. 1463 - 1502

Опубликована: Ноя. 8, 2023

Karvellas, Constantine J.; Bajaj, Jasmohan S.; Kamath, Patrick Napolitano, Lena; O'Leary, Jacqueline G.; Solà, Elsa; Subramanian, Ram; Wong, Florence; Asrani, Sumeet K. Author Information

Язык: Английский

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Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

Science Immunology, Год журнала: 2023, Номер 8(80)

Опубликована: Фев. 3, 2023

The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated critical importance of tissue-specific expression in cell survival. Here, we analyzed effects local versus peripheral sources model acute bacterial pneumonia induced Pseudomonas aeruginosa . Whereas mice with global deficiency had severe pneumonia-induced lung injury, those deficient only liver-derived remained protected, comparable to wild-type mice. Human transcriptome analysis showed that secretory epithelial cells, such as club express high levels mRNA. Mice tamoxifen-induced gene ablation from cells worse pulmonary injury compared similarly treated controls, despite maintaining normal circulating levels. Last, both mouse and cultured primary human airway stress-induced death associated parallels seen Factor B rather than C3a receptor deficiency. Moreover, C3-mediated reduction requires alternative pathway B. Thus, our findings suggest reliant on locally derived protects mucosal barrier.

Язык: Английский

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Bacterial translocation occurs early in cirrhosis and triggers a selective inflammatory response

Hepatology International, Год журнала: 2023, Номер 17(4), С. 1045 - 1056

Опубликована: Март 7, 2023

Experimental data suggest that bacterial translocation (BT) promotes systemic inflammation, portal hypertension, and circulatory dysfunction in advanced chronic liver disease (ACLD).Patients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement absence of acute decompensation or infections were included (n = 249). Serum biomarkers BT (lipopolysaccharide [LPS], lipoteichoic acid [LTA], DNA [bactDNA]), inflammation markers assessed. T-cell subsets intestinal biopsies 7 ACLD, n 4 controls) analyzed by flow cytometry.Patients had a median HVPG 18 (12-21) mmHg 56% decompensated ACLD. LPS (0.04 [0.02-0.06] vs. 0.64 [0.30-1.06] EU/mL), LTA (4.53 [3.58-5.97] 43.2 [23.2-109] pg/mL), detection bactDNA (≥ 5 pg/mL; 5% 41%) markedly higher patients than healthy controls 40; p < 0.001) but similar between different clinical stages compensated displayed no meaningful correlation hemodynamics. TNF-α IL-10 correlated (Spearman's rs 0.523, 0.001/rs 0.143, 0.024) not LTA. Presence was associated (0.54 [0.28-0.95] 0.88 [0.32-1.31] EU/mL, (15.3 [6.31-28.1] 20.9 [13.8-32.9] pg/mL). Patients exhibited decreased CD4:CD8-ratio increased TH1-cells the mucosa as compared to controls. During FU 14.7 (8.20-26.5) months, antigens did predict liver-related death (in contrast HVPG, IL-6, MAP) well at 24 months.BT occurs already early triggers inflammatory response via IL-10. Interestingly, showed clear hypertension stable ACLD.NCT03267615.

Язык: Английский

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