Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure

• Published in: BMC medicine Vol. 22; no. 1; pp. 95 - 17
• Main Authors: Hassan, Hozeifa Mohamed, Liang, Xi, Xin, Jiaojiao, Lu, Yingyan, Cai, Qun, Shi, Dongyan, Ren, Keke, Li, Jun, Chen, Qi, Li, Jiang, Li, Peng, Guo, Beibei, Yang, Hui, Luo, Jinjin, Yao, Heng, Zhou, Xingping, Hu, Wen, Jiang, Jing
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 05.03.2024; BioMed Central; BMC
• Subjects: Acute-On-Chronic Liver Failure; Analysis; Animals; Apoptosis; Biological markers; Biomarkers; Care and treatment; Cirrhosis; Development and progression; Enzyme-linked immunosorbent assay; Enzymes; Genes; Health aspects; Hepatitis; Hepatitis B; Hepatitis B virus; Hepatocellular apoptosis; Humans; Immune response; Immune system; Immune-metabolism disorder; Inflammation; Inflammatory response; Leukocytes, Mononuclear; Liver; Liver cancer; Liver Cirrhosis; Liver diseases; Liver failure; Liver transplants; Medical prognosis; Metabolism; Mice; Molecular mechanics; Mortality; Pathogenesis; Pathogens; Peripheral blood mononuclear cells; Phenotype; Polymerase chain reaction; Prospective Studies; Rats; Risk factors; Severity prediction; Survival analysis; Thrombospondin; Thrombospondin 1; Thrombospondin 1 - genetics; Transcriptomes; China; United States > US; Acute-on-chronic liver failure; Inflammatory response; Immune-metabolism disorder; Thrombospondin 1; Hepatocellular apoptosis; Severity prediction
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-024-03318-x

The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis. Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice. THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis. THBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.