Novel roles of lipopolysaccharide and TLR4/NF-κB signaling pathway in inflammatory response to liver injury in Budd-Chiari syndrome

Jie Li; Xiao-Ming Chen; Chun-Ze Zhou; Wei-Wei Fang; Wei-Fu Lv; De-Lei Cheng

doi:10.4240/wjgs.v13.i11.1448

Novel roles of lipopolysaccharide and TLR4/NF-κB signaling pathway in inflammatory response to liver injury in Budd-Chiari syndrome

World J Gastrointest Surg. 2021 Nov 27;13(11):1448-1462. doi: 10.4240/wjgs.v13.i11.1448.

Authors

Jie Li¹, Xiao-Ming Chen², Chun-Ze Zhou¹, Wei-Wei Fang³, Wei-Fu Lv¹, De-Lei Cheng⁴

Affiliations

¹ Department of Interventional Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China.
² Department of Gastroenterology, The Second Hospital of Anhui Medical University, Hefei 230000, Anhui Province, China.
³ Department of Radiology, The Third People's Hospital of Hefei, Hefei 230022, Anhui Province, China.
⁴ Department of Interventional Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China. 39055004@qq.com.

Abstract

Background: Budd-Chiari syndrome (BCS) is an uncommon disorder characterized by obstruction of hepatic venous outflow. To date, the exact mechanism underlying hepatic injury derived from the hepatic venous outflow obstruction in BCS remains largely unknown.

Aim: To assess the role of NF-κB-mediated inflammation in BCS-induced liver injury in humans and rats.

Methods: A total of 180 rats were randomly assigned into nine groups, including four BCS model groups (1, 3, 6 and 12 wk), four sham-operated groups (1, 3, 6 and 12 wk), and a control group. Lipopolysaccharide (LPS) levels in each group were detected by the Tachypleus Amebocyte Lysate assay. The mRNA and protein levels of TLR4, NF-κB, tumor necrosis factor (TNF)-α, interleukin (IL)-2 and interferon (IFN)-γ were quantified. In addition, 60 patients with BCS and 30 healthy controls were enrolled, and their blood samples were analyzed.

Results: Hepatic and plasma LPS levels were significantly increased in rats. The mRNA and protein expression levels of TLR4, NF-κB and inflammatory cytokines (TNF-α, IL-2 and IFN-γ) in liver tissues were significantly higher in the BCS model groups compared with the other two groups. In addition, the model groups (1, 3, 6 and 12 wk after BCS induction) showed significant differences in the levels of LPS, TLR4, NF-κB, TNF-α, IL-2 and IFN-γ. Notably, there was a significant correlation between the LPS concentrations and mRNA and protein levels of TLR4, NF-κB and inflammatory cytokines. Importantly, it was revealed that the levels of LPS, TLR4, NF-κB and inflammatory cytokines were significantly greater in chronic BCS patients than healthy controls and acute BCS patients.

Conclusion: LPS level is markedly elevated in BCS, in turn activating the TLR4/NF-κB signaling pathway, leading to induction of inflammatory cytokines (TNF-α, IL-2 and IFN-γ) in response to BCS-induced liver injury.

Keywords: Budd-Chiari syndrome; Lipopolysaccharide; Liver injury; Nuclear factor-kappa B; Toll-like receptor 4.