Heparin-Binding Protein Promotes Acute Lung Injury in Sepsis Mice by Blocking the Aryl Hydrocarbon Receptor Signaling Pathway

Kun Ye; Xiang Lin; Tai-Zhi Chen; Long-Hui Wang; Sheng-Xing Liu

doi:10.2147/JIR.S454777

Heparin-Binding Protein Promotes Acute Lung Injury in Sepsis Mice by Blocking the Aryl Hydrocarbon Receptor Signaling Pathway

J Inflamm Res. 2024 May 13:17:2927-2938. doi: 10.2147/JIR.S454777. eCollection 2024.

Authors

Kun Ye¹, Xiang Lin², Tai-Zhi Chen², Long-Hui Wang², Sheng-Xing Liu²

Affiliations

¹ Department of Orthopaedics, Qiantang Campus of Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, Zhejiang, 310018, People's Republic of China.
² Department of Orthopaedics, The Second Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, Hainan, 570311, People's Republic of China.

Abstract

Purpose: This study aimed to explore the therapeutic effect and potential mechanism of heparin-binding protein (HBP) reduction on sepsis-related acute lung injury.

Methods: We utilized a murine model of sepsis-induced by intraperitoneal injection of lipopolysaccharides (LPS) in C57BL/6J mice divided into four groups: Control, LPS, Anti-HBP, and ceftriaxone (CEF). Following sepsis induction, Anti-HBP or CEF treatments were administered, and survival rates were monitored for 48 h. We then used reverse-transcription quantitative PCR to analyze the expression levels of HBP in lung tissues, immunohistochemistry for protein localization, and Western blotting for protein quantification. Pulmonary inflammation was assessed using enzyme-linked immunosorbent assays of proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, and interferon-γ). The activation state of the aryl hydrocarbon receptor (AhR) signaling pathway was determined via Western blotting, evaluating both cytoplasmic and nuclear localization of AhR and the expression of cytochrome P450 1A1 protein by its target gene.

Results: Anti-HBP specifically reduced HBP levels. The survival rate of mice in the Anti-HBP and CEF groups was much higher than that in the LPS group. The severity of lung injury and pulmonary inflammatory response in the Anti-HBP and CEF groups was significantly lower than that in the LPS group. AhR signaling pathway activation was observed in the Anti-HBP and CEF groups. Additionally, there was no significant difference in the above indices between the Anti-HBP and CEF groups.

Conclusion: HBP downregulation in lung tissues significantly improved LPS-induced lung injury and the pulmonary inflammatory response, thereby prolonging the survival of sepsis mice, suggesting activation of the AhR signaling pathway. Moreover, the effect of lowering the HBP level was equivalent to that of the classical antibiotic CEF.

Trial registration: Not applicable.

Keywords: acute lung injury; aryl hydrocarbon receptor signaling pathway; heparin-binding protein; sepsis.

Grants and funding

This study is supported by the Science and Technology Project of Hainan Province (821MS140).