2. Academic Validation
  3. Extracellular ATP contributes to the reactive oxygen species burst and exaggerated mitochondrial damage in D-galactosamine and lipopolysaccharide-induced fulminant hepatitis

Extracellular ATP contributes to the reactive oxygen species burst and exaggerated mitochondrial damage in D-galactosamine and lipopolysaccharide-induced fulminant hepatitis

  • Int Immunopharmacol. 2024 Feb 17:130:111680. doi: 10.1016/j.intimp.2024.111680.
Rong-Xu 1,  Li-Sha Yuan 1,  Ying-Qing Gan 2,  Na Lu 2,  Ya-Ping Li 3,  Zhi-Ya Zhou 3,  Bo Hu 4,  Tak-Sui Wong 4,  Xian-Hui He 5,  Qing-Bing Zha 6,  Dong-Yun Ouyang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
  • 2 Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
  • 3 Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, the Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan 517000, China; Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan 517000, China.
  • 4 Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
  • 5 Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, the Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan 517000, China; Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan 517000, China. Electronic address: [email protected].
  • 6 Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, the Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan 517000, China; Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan 517000, China; Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China. Electronic address: [email protected].
PMID: 38368772 DOI: 10.1016/j.intimp.2024.111680
Abstract

Fulminant hepatitis (FH) is a severe clinical syndrome leading to hepatic failure and even mortality. D-galactosamine (D-GalN) plus lipopolysaccharide (LPS) challenge is commonly used to establish an FH mouse model, but the mechanism underlying D-GalN/LPS-induced liver injury is incompletely understood. Previously, it has been reported that extracellular ATP that can be released under cytotoxic and inflammatory stresses serves as a damage signal to induce potassium ion efflux and trigger the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome activation through binding to P2X7 receptor. In this study, we tried to investigate whether it contributed to the fulminant hepatitis (FH) induced by D-GalN plus LPS. In an in vitro cellular model, D-GalN plus extracellular ATP, instead of D-GalN alone, induced Pyroptosis and Apoptosis, accompanied by mitochondrial Reactive Oxygen Species (ROS) burst, and the oligomerization of Drp1, Bcl-2, and Bak, as well as the loss of mitochondrial membrane potential in LPS-primed macrophages, well reproducing the events induced by D-GalN and LPS in vivo. Moreover, these events in the cellular model were markedly suppressed by both A-804598 (an ATP receptor P2X7R inhibitor) and glibenclamide (an ATP-sensitive potassium ion channel inhibitor); in the FH mouse model, administration of A-804598 significantly mitigated D-GalN/LPS-induced hepatic injury, mitochondrial damage, and the activation of Apoptosis and Pyroptosis signaling, corroborating the contribution of extracellular ATP to the cell death. Collectively, our data suggest that extracellular ATP acts as an autologous damage-associated molecular pattern to augment mitochondrial damage, hepatic cell death, and liver injury in D-GalN/LPS-induced FH mouse model.

Keywords

Apoptosis; D-galactosamine; Fulminant hepatitis; Lipopolysaccharide; Mitochondrial damage; Pyroptosis.

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