1. Academic Validation
  2. Diphenyleneiodonium ameliorates acute liver rejection during transplantation by inhibiting neutrophil extracellular traps formation in vivo

Diphenyleneiodonium ameliorates acute liver rejection during transplantation by inhibiting neutrophil extracellular traps formation in vivo

  • Transpl Immunol. 2021 Oct;68:101434. doi: 10.1016/j.trim.2021.101434.
Yanyao Liu 1 Xiaoyan Qin 2 Zilun Lei 1 Hao Chai 1 Zhongjun Wu 3
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Department of General Surgery of Yuzhong District, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Children Health and Disorders, China International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China.
  • 3 Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: wzjtcy@126.com.
Abstract

Neutrophil extracellular traps (NETs) play critical roles in hepatic ischemic reperfusion injury (IRI) induced immune responses to inflammation. Diphenyleneiodonium (DPI) is an NADPH oxidative inhibitor that has been implicated in the regulation of NETs formation. However, the effects of NETs and their underlying mechanisms during DPI treatment of acute rejection (AR) after liver transplantation have not been elucidated. This study tested the hypothesis that blocking NETs formation by DPI treatment could be a potential therapeutic target against AR after liver transplantation. NETs were found to be excessively formed within the livers and serum of transplantation models, which could be an independent risk factor for AR. DPI was shown to alleviate hepatic injury and maintain liver functions by inhibiting NETs formation through the nicotinamide adenine dinucleotide phosphate (NADPH)/ROS/peptidylarginine deiminase 4 (PAD4) signaling pathway. NETs are highly involved in AR after liver transplantation. By inhibiting NETs formation, DPI suppresses activation of the NADPH/ROS/PAD4 signaling pathway which acts against AR after liver transplantation. Therefore, DPI is a potential candidate for the therapeutic management of AR after liver transplantation. Combination treatment containing both DPI and tacrolimus revealed a better antidamage efficacy than adjusting either treatment alone, suggesting that the joint therapy might be a promising solution in AR after liver transplantation.

Keywords

Acute rejection; Diphenyleneiodonium; Liver transplantation; Neutrophil extracellular traps (NETs).

Figures
Products