Bruton's Tyrosine Kinase Inhibitor Attenuates Warm Hepatic Ischemia/Reperfusion Injury via Modulation of the NLR Family Pyrin Domain Containing 3 Inflammasome

Our plain-English summary of Bruton's Tyrosine Kinase Inhibitor Attenuates Warm Hepatic Ischemia/Reperfusion Injury via Modulation of the NLR Family Pyrin Domain Containing 3 Inflammasome, by S.H. Song, F. Liu, Y.Y. Zhao, et al (Transplantation Proceedings, 2020).

The study

• Authors: S.H. Song, F. Liu, Y.Y. Zhao, K.Y. Sun, M. Guo, P.L. Li, H. Liu, G.S. Ding, Z.R. Fu
• Journal: Transplantation Proceedings
• Published: 2020;52(10):2947-2954
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The NLR family pyrin domain containing 3 (NLRP3) inflammasome is a widely studied inflammasome that plays a critical role in inflammatory responses. Many triggers, including microbial pathogens (ie, bacteria and viruses) and other signals (ie, reactive oxygen species, adenosine triphosphate, urate, silicon, and asbestos), can stimulate the NLRP3 inflammasome. Liver ischemia/reperfusion (I/R) injury is a common pathologic process during liver surgery and shock and can induce severe liver damage. Although its pathogenesis is still unclear, oxidative stress and overproduction of the inflammatory response are likely to contribute to I/R injury. The NLRP3 inflammasome is activated during the I/R process, resulting in further recruitment and activation of caspase-1. Activated caspase-1 cleaves the pro-forms of interleukin-1β and interleukin-18 and results in their maturation, triggering a proinflammatory cytokine cascade and causing liver damage. Bruton's tyrosine kinase is a critical molecule involved in diverse cellular pathways, such as proliferation, apoptosis, inflammation, and angiogenesis. Intrahepatic Bruton's tyrosine kinase is mainly expressed on Kupffer cells and sinusoidal endothelial cells, and the inflammasome is activated in Kupffer cells. Our study found that inhibition of Bruton's tyrosine kinase effectively attenuated liver I/R injury by suppressing activation of the NLRP3 inflammasome in Kupffer cells.

Copyright © 2019. Published by Elsevier Inc.

In plain English

This was a mouse study of liver injury caused by cutting off and then restoring blood flow (ischemia/reperfusion), as can happen in liver surgery and transplantation. It did not study asbestos. Asbestos appears only in the background, as one of many triggers of an inflammatory protein complex called the NLRP3 inflammasome. The authors clamped the blood supply to about 70% of the liver in healthy male mice for 60 minutes. Some mice first received ibrutinib, a drug that blocks Bruton's tyrosine kinase (BTK). Ibrutinib-treated mice had lower liver enzyme levels in the blood, less tissue damage, less cell death and lower levels of inflammatory signalling molecules. They also showed less activity of the NLRP3 inflammasome. In the lab, liver immune cells (Kupffer cells) lacking BTK were put through low oxygen followed by restored oxygen. They showed lower secreted IL-1 beta and lower mRNA for IL-6, IL-18 and TNF-alpha. The text gave no measured values for the results, only time points and whether differences were statistically significant. The authors concluded that blocking BTK reduced this liver injury by suppressing inflammasome activity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (mouse model of warm liver ischemia/reperfusion), with an additional cell-culture experiment
• Who was studied: Healthy male C57BL/6 mice aged 8 to 10 weeks and weighing 20 to 25 g, from a supplier in Shanghai, China. The number of mice per group was not reported. BTK-deficient Kupffer cells were also cultured in the laboratory.
• Exposure: No asbestos exposure was studied. The mice had 60 minutes of blocked blood flow to the left and median liver lobes (about 70% of the liver), followed by reperfusion. The drug ibrutinib (PCI-32765, 1 mg/kg), or the solvent DMSO as a control, was injected into the abdomen 30 minutes before surgery.
• Main results:
  • Serum ALT and AST (liver enzyme markers of damage) were lower in ibrutinib-treated mice after ischemia/reperfusion than in DMSO-treated mice, particularly at 6 hours.
  • The difference in AST/ALT was also statistically significant at 3 and 12 hours, and was not statistically significant after 24 hours.
  • Under the microscope, liver tissue damage graded by Suzuki's scoring was significantly reduced with ibrutinib.
  • Liver cell death (apoptosis, measured by TUNEL staining at 6 hours) was significantly lower with ibrutinib.
  • Ibrutinib reduced the serum inflammatory molecules IL-1 beta, IL-6, IL-18 and TNF-alpha after reperfusion.
  • In the liver, ibrutinib lowered caspase-1 protein and reduced the interaction between ASC and NLRP3, which the authors took as a sign of lower NLRP3 inflammasome activity.
  • BTK-deficient Kupffer cells were put through hypoxia followed by reoxygenation in the lab. Secreted IL-1 beta and the mRNA for IL-6, IL-18 and TNF-alpha were reported as significantly decreased.
• The authors' conclusion: The authors concluded that inhibiting BTK reduced liver ischemia/reperfusion injury and inflammation by suppressing inflammasome activity. They suggested BTK as a possible treatment target in liver surgery and transplantation.

Topics

Medical terms in this study, explained in our Lexicon: Tyrosine Kinase Inhibitor, Reactive Oxygen Species (ROS), Oxidative Stress, Cytokine, Apoptosis, Inflammation, Angiogenesis.

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