Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 17, Issue 1, Pages 69-80Publisher
WILEY
DOI: 10.1111/ajt.13991
Keywords
basic (laboratory) research; science; liver transplantation; hepatology; schemia reperfusion injury (IRI); macrophage; monocyte biology: activation
Categories
Funding
- Ministry of Education, Culture, Science and Sports of the Japan [15K10041]
- Translational Medical Research Project from the Tazuke Kofukai Medical Research Institute
- Grants-in-Aid for Scientific Research [24111009, 15K10041] Funding Source: KAKEN
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Liver ischemia reperfusion injury (IRI) is an important problem in liver transplantation. Thrombomodulin (TM), an effective drug for disseminated intravascular coagulation, is also known to exhibit an anti-inflammatory effect through binding to the high-mobility group box 1 protein (HMGB-1) known as a proinflammatory mediator. We examined the effect of recombinant human TM (rTM) on a partial warm hepatic IRI model in wild-type (WT) and toll-like receptor 4 (TLR-4) KO mice focusing on the HMGB-1/TLR-4 axis. As in vitro experiments, peritoneal macrophages were stimulated with recombinant HMGB-1 protein. The rTM showed a protective effect on liver IRI. The rTM diminished the downstream signals of TLR-4 and also HMGB-1 expression in liver cells, as well as release of HMGB-1 from the liver. Interestingly, neither rTM treatment in vivo nor HMGB-1 treatment in vitro showed any effect on TLR-4 KO mice. Parallel in vitro studies have confirmed that rTM interfered with the interaction between HMGB-1 and TLR-4. Furthermore, the recombinant N-terminal lectin-like domain 1 (D1) subunit of TM (rTMD1) also ameliorated liver IRI to the same extent as whole rTM. Not only rTM but also rTMD1 might be a novel and useful medicine for liver transplantation. This is the first report clarifying that rTM ameliorates inflammation such as IRI in a TLR-4 pathway-dependent manner. Recombinant thrombomodulin suppresses high mobility group box-1 protein expression in liver cells, as well as its release from the liver, and it ameliorates liver ischemia-reperfusion injury in a toll-like receptor 4 pathway- dependent manner. See the editorial from Ke on page 7.
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