The lectin-like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice

Abstract

Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin‐like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion‐induced liver damage in a dose‐dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage.

Propionic Acid, Induced in Gut by an Inulin Diet, Suppresses Inflammation and Ameliorates Liver Ischemia and Reperfusion Injury in Mice

“…HMGB-1 has been reported as one of the DAMPs released from necrotic cells and hepatocytes in the case of liver IR insult, which leads to the activation of macrophages, followed by the production of proinflammatory cytokines ( 3 , 8 ). Our previous study revealed that the HMGB-1/TLR-4 pathway played a critical role in the process of liver IRI ( 5 , 6 ). To clarify how intraperitoneal PA administration affects the HMGB-1/TLR-4 pathway, HMGB-1 levels after the IR treatment were measured in the sera of PA and saline-injected mice.…”

“…We used the established mouse model of partial warm liver IRI ( 5 , 6 ). Mice were anesthetized under isoflurane and injected with heparin (100 U/kg).…”

“…It has been shown that HMGB-1 released from an IR-injured liver acts through the Toll-like receptor 4 (TLR-4) on hepatocytes and macrophages, which results in the apoptotic cell death of hepatocytes and induction of severe inflammatory responses by macrophages ( 8 ). Blocking the interaction between HMGB-1 and TLR-4 could prevent liver IRI in a TLR-4 dependent manner ( 5 , 6 ). Recently, the Enhanced Recovery After Surgery (ERAS) protocol is advocated in the field of liver surgery.…”

Role of Extracellular High-Mobility Group Box-1 as a Therapeutic Target of Gastric Cancer

“…rTM is a drug that is approved in Japan for the treatment of disseminated intravascular coagulation syndrome. It binds to HMGB1 via its N -terminal lectin-like domain and assists in the proteolysis of HMGB1 by thrombin [ 30 , 31 , 32 ]. This molecular mechanism inhibits the RAGE pathway and NF-kB phosphorylation, which have recently been reported to exert anti-tumor effects [ 21 , 33 ].…”

“…Activated protein C then inactivates factors VIIIa and Va in the presence of protein S, which exerts anticoagulant effects [ 29 ]. Regarding its other functions, rTM binds to HMGB1 via its N -terminal lectin-like domain, and assists in the proteolysis of HMGB1 by thrombin, degrading HMGB1 to a less inflammatory form [ 30 , 31 , 32 ]. The antitumor effects of rTM have also recently been reported [ 33 ].…”