Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1

Abstract

Transplantation using grafts obtained after cardiac death (CD) is considered a promising solution for graft shortages. However, no standard criteria for organ preservation have been established for CD donors. High-mobility group box 1 (HMGB1) is a DNA-binding protein that is released from dying hepatocytes as an early mediator of inflammation and organ tissue damage. HMGB1 stimulates immunocytes to produce inflammatory cytokines, thereby amplifying the inflammatory response. Thrombomodulin is an integral membrane protein that functions as an endothelial anticoagulant cofactor, and it binds HMGB1 through the extracellular domain. We investigated the effects of ART-123, recombinant human soluble thrombomodulin, on warm ischemia-reperfusion injury in liver grafts. Male Wistar rats were divided into four ex vivo groups: heart-beating (HB) group, in which livers were isolated from HB donors; CD group, in which livers were isolated from CD donors exposed to apnea-induced conditions and warm ischemic conditions for 30 min after cardiac arrest; and two CD groups pretreated with ART-123 (1 or 5 mg/kg). Each isolated liver was reperfused for 1 h after cold preservation for 6 h. The perfusate levels of HMGB1, LDH, TNF-α, and IL-6 were significantly lower in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. Bile production was significantly higher in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. The sinusoidal spaces were significantly narrower in the CD group than in the other groups. We propose that ART-123 maintains sinusoidal microcirculation by reducing endothelial cell damage during warm ischemia-reperfusion injury.

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

“…In previous reports, rTM and other treatments were generally administered before the onset of ischemia 7,12‐14,17,23,40‐44 . The IR insult was also more profound in genetically modified mice lacking the N‐terminal lectin‐like domain of TM 21,22 .…”

“…rTM has been utilized clinically in Japan for the treatment of disseminated intravascular coagulation (DIC) by an activity promoted by domain 2 11 . There are many reports that suggest that the administration of rTM might ameliorate IR‐induced damage in various organs 12‐17 . We have previously reported that rTM blocked HMGB‐1 binding to TLR‐4, which was followed by suppression of nuclear factor kappa B (NF‐κB)–induced inflammation and diminished levels of IR‐induced liver injury in mice 7 .…”

Normothermic Ex-vivo Liver Perfusion and the Clinical Implications for Liver Transplantation

“…Negrath et al , 43 using various defatting cocktails, showed that successful defatting was associated with improved recovery from IRI. 43 Preconditioning of livers on the NMP circuit with Nodosin, 44 as well as with thrombomodulin, 45 was also associated with improvement in endothelial damage and in IRI.…”

Danger signals in regulating the immune response to solid organ transplantation

“…A recent study investigated the impact of recombinant soluble thrombomodulin, which can bind HMGB1 and prevent HMGB1-mediated proinflammatory responses, on IRI in liver grafts. Thrombomodulin treatment attenuated levels of HMGB1 and inflammatory cytokines, decreased markers of liver graft injury, and improved organ function (104). Other studies suggest that HA production may be an actionable target.…”