Recombinant human thrombomodulin attenuated sepsis severity in a non-surgical preterm mouse model

Mariko Ashina,Toshihiko Ikuta,Kazumichi Fujioka,Masakazu Shinohara,Saki Okubo,Kosuke Nishida,Kazumoto Iijima

doi:10.1038/s41598-019-57265-2

Abstract

Neonatal sepsis is characterised by dysregulated immune responses. Lipid mediators (LMs) are involved in the regulation of inflammation. Human recombinant thrombomodulin (rhTM), an anticoagulant, has anti-inflammatory effects and might be useful for sepsis treatment. A stock caecal slurry (CS) solution was prepared from adult caeca. To induce sepsis, 1.5 mg/g of CS was administered intraperitoneally to 4 d-old wild-type FVB mouse pups. Saline (Veh-CS) or rhTM (3 or 10 mg/kg; rhTM3-CS or rhTM10-CS) was administered subcutaneously 6 h prior to sepsis induction, and liver LM profiles at 3 and 6 h post-sepsis induction and survival up to 7 days were examined. Mortality was significantly lower (47%) in the rhTM3-CS group and significantly higher (100%) in the rhTM10-CS group, compared with the Veh-CS group (79%, p < 0.05). Eleven LMs (12-HEPE, EPA, 14-HDHA, DHA, PD1, PGD2, 15d-PGJ2, 12S-HHT, lipoxin B4, 12-HETE, AA) were significantly increased at 3 h, and five LMs (5-HEPE, 15-HEPE, 18-HEPE, 17-HDHA, PD1) were significantly increased at 6 h post-sepsis induction. Increased EPA, DHA, 12S-HHT, lipoxin B4, and AA were significantly suppressed by rhTM pre-treatment. rhTM was protective against neonatal sepsis. This protective effect might be mediated via LM modulation. Further post-sepsis studies are needed to determine clinical plausibility.

Highlights

Neonatal sepsis is characterised by dysregulated immune responses
Levels of several inflammatory Lipid mediators (LMs) were increased at 3 and 6 h post-sepsis induction, and these increases were partially suppressed by recombinant human thrombomodulin (rhTM) pre-treatment
In our preterm sepsis mouse model, subcutaneous administration of 3 mg/kg of rhTM at 6 h prior to sepsis induction led to improvements in the blood gas parameters and mortality rate

Summary

Introduction

Neonatal sepsis is characterised by dysregulated immune responses. Lipid mediators (LMs) are involved in the regulation of inflammation. Human recombinant thrombomodulin (rhTM), an anticoagulant, has anti-inflammatory effects and might be useful for sepsis treatment. The anti-inflammatory function of LMs is reportedly associated with the resolution of inflammation, and the dysregulated balance of LMs has attracted attention as a pathway involved in the pathogenesis of sepsis[4]. Low-dose corticosteroids[9], orally administered protease inhibitors[10], and mesenchymal stem cell therapy[11] are currently being investigated in clinical trials No such trials have been initiated for neonatal sepsis. The pleiotropic and anti-inflammatory effects of rhTM have attracted attention These include inhibition of intercellular adhesion molecule-1 expression (ICAM-1), activation of protease activated receptor-1 (PAR-1)[15], neutralisation of endotoxins, and adsorptive dissolution of HMGB-1 proteins[16]. The target of LMs is presumed to be the pathology of sepsis, there has been no human or animal study on the effects of LMs in neonatal sepsis

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