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Abstract
Recombinant thrombomodulin (rTM) has been used for treatment of sepsis-associated disseminated intravascular coagulation. Recent studies have suggested that anticoagulant therapy might dampen the protective role of immunothrombosis. We examined if rTM might worsen infectious diseases. Male Sprague–Dawley rats with jugular-vein catheterization were divided into three groups: no anticoagulation; rTM pretreatment; rTM treatment at 6 h. Live methicillin-resistant Staphylococcus aureus (MRSA) was inoculated into the tail vein of rats. rTM was administered into the jugular-vein catheter before or 6 h after MRSA inoculation, while an equal volume of saline was administered in the no-anticoagulation group. Blood samples were collected from the jugular-vein catheter before, 6 h and 12 h after MRSA inoculation. Tissue samples were collected from anesthetized rats when moribund or 18 h after MRSA inoculation. The survival rate of rats in the no-anticoagulation group, rTM pretreatment group, and rTM treatment at 6-h group was 50%, 25%, and 75%, respectively. Bacterial burden in blood, lung, liver, and spleen was neither increased nor decreased in rats treated with rTM. The ratio of bacteria found in the extravascular space to those in the intravascular space was increased in rats treated with rTM although the statistical power for this was low because of the small sample size. Metabolomics analysis revealed that rTM treatment alleviated oxidative stress, as evidenced by the decrease in levels of oxidized glutathione with reference to reduced glutathione. rTM did not promote bacterial propagation but alleviated oxidative stress in our rat model of bloodstream infection with MRSA. Further large-scale studies are needed to confirm these findings.
Highlights
Abbreviations colony-forming units (CFUs) Colony-forming unit disseminated intravascular coagulation (DIC) Disseminated intravascular coagulation GSH Reduced glutathione GSSG Oxidized glutathione methicillin-resistant Staphylococcus aureus (MRSA) Methicillin-resistant Staphylococcus aureu neutrophil extracellular traps (NETs) Neutrophil extracellular traps PBS Phosphate buffered saline recombinant thrombomodulin (rTM) Recombinant thrombomodulin UDP Uridine 5′-diphospate
To validate the plausibility of this hypothesis, we examined bacterial burden in organs and blood in the presence or absence of rTM in rats infected with methicillin-resistant Staphylococcus aureus (MRSA), a major bacterial species causing bloodstream infection and release of NETs 18
We examined if the timing of rTM administration, before or after MRSA inoculation, affected bacterial burden
Summary
Abbreviations CFU Colony-forming unit DIC Disseminated intravascular coagulation GSH Reduced glutathione GSSG Oxidized glutathione MRSA Methicillin-resistant Staphylococcus aureu NETs Neutrophil extracellular traps PBS Phosphate buffered saline rTM Recombinant thrombomodulin UDP Uridine 5′-diphospate. We examined if the timing of rTM administration, before or after MRSA inoculation, affected bacterial burden. Anticoagulation therapy was conducted in some rats, for which rTM (1 mg/kg; Asahi Kasei Pharma, Tokyo, Japan) was administered into the jugular-vein catheter immediately before (rTM pretreatment group) or 6 h after the first MRSA inoculation (rTM treatment at 6-h group).
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