Thrombomodulin improved liver injury, coagulopathy, and mortality in an experimental heatstroke model in mice.
BACKGROUND
Heatstroke is a life-threatening illness and causes high mortality due to multiple organ injuries. Thrombomodulin (TM) is an endothelial anticoagulant cofactor that plays an important role in the regulation of intravascular coagulation. In this study, we investigated the effect of TM on the inflammatory process, liver function, coagulation status, and mortality in experimental heatstroke.


METHODS
Male C3H/HeN (8-10 weeks) mice were randomly assigned to the TM-treated group (TG-Pre) or nontreated heatstroke group (HS). In group TG-Pre, mice were treated with recombinant soluble TM (1 mg/kg, intraperitoneally) before heat exposure. In some experiments, recombinant soluble TM was administrated during heat exposure (TG-Delay). Heatstroke was induced by exposure to ambient temperature of 38°C for 4 hours. After heat exposure, the levels of tumor necrosis factor-α, interleukin-6, and plasma high-mobility group box 1 (HMGB1), liver function, plasma aspartate aminotransferase and alanine aminotransferase concentrations, and immunohistochemical and histopathological characteristics of the livers were determined. The coagulation status, plasma protein C levels, and thrombin-antithrombin complex levels were also measured.


RESULTS
In group HS, plasma cytokines and HMGB1 concentrations increased after heat exposure. Plasma aspartate aminotransferase and alanine aminotransferase concentrations increased after heat exposure. In group HS livers, strong and extensive immunostaining for HMGB1 was observed. In addition, there was extensive hepatocellular necrosis and collapse of nuclei observed. In group HS, plasma protein C levels were suppressed and plasma thrombin-antithrombin complex levels increased. In group TG-Pre, plasma cytokines and HMGB1 concentrations were suppressed after heat exposure compared with group HS. Liver injury, coagulopathy, and mortality also improved in group TG-Pre. Furthermore, recombinant soluble TM treatment decreased mortality even with delayed treatment.


CONCLUSIONS
This study demonstrated that recombinant soluble TM suppressed plasma cytokines and HMGB1 concentrations after heat exposure. Recombinant soluble TM also improved liver injury and coagulopathy. Recombinant soluble TM treatment improved mortality even with delayed treatment. Recombinant soluble TM may be a beneficial treatment for heatstroke patients.
From the Department of Anesthesiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Takashi
T
Kawasaki
Kohji
K
Okamoto
Chika
C
Kawasaki
Takeyoshi
T
Sata
D000818:Animals; D000991:Antithrombins / Q000032:analysis; D001778:Blood Coagulation Disorders / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000378:metabolism; D018883:Heat Stroke / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020556:Neutrophil Infiltration; D009195:Peroxidase / Q000032:analysis; D011486:Protein C / Q000032:analysis; D011994:Recombinant Proteins / Q000627:therapeutic use; D013534:Survival; D013917:Thrombin / Q000032:analysis; D018180:Thrombomodulin / Q000627:therapeutic use*
D000991:Antithrombins; D016207:Cytokines; D024243:HMGB1 Protein; D011486:Protein C; D011994:Recombinant Proteins; D018180:Thrombomodulin; D009195:Peroxidase; D013917:Thrombin