High-dose antithrombin III prevents heat stroke by attenuating systemic inflammation in rats.
OBJECTIVE
Systemic inflammatory mediators, including the high mobility group box 1 (HMGB1) protein, play important roles in the development of various inflammatory conditions. Although anticoagulants, such as antithrombin III (AT III), inhibit inflammation resulting from various causes, their anti-inflammatory mechanism of action is not well understood. Nevertheless, as heat stroke is a severe inflammatory response disease, we hypothesized that AT III would inhibit inflammation and prevent heat stress-induced acute heat stroke.


METHODS
Male Wistar rats received a bolus injection of saline or 250 U of AT III per kg of body weight into the tail vein, followed by heat stress (exposure to 42 degrees C for 30 min). Levels of cytokines (interleukin-1 beta, interleukin-6, and TNF-alpha), NOx, and HMGB1 were measured in serum and tissue at regular intervals for 6 h after the heat stress induction.


RESULTS
Levels of cytokines, NOx, and HMGB1 in serum decreased over time in AT III-treated rats. AT III pretreatment also reduced NOx levels during heat stress-induced inflammation. As a result, AT III pretreatment improved survival in a rat model of heat stress-induced acute inflammation.


CONCLUSIONS
Our data suggest that AT III pretreatment inhibited the secretion of cytokines, NOx, and HMGB1, and prevented heat stress-induced acute inflammation.
Hagiwara
Satoshi
S
Department of Anesthesiology and Intensive Care Medicine, Oita University, Yufu City, Japan. saku@med.oita-u.ac.jp
Iwasaka
Hideo
H
Shingu
Chihiro
C
Matsumoto
Shigekiyo
S
Uchida
Tomohisa
T
Noguchi
Takayuki
T
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D000990:Antithrombin III / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D024243:HMGB1 Protein / Q000097:blood; D018883:Heat Stroke / Q000097:blood / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D007249:Inflammation / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000097:blood; D009573:Nitrites / Q000097:blood; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000925:Anticoagulants; D016207:Cytokines; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000990:Antithrombin III