Adenosine diphosphate receptor antagonist clopidogrel sulfate attenuates LPS-induced systemic inflammation in a rat model.
Septic shock is characterized by systemic inflammation and can lead to hemorrhage and necrosis in multiple organs. Septic shock is one of the leading causes of death. Studies have reported that septic shock is strongly associated with coagulation abnormality. The adenosine diphosphate (ADP) receptor antagonist, clopidogrel sulfate (CS), inhibits platelet function. Thus, we hypothesized that CS could inhibit LPS-induced systemic inflammation in a rat model. Male Wistar rats weighing 250 to 300 g received an LPS injection, followed 6 h later by filtration leukocytapheresis or mock treatment for 30 min under sevoflurane anesthesia. Five days before LPS injection, rats were given an oral dose of water or CS (10 mg/kg body weight). Levels of proinflammatory markers were determined in serum and tissue samples, and high-mobility group box 1 (HMGB1) expression was evaluated in lung and liver tissues. Compared with LPS-treated rats, induction of cytokines (IL-6 and TNF-α) was reduced in rats pretreated with CS. In addition, histological changes observed in lung and liver tissue samples of LPS-treated rats were attenuated in CS-pretreated rats. Clopidogrel sulfate pretreatment also reduced LPS-induced HMGB1 expression in lung and liver tissues. Collectively, our findings demonstrate that CS pretreatment may have value as a new therapeutic tool against systemic inflammation.
Hagiwara
Satoshi
S
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan. saku@med.oita-u.ac.jp
Iwasaka
Hideo
H
Hasegawa
Akira
A
Oyama
Masayoshi
M
Imatomi
Rhyota
R
Uchida
Tomohisa
T
Noguchi
Takayuki
T
D000818:Animals; D015153:Blotting, Western; D000077144:Clopidogrel; D024243:HMGB1 Protein / Q000097:blood / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D024243:HMGB1 Protein; D015850:Interleukin-6; D008070:Lipopolysaccharides; D058921:Purinergic P2Y Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D000077144:Clopidogrel; D013988:Ticlopidine