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Prepublished online as a Blood First Edition Paper on December 12, 2002; DOI 10.1182/blood-2002-08-2406.
Submitted August 8, 2002
Accepted December 5, 2002
Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production
Akio Mizutani, Kenji Okajima*, Mitsuhiro Uchiba, Hirotaka Isobe, Naoaki Harada, Sachiko Mizutani, and Takayuki Noguchi
Intensive Care Unit, Oita Medical University, Oita, Japan; Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan
Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan
Department of Pharmacology, Fukuoka University School of Medicine, Fukuoka, Japan
Department of Maternal-Pediatric Nursing, Oita Medical University, Oita, Japan
Intensive Care Unit, Oita Medical University, Oita, Japan
* Corresponding author; email: whynot{at}kaiju.medic.kumamoto-u.ac.jp.
Antithrombin (AT) supplementation in patients with severe sepsis has been shown to improve organ failures in which activated leukocytes are critically involved. However, the precise mechanism(s) for the therapeutic effects of AT are not well understood. We examined in rats whether AT reduces ischemia/reperfusion (I/R)-induced renal injury by inhibiting leukocyte activation. AT markedly reduced the I/R-induced renal dysfunction and histological changes, whereas neither dansyl-glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-F.Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Renal tissue levels of 6-keto-PGF1 , a stable metabolite of prostacyclin (PGI2), increased after renal I/R. AT enhanced the I/R-induced increases in renal tissue levels of 6-keto-PGF1, while neither DEGR-F.Xa nor Trp49-modified AT had any effect. AT significantly inhibited I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability. Ischemia/reperfusion-induced increases in renal tissue levels of tumor necrosis factor-, cytokine-induced neutrophil chemoattractant and myeloperoxidase were significantly inhibited in animals given AT. Pretreatment of animals with indomethacin reversed the effects induced by AT. Iloprost, an analog of PGI2, produced effects similar to those induced by AT. These observations strongly suggest that AT reduces the I/R-induced renal injury by inhibiting leukocyte activation. The therapeutic effects of AT might be mainly mediated by PGI2 released from endothelial cells through interaction of AT with cell-surface glycosaminoglycans.
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