title: Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production.
abstract: 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 is 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 histologic 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-PGF(1 alpha), a stable metabolite of prostacyclin (PGI(2)), increased after renal I/R. AT enhanced the I/R-induced increases in renal tissue levels of 6-keto-PGF(1 alpha), whereas 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-alpha, 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 PGI(2), 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 PGI(2) released from endothelial cells through interaction of AT with cell surface glycosaminoglycans.
authors.affiliation: Intensive Care Unit, Oita Medical University, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Mizutani
authors.forename: Kenji
authors.initials: K
authors.lastname: Okajima
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Uchiba
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Isobe
authors.forename: Naoaki
authors.initials: N
authors.lastname: Harada
authors.forename: Sachiko
authors.initials: S
authors.lastname: Mizutani
authors.forename: Takayuki
authors.initials: T
authors.lastname: Noguchi
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis* / Q000235:genetics; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D000990:Antithrombin III / Q000494:pharmacology / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis* / Q000235:genetics; D015951:Factor Xa / Q000494:pharmacology; D016285:Iloprost / Q000494:pharmacology / Q000627:therapeutic use; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use; D007511:Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D009195:Peroxidase / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; C097736:dansyl-glutamyl-glycyl-arginyl chloromethyl ketone-treated factor Xa; D015121:6-Ketoprostaglandin F1 alpha; D000990:Antithrombin III; D011464:Epoprostenol; D009195:Peroxidase; D015951:Factor Xa; D016285:Iloprost; D007213:Indomethacin