title: Effects of human soluble thrombomodulin on experimental glomerulonephritis.
abstract: BACKGROUND
  Coagulation and inflammation are both important processes that contribute to glomerular injury. The present study was performed to evaluate the effects of recombinant human soluble thrombomodulin (RHS-TM) in a lethal model of thrombotic glomerulonephritis and to investigate the possible mechanisms.
  
  
  METHODS
  Thrombotic glomerulonephritis was induced in rats by administration of lipopolysaccharide and rabbit anti-rat glomerular basement membrane antibody. One hour later, RHS-TM or heparin was administered, and the histological findings, renal functions, and coagulation parameters were evaluated. To evaluate the contribution of carboxypeptidase R (CPR) to the results obtained in rats treated with RHS-TM, plasma CPR levels were measured. Then, carboxypeptidase inhibitor (CPI), which prevents the function of CPR, was administered.
  
  
  RESULTS
  Massive glomerular thrombosis and lung hemorrhage developed within five hours of disease induction, and all rats died within 24 hours. RHS-TM (3 mg/kg) prevented the progression of the disease and all rats survived. Heparin (250 U/kg/h) showed similar anti-thrombotic effect, but induced massive hemorrhage in the lungs or stomach. RHS-TM attenuated leukocyte/neutrophil infiltration in the glomerulus but heparin did not, suggesting that RHS-TM has anti-inflammatory properties. CPR levels in plasma were about threefold higher in rats treated with RHS-TM compared to those in rats treated with heparin. Furthermore, the inhibitory effect of RHS-TM on leukocyte/neutrophil infiltration was significantly diminished by injection of CPI.
  
  
  CONCLUSIONS
  RHS-TM effectively attenuates the injuries of thrombotic glomerulonephritis in rats. The results indicate that RHS-TM, in addition to its anti-thrombotic action, may exert its anti-inflammatory properties by converting proCPR to CPR, which then inactivates anaphylatoxins. RHS-TM is a potential novel therapeutic tool for thrombotic glomerular injury and related disorders.
authors.affiliation: Internal Medicine III, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeguchi
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Morita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujita
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kato
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Natori
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.forename: William
authors.initials: W
authors.lastname: Campbell
authors.forename: Noriko
authors.initials: N
authors.lastname: Okada
authors.forename: Hidechika
authors.initials: H
authors.lastname: Okada
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yuzawa
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
mesh_terms: D000706:Anaphylatoxins / Q000378:metabolism; D000818:Animals; D001777:Blood Coagulation; D001806:Blood Urea Nitrogen; D025901:Carboxypeptidase B2 / Q000097:blood; D015936:Complement C5a / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007958:Leukocyte Count; D001121:Lysine Carboxypeptidase / Q000097:blood; D010314:Partial Thromboplastin Time; D010976:Platelet Count; D011517:Prothrombin Time; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000008:administration & dosage*; D013927:Thrombosis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology
chemical_list: D000706:Anaphylatoxins; D018180:Thrombomodulin; D015936:Complement C5a; D005337:Fibrin; D003404:Creatinine; D025901:Carboxypeptidase B2; D001121:Lysine Carboxypeptidase; D013917:Thrombin