title: The effect of selective inhibition of cyclooxygenase (COX)-2 on acute cardiac allograft rejection.
abstract: BACKGROUND
  Using a rat (Lewis-Wistar Furth) abdominal heterotopic transplantation model, we reported previously that the expression of cyclooxygenase (COX)-2 is increased in parallel with that of nitric oxide synthase (NOS)-2 during cardiac allograft rejection.
  
  
  METHODS
  To investigate effects of COX-2 inhibition in this model, allograft recipients were treated orally (PO) with 5 mg/kg per day of the tetra substituted furanone selective COX-2 inhibitor 5,5-dimethyl-3-(3 fluorophenyl)-4-(4 methylsulfonal) phenyl-2 (5H)-furanone (DFU) in 1% methyl cellulose solution.
  
  
  RESULTS
  In the treated animals, allograft survival was increased from 6.3+/-0.5 to 12.6+/-2.6 days (P = .001). At days 3 and 5 posttransplantation, there were reductions in the extent of the inflammatory infiltrate, endovasculitis, myocardial edema, and cardiomyocyte damage in rejecting allografts. The mean numbers of apoptotic cardiomyocytes determined with the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) technique were significantly reduced in DFU-treated grafts compared with untreated controls (P < 0.05). At day 3 posttransplantation, prostaglandin E2 synthesis by myocardial slices incubated with 100 microM bradykinin was reduced from 1,097+/-156 to 153+/-63 pg/mg of protein in the treated allografts (P < .005). At day 5, COX-2 protein and mRNA together with COX-2, NOS-2, and nitrotyrosine immunostaining in damaged cardiomyocytes were diminished in treated versus control grafts.
  
  
  CONCLUSIONS
  The data indicate that the inhibition of COX-2 prolongs allograft survival and reduces myocardial damage and inflammation during acute cardiac allograft rejection.
authors.affiliation: Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Ningsheng
authors.initials: N
authors.lastname: Ma
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Szabolcs
authors.forename: Ji
authors.initials: J
authors.lastname: Sun
authors.forename: Arline
authors.initials: A
authors.lastname: Albala
authors.forename: Robert R
authors.initials: RR
authors.lastname: Sciacca
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
authors.forename: Niloo
authors.initials: N
authors.lastname: Edwards
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cannon
mesh_terms: D000208:Acute Disease; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D005663:Furans / Q000627:therapeutic use*; D006084:Graft Rejection / Q000188:drug therapy*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D014184:Transplantation, Homologous; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007527:Isoenzymes; D012333:RNA, Messenger; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases