title: Inhibition of tumor necrosis factor-alpha attenuates myocardial remodeling in rat cardiac allografts.
abstract: BACKGROUND
  Tumor necrosis factor-alpha (TNF-alpha) elicits a wide range of pro-inflammatory activities on target cells and mediates diverse cardiovascular processes ranging from heart failure to atherosclerosis. Recently, we demonstrated that TNF-alpha regulates the platelelet-derived growth factor (PDGF)-A/PDGF-Ralpha activation pathway in rat cardiac allograft arteriosclerosis. The aim of this study was to determine the kinetics and biologic role of TNF-alpha and its receptors, TNF-R1 and TNF-R2, in rat cardiac allografts.
  
  
  METHODS
  Heterotopic heart transplantations were performed from Dark Agouti to Wistar-Furth rats. In the acute rejection model, recipients were given no immunosuppression and grafts were removed 5 days after transplantation. In the chronic rejection model, cyclosporine (CsA) was administered and grafts were removed at 60 days. To investigate the functional role of TNF-alpha in chronic rejection, recipients received recombinant human soluble TNF receptor p80/IgG1 Fc fusion protein (rhu TNF-R2:Fc).
  
  
  RESULTS
  During acute and chronic rejection, an increase in intragraft TNF-alpha and TNF-R2 mRNA expression was recorded, but not TNF-R1 mRNA expression. Prominent induction of TNF-alpha and TNF-R2 immunoreactivity was localized to medial cells of coronary arteries and interstitial inflammatory cells, whereas cardiomyocytes showed moderate immunoreactivity to TNF-alpha and its receptors. Inhibition of the TNF-alpha-mediated pathway by TNF-R2:Fc did not affect the incidence or intensity of arteriosclerotic lesions in rat cardiac allografts; however, it significantly inhibited myocardial remodeling with a concomitant decrease in myocardial TNF-alpha expression but not intragraft PDGF immunoreactivity.
  
  
  CONCLUSIONS
  We conclude that inhibition of TNF-alpha attenuates myocardial remodeling but is not rate-limiting for arteriosclerotic lesion formation.
authors: Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, Helsinki, Finland. roope.sihvola@helsinki.fi
authors: Roope K
authors: RK
authors: Sihvola
authors: Petri K
authors: PK
authors: Koskinen
authors: Ville P
authors: VP
authors: Pulkkinen
authors: Jussi M
authors: JM
authors: Tikkanen
authors: Karl B
authors: KB
authors: Lemström