Obliterative airway disease in rat tracheal allografts requires tumor necrosis factor alpha

Exp Mol Pathol. 2005 Jun;78(3):190-7. doi: 10.1016/j.yexmp.2004.10.008. Epub 2005 Feb 19.


Obliterative bronchiolitis is the major complication affecting long-term lung transplant survivors. Tumor necrosis factor-alpha (TNF-alpha) promotes inflammation and fibrosis in chronic lung injury models. These experiments defined the role of TNF-alpha in an established model of obliterative airway disease (OAD). Rat tracheas were transplanted from Brown-Norway donors into Lewis recipients, and explanted on days 7 and 14. Treated groups received either anti-TNF-alpha antibodies or a novel TNF-alpha translational inhibitor, RDP-58, beginning either immediately or on post-transplant day 7. Morphometry assessed epithelial loss and luminal obliteration, while separate tracheas were processed for TNF-alpha mRNA expression by RQRT-PCR or protein localization/expression by immunohistochemistry. EMSAs evaluated NFkappaB activation. 14-day control allografts averaged 58% occlusion and 98% epithelial loss. These parameters were significantly improved with TNF-alpha inhibition, averaging 32% luminal obliteration and 37% epithelial preservation. TNF-alpha mRNA expression increased at 14-days relative to native tracheas, and was unchanged by RDP-58 treatment. However, TNF-alpha protein expression, localized to the mucosa/submucosa, was markedly reduced with RDP-58, and resulted in diminished global NFkappaB activation in allografts. Delayed RDP treatment reduced disease progression during the second week, as luminal occlusion increased from 26% to only 35%, while respiratory epithelium persisted at 21%. TNF-alpha promotes the development of OAD in tracheal allografts via an NFkappaB-dependent mechanism, and its inhibition may prove beneficial clinically.

MeSH terms

  • Animals
  • Bronchiolitis Obliterans / etiology*
  • Bronchiolitis Obliterans / metabolism
  • Disease Models, Animal
  • Electrophoretic Mobility Shift Assay
  • Immunohistochemistry
  • Lung Transplantation / adverse effects*
  • Male
  • NF-kappa B / metabolism
  • RNA, Messenger / analysis
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trachea / pathology*
  • Trachea / transplantation*
  • Transplantation, Homologous
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*


  • NF-kappa B
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha