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

Obliterative bronchiolitis is the major complication affecting long-term lung transplant survivors. Tumor necrosis factor-alpha (TNF-α) promotes inflammation and fibrosis in chronic lung injury models. These experiments defined the role of TNF-α 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-α antibodies or a novel TNF-α 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-α mRNA expression by RQRT-PCR or protein localization/expression by immunohistochemistry. EMSAs evaluated NFκB activation. 14-day control allografts averaged 58% occlusion and 98% epithelial loss. These parameters were significantly improved with TNF-α inhibition, averaging 32% luminal obliteration and 37% epithelial preservation. TNF-α mRNA expression increased at 14-days relative to native tracheas, and was unchanged by RDP-58 treatment. However, TNF-α protein expression, localized to the mucosa/submucosa, was markedly reduced with RDP-58, and resulted in diminished global NFκB 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-α promotes the development of OAD in tracheal allografts via an NFκB-dependent mechanism, and its inhibition may prove beneficial clinically.