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

Farivar AS, Mackinnon-Patterson B, McCourtie AS, Namkung J, Ward PA, Mulligan MS

Department of Surgery, Division of Cardiothoracic Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Box 356310, Seattle, WA 98195, USA.

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.

Published 31 May 2005 in Exp Mol Pathol, 78(3): 190-7.
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