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-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.
Farivar
Alexander S
AS
Department of Surgery, Division of Cardiothoracic Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Box 356310, Seattle, WA 98195, USA.
Mackinnon-Patterson
Brendan
B
McCourtie
Anton S
AS
Namkung
Jane
J
Ward
Peter A
PA
Mulligan
Michael S
MS
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D007150:Immunohistochemistry; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014132:Trachea / Q000473:pathology* / Q000637:transplantation*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha