Journal article
Obliterative airway disease in rat tracheal allografts requires tumor necrosis factor alpha
Experimental and molecular pathology, Vol.78(3), pp.190-197
2005
DOI: 10.1016/j.yexmp.2004.10.008
PMID: 15924870
Abstract
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.
Details
- Title: Subtitle
- Obliterative airway disease in rat tracheal allografts requires tumor necrosis factor alpha
- Creators
- Alexander S Farivar - University of Washington Medical CenterBrendan Mackinnon-Patterson - University of Washington Medical CenterAnton S McCourtie - University of Washington Medical CenterJane Namkung - University of Washington Medical CenterPeter A Ward - University of Michigan Medical SchoolMichael S Mulligan - University of Washington Medical Center
- Resource Type
- Journal article
- Publication Details
- Experimental and molecular pathology, Vol.78(3), pp.190-197
- DOI
- 10.1016/j.yexmp.2004.10.008
- PMID
- 15924870
- NLM abbreviation
- Exp Mol Pathol
- ISSN
- 0014-4800
- eISSN
- 1096-0945
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 2005
- Academic Unit
- Orthopedics and Rehabilitation
- Record Identifier
- 9984040458702771
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