PMID- 15924870
OWN - NLM
STAT- MEDLINE
DCOM- 20050714
LR  - 20050531
IS  - 0014-4800 (Print)
IS  - 0014-4800 (Linking)
VI  - 78
IP  - 3
DP  - 2005 Jun
TI  - Obliterative airway disease in rat tracheal allografts requires tumor necrosis 
      factor alpha.
PG  - 190-7
AB  - 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.
FAU - Farivar, Alexander S
AU  - Farivar AS
AD  - Department of Surgery, Division of Cardiothoracic Surgery, University of 
      Washington Medical Center, 1959 NE Pacific Street, Box 356310, Seattle, WA 98195, 
      USA.
FAU - Mackinnon-Patterson, Brendan
AU  - Mackinnon-Patterson B
FAU - McCourtie, Anton S
AU  - McCourtie AS
FAU - Namkung, Jane
AU  - Namkung J
FAU - Ward, Peter A
AU  - Ward PA
FAU - Mulligan, Michael S
AU  - Mulligan MS
LA  - eng
PT  - Journal Article
DEP - 20050219
PL  - Netherlands
TA  - Exp Mol Pathol
JT  - Experimental and molecular pathology
JID - 0370711
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Bronchiolitis Obliterans/*etiology/metabolism
MH  - Disease Models, Animal
MH  - Electrophoretic Mobility Shift Assay
MH  - Immunohistochemistry
MH  - Lung Transplantation/*adverse effects
MH  - Male
MH  - NF-kappa B/metabolism
MH  - RNA, Messenger/analysis
MH  - Rats
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Trachea/*pathology/*transplantation
MH  - Transplantation, Homologous
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors/*metabolism
EDAT- 2005/06/01 09:00
MHDA- 2005/07/15 09:00
CRDT- 2005/06/01 09:00
PHST- 2004/10/08 00:00 [received]
PHST- 2004/10/18 00:00 [accepted]
PHST- 2005/06/01 09:00 [pubmed]
PHST- 2005/07/15 09:00 [medline]
PHST- 2005/06/01 09:00 [entrez]
AID - S0014-4800(04)00111-X [pii]
AID - 10.1016/j.yexmp.2004.10.008 [doi]
PST - ppublish
SO  - Exp Mol Pathol. 2005 Jun;78(3):190-7. doi: 10.1016/j.yexmp.2004.10.008. Epub 2005 
      Feb 19.