PMID- 15312830
OWN - NLM
STAT- MEDLINE
DCOM- 20050106
LR  - 20151119
IS  - 1053-2498 (Print)
IS  - 1053-2498 (Linking)
VI  - 23
IP  - 8
DP  - 2004 Aug
TI  - Poly (ADP) ribose synthetase inhibition reduces obliterative airway disease in 
      rat tracheal allografts.
PG  - 993-1002
AB  - BACKGROUND: Obliterative bronchiolitis (OB) is the major long-term complication 
      affecting lung transplant recipients, and is characterized pathologically by 
      chronic inflammatory and fibroproliferative airway disease. Based on studies 
      revealing anti-inflammatory and anti-apoptotic properties of poly (ADP)-ribose 
      synthetase (PARS) inhibitors, we hypothesized that their administration would be 
      protective in a heterotopic model of experimental OB. METHODS: We transplanted 
      rat tracheas from Brown-Norway donors into Lewis recipients, and treated 2 groups 
      with a novel PARS inhibitor, INO-1001. One group received 14 days of treatment, 
      whereas a second received delayed treatment beginning on Day 7 post-transplant. 
      Tracheas were analyzed by light microscopy and computerized morphometry. Effects 
      on cytokine transcription, nuclear transcription factor activation and cellular 
      death were assessed by in situ hybridization for tumor necrosis factor-alpha 
      (TNF-alpha), electromobility shift assays for nuclear factor-kappaB (NF-kappaB) 
      and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) 
      assays, respectively. RESULTS: PARS inhibition significantly decreased luminal 
      obstruction (p < 0.001) and enhanced preservation of epithelial lining (p < 
      0.001) at 14 days post-transplant. Day 7 controls confirmed the development of an 
      obstructive lesion in the lumen, averaging 28% occlusion. Delayed treatment 
      (beginning on Day 7) arrested (p < 0.001) progression of the established lesion. 
      Allograft airways treated with INO-1001 demonstrated attenuated NF-kappaB nuclear 
      translocation, reduced transcription of TNF-alpha mRNA, and decreased cellular 
      death on TUNEL and caspase 3 staining. CONCLUSIONS: PARS inhibition is 
      anti-inflammatory, protects against experimental OB, and is associated with 
      enhanced preservation of respiratory epithelium and decreased cellular death. 
      Delayed treatment with INO-1001 arrests progression of the lesion developed by 
      Day 7. These studies suggest that activation of PARS plays a critical role in the 
      development of airway obliterative disease.
FAU - Farivar, Alexander S
AU  - Farivar AS
AD  - Department of Surgery, Division of Cardiothoracic Surgery, University of 
      Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195, USA. 
      afarivar@u.washington.edu
FAU - Woolley, Steven M
AU  - Woolley SM
FAU - Naidu, Babu V
AU  - Naidu BV
FAU - Fraga, Charles H
AU  - Fraga CH
FAU - Byrne, Karen
AU  - Byrne K
FAU - Thomas, Robert
AU  - Thomas R
FAU - Salzman, Andrew L
AU  - Salzman AL
FAU - Szabo, Csaba S
AU  - Szabo CS
FAU - Mulligan, Michael S
AU  - Mulligan MS
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - J Heart Lung Transplant
JT  - The Journal of heart and lung transplantation : the official publication of the 
      International Society for Heart Transplantation
JID - 9102703
RN  - 0 (INO 1001)
RN  - 0 (Indoles)
RN  - 0 (NF-kappa B)
RN  - 0 (Poly(ADP-ribose) Polymerase Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 3.4.22.- (Casp3 protein, rat)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Animals
MH  - Bronchiolitis Obliterans/*drug therapy/metabolism
MH  - Caspase 3
MH  - Caspases/metabolism
MH  - Electrophoretic Mobility Shift Assay
MH  - In Situ Hybridization
MH  - In Situ Nick-End Labeling
MH  - Indoles/*pharmacology
MH  - Male
MH  - Models, Animal
MH  - NF-kappa B/analysis/metabolism
MH  - *Poly(ADP-ribose) Polymerase Inhibitors
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Postoperative Complications/drug therapy
MH  - RNA, Messenger/genetics/metabolism
MH  - Rats
MH  - Rats, Inbred Lew
MH  - Trachea/*metabolism/pathology/transplantation
MH  - Transplantation, Homologous
MH  - Tumor Necrosis Factor-alpha/genetics
EDAT- 2004/08/18 05:00
MHDA- 2005/01/07 09:00
CRDT- 2004/08/18 05:00
PHST- 2003/05/10 00:00 [received]
PHST- 2003/07/31 00:00 [revised]
PHST- 2003/08/02 00:00 [accepted]
PHST- 2004/08/18 05:00 [pubmed]
PHST- 2005/01/07 09:00 [medline]
PHST- 2004/08/18 05:00 [entrez]
AID - S1053249803004029 [pii]
AID - 10.1016/j.healun.2003.08.009 [doi]
PST - ppublish
SO  - J Heart Lung Transplant. 2004 Aug;23(8):993-1002. doi: 
      10.1016/j.healun.2003.08.009.