Poly (ADP) ribose synthetase inhibition reduces obliterative airway disease in rat tracheal allografts

Alexander S. Farivar, Steven M. Woolley, Babu V. Naidu, Charles H. Fraga, Karen Byrne, Robert Thomas, Andrew L. Salzman, Csaba Szabo, Michael S. Mulligan

Research output: Contribution to journalArticle

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Abstract

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-α), electromobility shift assays for nuclear factor-kappaB (NF-κB) 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-κB nuclear translocation, reduced transcription of TNF-α 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.

Original languageEnglish (US)
Pages (from-to)993-1002
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume23
Issue number8
DOIs
StatePublished - Aug 2004
Externally publishedYes

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Poly Adenosine Diphosphate Ribose
Ligases
Allografts
Bronchiolitis
Trachea
Anti-Inflammatory Agents
Tumor Necrosis Factor-alpha
Transplants
Respiratory Mucosa
DNA Nucleotidylexotransferase
Norway
Transferases
Caspase 3
Transcriptional Activation
In Situ Hybridization
Microscopy
Transcription Factors
Theoretical Models
Therapeutics
Tissue Donors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Transplantation

Cite this

Farivar, A. S., Woolley, S. M., Naidu, B. V., Fraga, C. H., Byrne, K., Thomas, R., ... Mulligan, M. S. (2004). Poly (ADP) ribose synthetase inhibition reduces obliterative airway disease in rat tracheal allografts. Journal of Heart and Lung Transplantation, 23(8), 993-1002. https://doi.org/10.1016/j.healun.2003.08.009

Poly (ADP) ribose synthetase inhibition reduces obliterative airway disease in rat tracheal allografts. / Farivar, Alexander S.; Woolley, Steven M.; Naidu, Babu V.; Fraga, Charles H.; Byrne, Karen; Thomas, Robert; Salzman, Andrew L.; Szabo, Csaba; Mulligan, Michael S.

In: Journal of Heart and Lung Transplantation, Vol. 23, No. 8, 08.2004, p. 993-1002.

Research output: Contribution to journalArticle

Farivar, AS, Woolley, SM, Naidu, BV, Fraga, CH, Byrne, K, Thomas, R, Salzman, AL, Szabo, C & Mulligan, MS 2004, 'Poly (ADP) ribose synthetase inhibition reduces obliterative airway disease in rat tracheal allografts', Journal of Heart and Lung Transplantation, vol. 23, no. 8, pp. 993-1002. https://doi.org/10.1016/j.healun.2003.08.009
Farivar, Alexander S. ; Woolley, Steven M. ; Naidu, Babu V. ; Fraga, Charles H. ; Byrne, Karen ; Thomas, Robert ; Salzman, Andrew L. ; Szabo, Csaba ; Mulligan, Michael S. / Poly (ADP) ribose synthetase inhibition reduces obliterative airway disease in rat tracheal allografts. In: Journal of Heart and Lung Transplantation. 2004 ; Vol. 23, No. 8. pp. 993-1002.
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abstract = "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-α), electromobility shift assays for nuclear factor-kappaB (NF-κB) 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-κB nuclear translocation, reduced transcription of TNF-α 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.",
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T1 - Poly (ADP) ribose synthetase inhibition reduces obliterative airway disease in rat tracheal allografts

AU - Farivar, Alexander S.

AU - Woolley, Steven M.

AU - Naidu, Babu V.

AU - Fraga, Charles H.

AU - Byrne, Karen

AU - Thomas, Robert

AU - Salzman, Andrew L.

AU - Szabo, Csaba

AU - Mulligan, Michael S.

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N2 - 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-α), electromobility shift assays for nuclear factor-kappaB (NF-κB) 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-κB nuclear translocation, reduced transcription of TNF-α 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.

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-α), electromobility shift assays for nuclear factor-kappaB (NF-κB) 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-κB nuclear translocation, reduced transcription of TNF-α 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.

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