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Role of poly (ADP) ribose synthetase in lung ischemia-reperfusion injury.
J Heart Lung Transplant. 2004 Nov; 23(11):1290-6.JH

Abstract

BACKGROUND

The activation of poly (adenosine diphosphate) ribose synthetase (PARS) is known to be important in the cellular response to oxidative stress. Previous studies have reported that PARS inhibition confers protection in models of endotoxic shock and ischemia-reperfusion. The purpose of this study was to determine the role of PARS inhibition in lung ischemia-reperfusion injury (LIRI).

METHODS

Left lungs of Long-Evans rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received 3 mg/kg of INO-1001 (a PARS inhibitor) intravenously 30 minutes before ischemia. Injury was quantitated in terms of tissue myeloperoxidase (MPO) content, vascular permeability ((125)I radiolabeled bovine serum albumin extravasation) and bronchoalveolar lavage (BAL) leukocyte content. BAL fluid was assessed for cytokine and chemokine content by enzyme-linked immunoassay. Further samples were processed for nuclear protein analysis by electromobility shift assay (EMSA) and cellular death by terminal deoxyribonucleotidyl transferase-mediated d-UTP biotin nick-end labeling (TUNEL) assay and caspase-3 staining.

RESULTS

Lung vascular permeability was reduced in treated animals by 73% compared with positive controls (p < 0.009). The protective effects of PARS inhibition correlated with a 46% reduction in tissue MPO content (p < 0.008) and marked reductions in BAL leukocyte accumulation. This positively correlated with the diminished expression of pro-inflammatory mediators and nuclear transcription factors, as well as decreased levels of cellular death.

CONCLUSIONS

The deleterious effects of LIRI are in part mediated by the formation of free radicals and superoxides, which lead to DNA single-strand breaks. This leads to activation of PARS, which causes rapid cellular energy depletion and cell death. PARS inhibition is protective against this and represents a potentially useful therapeutic tool in the prevention of LIRI.

Authors+Show Affiliations

Woolley SM
Department of Cardiothoracic Surgery, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Farivar AS
No affiliation info available
Naidu BV
No affiliation info available
Salzman A
No affiliation info available
Szabo C
No affiliation info available
Thomas R
No affiliation info available
Fraga C
No affiliation info available
Mulligan MS
No affiliation info available

MeSH

AnimalsIndolesMalePoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesRatsRats, Long-EvansReperfusion Injury

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15539128

Citation

Woolley, Steven M., et al. "Role of Poly (ADP) Ribose Synthetase in Lung Ischemia-reperfusion Injury." The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation, vol. 23, no. 11, 2004, pp. 1290-6.
Woolley SM, Farivar AS, Naidu BV, et al. Role of poly (ADP) ribose synthetase in lung ischemia-reperfusion injury. J Heart Lung Transplant. 2004;23(11):1290-6.
Woolley, S. M., Farivar, A. S., Naidu, B. V., Salzman, A., Szabo, C., Thomas, R., Fraga, C., & Mulligan, M. S. (2004). Role of poly (ADP) ribose synthetase in lung ischemia-reperfusion injury. The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation, 23(11), 1290-6.
Woolley SM, et al. Role of Poly (ADP) Ribose Synthetase in Lung Ischemia-reperfusion Injury. J Heart Lung Transplant. 2004;23(11):1290-6. PubMed PMID: 15539128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of poly (ADP) ribose synthetase in lung ischemia-reperfusion injury. AU - Woolley,Steven M, AU - Farivar,Alexander S, AU - Naidu,Babu V, AU - Salzman,Andrew, AU - Szabo,Csaba, AU - Thomas,Robert, AU - Fraga,Charles, AU - Mulligan,Michael S, PY - 2003/08/06/received PY - 2003/08/22/accepted PY - 2004/11/13/pubmed PY - 2005/7/13/medline PY - 2004/11/13/entrez SP - 1290 EP - 6 JF - The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation JO - J Heart Lung Transplant VL - 23 IS - 11 N2 - BACKGROUND: The activation of poly (adenosine diphosphate) ribose synthetase (PARS) is known to be important in the cellular response to oxidative stress. Previous studies have reported that PARS inhibition confers protection in models of endotoxic shock and ischemia-reperfusion. The purpose of this study was to determine the role of PARS inhibition in lung ischemia-reperfusion injury (LIRI). METHODS: Left lungs of Long-Evans rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received 3 mg/kg of INO-1001 (a PARS inhibitor) intravenously 30 minutes before ischemia. Injury was quantitated in terms of tissue myeloperoxidase (MPO) content, vascular permeability ((125)I radiolabeled bovine serum albumin extravasation) and bronchoalveolar lavage (BAL) leukocyte content. BAL fluid was assessed for cytokine and chemokine content by enzyme-linked immunoassay. Further samples were processed for nuclear protein analysis by electromobility shift assay (EMSA) and cellular death by terminal deoxyribonucleotidyl transferase-mediated d-UTP biotin nick-end labeling (TUNEL) assay and caspase-3 staining. RESULTS: Lung vascular permeability was reduced in treated animals by 73% compared with positive controls (p < 0.009). The protective effects of PARS inhibition correlated with a 46% reduction in tissue MPO content (p < 0.008) and marked reductions in BAL leukocyte accumulation. This positively correlated with the diminished expression of pro-inflammatory mediators and nuclear transcription factors, as well as decreased levels of cellular death. CONCLUSIONS: The deleterious effects of LIRI are in part mediated by the formation of free radicals and superoxides, which lead to DNA single-strand breaks. This leads to activation of PARS, which causes rapid cellular energy depletion and cell death. PARS inhibition is protective against this and represents a potentially useful therapeutic tool in the prevention of LIRI. SN - 1053-2498 UR - https://www.unboundmedicine.com/medline/citation/15539128/Role_of_poly__ADP__ribose_synthetase_in_lung_ischemia_reperfusion_injury_ DB - PRIME DP - Unbound Medicine ER -