Role of poly (ADP) ribose synthetase in lung ischemia - Reperfusion injury

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 (125I 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.

Original languageEnglish (US)
Pages (from-to)1290-1296
Number of pages7
JournalJournal of Heart and Lung Transplantation
Volume23
Issue number11
DOIs
StatePublished - Nov 2004
Externally publishedYes

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Poly Adenosine Diphosphate Ribose
Adenosine Diphosphate Ribose
Ligases
Reperfusion Injury
Lung
Capillary Permeability
Bronchoalveolar Lavage
Peroxidase
Leukocytes
Ischemia
Single-Stranded DNA Breaks
Long Evans Rats
Uridine Triphosphate
DNA Nucleotidylexotransferase
Bronchoalveolar Lavage Fluid
Septic Shock
Biotin
Bovine Serum Albumin
Nuclear Proteins
Immunoenzyme Techniques

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Transplantation

Cite this

Woolley, S. M., Farivar, A. S., Naidu, B. V., Salzman, A., Szabo, C., Thomas, R., ... Mulligan, M. S. (2004). Role of poly (ADP) ribose synthetase in lung ischemia - Reperfusion injury. Journal of Heart and Lung Transplantation, 23(11), 1290-1296. https://doi.org/10.1016/j.healun.2003.08.036

Role of poly (ADP) ribose synthetase in lung ischemia - Reperfusion injury. / Woolley, Steven M.; Farivar, Alexander S.; Naidu, Babu V.; Salzman, Andrew; Szabo, Csaba; Thomas, Robert; Fraga, Charles; Mulligan, Michael S.

In: Journal of Heart and Lung Transplantation, Vol. 23, No. 11, 11.2004, p. 1290-1296.

Research output: Contribution to journalArticle

Woolley, SM, Farivar, AS, Naidu, BV, Salzman, A, Szabo, C, Thomas, R, Fraga, C & Mulligan, MS 2004, 'Role of poly (ADP) ribose synthetase in lung ischemia - Reperfusion injury', Journal of Heart and Lung Transplantation, vol. 23, no. 11, pp. 1290-1296. https://doi.org/10.1016/j.healun.2003.08.036
Woolley, Steven M. ; Farivar, Alexander S. ; Naidu, Babu V. ; Salzman, Andrew ; Szabo, Csaba ; Thomas, Robert ; Fraga, Charles ; Mulligan, Michael S. / Role of poly (ADP) ribose synthetase in lung ischemia - Reperfusion injury. In: Journal of Heart and Lung Transplantation. 2004 ; Vol. 23, No. 11. pp. 1290-1296.
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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 (125I 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.",
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AU - Szabo, Csaba

AU - Thomas, Robert

AU - Fraga, Charles

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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 (125I 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.

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