Intratracheal poly (ADP) ribose synthetase inhibition ameliorates lung ischemia reperfusion injury

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

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    Abstract

    Background We previously demonstrated that intravenous poly (ADP) ribose synthetase (PARS) inhibition protects against experimental lung ischemia reperfusion injury (LIRI) in an in situ, hilar occlusion model. This study determined its efficacy when administered intratracheally (IT). Methods Left lungs of rats were rendered ischemic for 90 minutes, and reperfused for up to 4 hours. Treated animals received INO-1001, a PARS inhibitor, intratracheally 30 minutes before ischemia, while controls were given IT vehicle at equivalent volumes. All groups contained at least 4 animals. Lung injury was quantitated utilizing vascular permeability to radiolabeled albumin, tissue myeloperoxidase (MPO) content, alveolar leukocyte cell counts, and arterial pO2 at 4 hours of reperfusion. Electrophoretic mobility shift assays (EMSA) assessed the nuclear translocation of NFκB and AP-1 in injured left lungs, while ELISAs quantitated secreted cytokine induced neutrophil chemoattractant (CINC) and MCP-1 protein in bronchoalveolar lavage fluid. Results Intratracheal PARS inhibition was 73% (p < 0.0001) and 87% (p < 0.0001) protective against increases in vascular permeability and alveolar leukocyte accumulation, respectively, and improved arterial pO2 (p < 0.0004) at 4 hours of reperfusion. Myeloperoxidase (MPO) activity in treated lungs was reduced by 70% (p < 0.02). The nuclear translocation of NFκB and AP-1 was attenuated at 15 minutes of reperfusion, and the secretion of CINC and MCP-1 (p < 0.05) protein into the alveolus was diminished at 4 hours of reperfusion. Conclusions Intratracheal INO-1001 protects against experimental LIRI. The reduction in secreted chemokine protein at 4 hours of reperfusion appears to be mediated at the pretranscriptional level through attenuated NFκB and AP-1 activation. This route may optimize future donor organ management and improve lung recipient outcomes.

    Original languageEnglish (US)
    Pages (from-to)1938-1943
    Number of pages6
    JournalAnnals of Thoracic Surgery
    Volume77
    Issue number6
    DOIs
    StatePublished - Jun 1 2004

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    Keywords

    • 12

    ASJC Scopus subject areas

    • Surgery
    • Pulmonary and Respiratory Medicine
    • Cardiology and Cardiovascular Medicine

    Cite this

    Farivar, A. S., Woolley, S. M., Fraga, C. H., Thomas, R., Salzman, A. L., Szabo, C., & Mulligan, M. S. (2004). Intratracheal poly (ADP) ribose synthetase inhibition ameliorates lung ischemia reperfusion injury. Annals of Thoracic Surgery, 77(6), 1938-1943. https://doi.org/10.1016/j.athoracsur.2003.10.120