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Ann Thorac Surg 2004;77:1938-1943
© 2004 The Society of Thoracic Surgeons

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Original article: general thoracic

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

^a Department of Surgery, Division of Cardiothoracic Surgery, University of Washington Medical Center, Seattle, Washington, USA
^b Inotek Corp, Beverly, Massachusetts, USA

Accepted for publication October 8, 2003.

^* Address reprint requests to Dr Farivar, Division of Cardiothoracic Surgery, Box 356310, University of Washington Medical Center, Seattle, WA 98195, USA
e-mail: afarivar{at}u.washington.edu

Presented at the Poster Session of the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.

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 NFB 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 NFB 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 NFB and AP-1 activation. This route may optimize future donor organ management and improve lung recipient outcomes.

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				A. S. Farivar, A. S. McCourtie, B. C. MacKinnon-Patterson, S. M. Woolley, A. D. Barnes, M. Chen, P. Jagtap, C. Szabo, C. T. Salerno, and M. S. Mulligan Poly (ADP) Ribose Polymerase Inhibition Improves Rat Cardiac Allograft Survival Ann. Thorac. Surg., September 1, 2005; 80(3): 950 - 956. [Abstract] [Full Text] [PDF]