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Intratracheal poly (ADP) ribose synthetase inhibition ameliorates lung ischemia reperfusion injury.
Ann Thorac Surg. 2004 Jun; 77(6):1938-43.AT

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 pO(2) at 4 hours of reperfusion. Electrophoretic mobility shift assays (EMSA) assessed the nuclear translocation of NFkappaB 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 pO(2) (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 NFkappaB 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 NFkappaB and AP-1 activation. This route may optimize future donor organ management and improve lung recipient outcomes.

Authors+Show Affiliations

Department of Surgery, University of Washington Medical Center, Seattle, Washington 98195, USA. afarivar@u.washington.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15172241

Citation

Farivar, Alexander S., et al. "Intratracheal Poly (ADP) Ribose Synthetase Inhibition Ameliorates Lung Ischemia Reperfusion Injury." The Annals of Thoracic Surgery, vol. 77, no. 6, 2004, pp. 1938-43.
Farivar AS, Woolley SM, Fraga CH, et al. Intratracheal poly (ADP) ribose synthetase inhibition ameliorates lung ischemia reperfusion injury. Ann Thorac Surg. 2004;77(6):1938-43.
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. The Annals of Thoracic Surgery, 77(6), 1938-43.
Farivar AS, et al. Intratracheal Poly (ADP) Ribose Synthetase Inhibition Ameliorates Lung Ischemia Reperfusion Injury. Ann Thorac Surg. 2004;77(6):1938-43. PubMed PMID: 15172241.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intratracheal poly (ADP) ribose synthetase inhibition ameliorates lung ischemia reperfusion injury. AU - Farivar,Alexander S, AU - Woolley,Steven M, AU - Fraga,Charles H, AU - Thomas,Robert, AU - Salzman,Andrew L, AU - Szabo,Csaba, AU - Mulligan,Michael S, PY - 2003/10/08/accepted PY - 2004/6/3/pubmed PY - 2004/6/30/medline PY - 2004/6/3/entrez SP - 1938 EP - 43 JF - The Annals of thoracic surgery JO - Ann Thorac Surg VL - 77 IS - 6 N2 - 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 pO(2) at 4 hours of reperfusion. Electrophoretic mobility shift assays (EMSA) assessed the nuclear translocation of NFkappaB 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 pO(2) (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 NFkappaB 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 NFkappaB and AP-1 activation. This route may optimize future donor organ management and improve lung recipient outcomes. SN - 0003-4975 UR - https://www.unboundmedicine.com/medline/citation/15172241/Intratracheal_poly__ADP__ribose_synthetase_inhibition_ameliorates_lung_ischemia_reperfusion_injury_ DB - PRIME DP - Unbound Medicine ER -