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Endotracheal calcineurin inhibition ameliorates injury in an experimental model of lung ischemia-reperfusion.
J Thorac Cardiovasc Surg. 2004 Feb; 127(2):376-84.JT

Abstract

OBJECTIVES

We previously demonstrated that calcineurin inhibitors given intravenously ameliorate experimental lung ischemia-reperfusion injury. This study evaluates whether these effects can be achieved when these agents are delivered endotracheally.

METHODS

Left lungs of Long Evans rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received tacrolimus endotracheally at doses of 0.2, 0.1, or 0.025 mg/kg 60 minutes before ischemia. Injury was quantitated in terms of vascular permeability. Additional animals treated at a dose of 0.1 mg/kg were assessed for lung tissue myeloperoxidase content and bronchoalveolar lavage leukocyte content. Bronchoalveolar lavage fluid was assessed for cytokine and chemokine content by enzyme-linked immunosorbent assay. Tissue samples were processed for nuclear factor-kappaB activation, and blood levels of tacrolimus were measured in treated animals.

RESULTS

Left lung vascular permeability was reduced in treated animals in a dose-dependent fashion compared with controls. The protective effects correlated with a 47% (0.50% +/- 0.06% vs 0.27% +/- 0.08%, respectively) reduction in tissue myeloperoxidase content (P <.004) and marked reductions in bronchoalveolar lavage leukocyte accumulation. This protection was also associated with decreased nuclear factor-kappaB activation and diminished expression of proinflammatory mediators. Blood tacrolimus levels in treated animals at 4 hours of reperfusion were undetectable.

CONCLUSIONS

Tacrolimus administered endotracheally is protective against lung ischemia-reperfusion injury in our model. This protection is associated with a decrease in nuclear factor-kappaB activation. This route of tacrolimus administration broadens its potential clinical use and decreases concerns about systemic and renal toxicity. It may be a useful therapy in lung donors to protect against lung ischemia-reperfusion injury.

Authors+Show Affiliations

Division of Cardiothoracic Surgery, University of Washington, Seattle 98195, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Evaluation Study
Journal Article

Language

eng

PubMed ID

14762344

Citation

Woolley, Steven M., et al. "Endotracheal Calcineurin Inhibition Ameliorates Injury in an Experimental Model of Lung Ischemia-reperfusion." The Journal of Thoracic and Cardiovascular Surgery, vol. 127, no. 2, 2004, pp. 376-84.
Woolley SM, Farivar AS, Naidu BV, et al. Endotracheal calcineurin inhibition ameliorates injury in an experimental model of lung ischemia-reperfusion. J Thorac Cardiovasc Surg. 2004;127(2):376-84.
Woolley, S. M., Farivar, A. S., Naidu, B. V., Rosengart, M., Thomas, R., Fraga, C., & Mulligan, M. S. (2004). Endotracheal calcineurin inhibition ameliorates injury in an experimental model of lung ischemia-reperfusion. The Journal of Thoracic and Cardiovascular Surgery, 127(2), 376-84.
Woolley SM, et al. Endotracheal Calcineurin Inhibition Ameliorates Injury in an Experimental Model of Lung Ischemia-reperfusion. J Thorac Cardiovasc Surg. 2004;127(2):376-84. PubMed PMID: 14762344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endotracheal calcineurin inhibition ameliorates injury in an experimental model of lung ischemia-reperfusion. AU - Woolley,Steven M, AU - Farivar,Alexander S, AU - Naidu,Babu V, AU - Rosengart,Matthew, AU - Thomas,Robert, AU - Fraga,Charles, AU - Mulligan,Michael S, PY - 2004/2/6/pubmed PY - 2004/5/27/medline PY - 2004/2/6/entrez SP - 376 EP - 84 JF - The Journal of thoracic and cardiovascular surgery JO - J Thorac Cardiovasc Surg VL - 127 IS - 2 N2 - OBJECTIVES: We previously demonstrated that calcineurin inhibitors given intravenously ameliorate experimental lung ischemia-reperfusion injury. This study evaluates whether these effects can be achieved when these agents are delivered endotracheally. METHODS: Left lungs of Long Evans rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received tacrolimus endotracheally at doses of 0.2, 0.1, or 0.025 mg/kg 60 minutes before ischemia. Injury was quantitated in terms of vascular permeability. Additional animals treated at a dose of 0.1 mg/kg were assessed for lung tissue myeloperoxidase content and bronchoalveolar lavage leukocyte content. Bronchoalveolar lavage fluid was assessed for cytokine and chemokine content by enzyme-linked immunosorbent assay. Tissue samples were processed for nuclear factor-kappaB activation, and blood levels of tacrolimus were measured in treated animals. RESULTS: Left lung vascular permeability was reduced in treated animals in a dose-dependent fashion compared with controls. The protective effects correlated with a 47% (0.50% +/- 0.06% vs 0.27% +/- 0.08%, respectively) reduction in tissue myeloperoxidase content (P <.004) and marked reductions in bronchoalveolar lavage leukocyte accumulation. This protection was also associated with decreased nuclear factor-kappaB activation and diminished expression of proinflammatory mediators. Blood tacrolimus levels in treated animals at 4 hours of reperfusion were undetectable. CONCLUSIONS: Tacrolimus administered endotracheally is protective against lung ischemia-reperfusion injury in our model. This protection is associated with a decrease in nuclear factor-kappaB activation. This route of tacrolimus administration broadens its potential clinical use and decreases concerns about systemic and renal toxicity. It may be a useful therapy in lung donors to protect against lung ischemia-reperfusion injury. SN - 0022-5223 UR - https://www.unboundmedicine.com/medline/citation/14762344/Endotracheal_calcineurin_inhibition_ameliorates_injury_in_an_experimental_model_of_lung_ischemia_reperfusion_ DB - PRIME DP - Unbound Medicine ER -