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J Thorac Cardiovasc Surg 2004;127:376-384
© 2004 The American Association for Thoracic Surgery

General thoracic surgery

Endotracheal calcineurin inhibition ameliorates injury in an experimental model of lung ischemia-reperfusion

^a Division of Cardiothoracic Surgery, University of Washington, Seattle, Wash, USA

Read at the Eighty-third Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 4-7, 2003.

Received for publication May 2, 2003; revisions received September 25, 2003; accepted for publication September 30, 2003.

^* Address for reprints: Michael Mulligan, MD, FACS, Box 356310, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
msmmd{at}u.washington.edu

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-B 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-B 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-B 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.

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