HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Steven M. Woolley Babu V. Naidu Michael S. Mulligan Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Woolley, S. M. Articles by Mulligan, M. S. Search for Related Content PubMed PubMed Citation Articles by Woolley, S. M. Articles by Mulligan, M. S. Related Collections Lung - transplantation

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.