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-κB 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-κB 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-κB 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.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine