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

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-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.

Keywords: 12