Endotracheal calcineurin inhibition ameliorates injury in an experimental model of lung ischemia-reperfusion.
OBJECTIVE
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.
Woolley
Steven M
SM
Division of Cardiothoracic Surgery, University of Washington, Seattle 98195, USA.
Farivar
Alexander S
AS
Naidu
Babu V
BV
Rosengart
Matthew
M
Thomas
Robert
R
Fraga
Charles
C
Mulligan
Michael S
MS
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D019703:Calcineurin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D002452:Cell Count; D019743:Chemokines, CXC / Q000096:biosynthesis; D016207:Cytokines / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D008955:Models, Cardiovascular; D016328:NF-kappa B / Q000187:drug effects; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D016896:Treatment Outcome
D019743:Chemokines, CXC; D016207:Cytokines; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009195:Peroxidase; D019703:Calcineurin; D016559:Tacrolimus