Decreased lung ischemia-reperfusion injury in rats after preoperative administration of cyclosporine and tacrolimus.
OBJECTIVE
Calcineurin inhibitors reduce experimental reperfusion injury in the liver, brain, heart, kidney, and small bowel. These studies were undertaken to determine whether these agents are similarly protective against lung ischemia-reperfusion injury.


METHODS
Left lungs of male rats were rendered ischemic for 90 minutes and reperfused for as long as 4 hours. Treated animals received cyclosporine A (INN: ciclosporin; 1 or 5 mg/kg) or tacrolimus (0.2 mg/kg) 6 hours before ischemia, at reperfusion, or 2 hours after reperfusion. Injury was quantitated in terms of tissue polymorphonuclear leukocyte accumulation (myeloperoxidase content), vascular permeability (iodine 125-labeled bovine serum albumin extravasation), and bronchoalveolar lavage leukocyte content. Separate tissue samples were processed for nuclear protein and cytokine messenger RNA.


RESULTS
Treatment with cyclosporine (5 mg/kg) or tacrolimus (0.2 mg/kg) 6 hours before reperfusion reduced lung vascular permeability by 54% and 56% relative to control animals (P <.03). The protective effects of cyclosporine and tacrolimus treatment before reperfusion correlated with 42% and 43% reductions in tissue polymorphonuclear leukocyte (myeloperoxidase) content (P <.008) and marked reductions in bronchoalveolar lavage leukocyte accumulation (P <.01). Administration of cyclosporine or tacrolimus at the time of reperfusion or 2 hours into the reperfusion period offered little or no protection. Animals treated before reperfusion also demonstrated marked reductions in nuclear factor kappaB activation and expression of proinflammatory cytokine messenger RNA.


CONCLUSIONS
Cyclosporine and tacrolimus treatment before reperfusion was protective against lung ischemia-reperfusion injury in rats. The mechanism of these protective effects may involve the inhibition of nuclear factor kappaB, a central transcription factor mediating inflammatory injury. The decreased expression of cytokine messenger RNA indicates that both cyclosporine and tacrolimus may exert their protective effects at the pretranscriptional level.
Krishnadasan
B
B
Division of Cardiothoracic Surgery, University of Washington, Seattle 98195, USA.
Naidu
B
B
Rosengart
M
M
Farr
A L
AL
Barnes
A
A
Verrier
E D
ED
Mulligan
M S
MS
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007962:Leukocytes / Q000187:drug effects; D008168:Lung / Q000098:blood supply*; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis / Q000187:drug effects; D009195:Peroxidase / Q000187:drug effects; D011300:Preoperative Care; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000517:prevention & control*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome
D016207:Cytokines; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D012333:RNA, Messenger; D016572:Cyclosporine; D009195:Peroxidase; D016559:Tacrolimus