Immunosuppression with aerosolized cyclosporine for prevention of lung rejection in a rat model.
The efficacy of local delivery of aerosol cyclosporine (CsA) for prevention of lung rejection was compared with the intramuscular route (IM) in a fully allogeneic rat model (BN/LEW) of lung transplantation (LTx). Control rats (group 1, n = 6) received no CsA after LTx. Rats in group 2 (n = 10) received 4 doses of CsA in olive oil (25 mg/kg) intramuscularly starting on postoperative day (POD) 0. Group 3 (n = 9) was treated with aerosolized CsA for 3 h/day for 7 days starting on POD 0. All animals were sacrificed on POD 6. Transplanted lungs were graded histologically in a blind manner on a 0-4 scale. Control animals all showed grade 4 rejection. i.m. CsA therapy reduced lung rejection with a rejection grade of 1.8 +/- 0.35 (mean +/- SD) but was associated with a 50% incidence of pneumonia. Aerosol CsA provided better control of rejection with a rejection grade of 1.2 +/- 0.4 (group 3 vs. group 2: P less than 0.05 Wilcoxon) and none of these animals had penumonia. Trough blood levels of CsA were significantly lower in the group treated with aerosolized CsA when compared with the IM group (P less than 0.05). Therefore we conclude that: (1) aerosol CsA is effective in preventing lung allograft rejection following lung transplantation in rats, and (2) local delivery of aerosol CsA is superior to the i.m. route because better control of rejection is achieved with a lower systemic delivery of CsA.
Zenati
M
M
Division of Cardiac Surgery, University of Verona, Italy.
Duncan
A J
AJ
Burckart
G J
GJ
Schaper
M
M
Yousem
S A
SA
Griffith
B P
BP
Casarotto
D
D
D000336:Aerosols; D000818:Animals; D003524:Cyclosporins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006084:Graft Rejection / Q000187:drug effects*; D008168:Lung / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology*; D051381:Rats; D011914:Rats, Inbred BN
D000336:Aerosols; D003524:Cyclosporins