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Eur J Cardiothorac Surg 2003;24:196-200
© 2003 Elsevier Science NL

Strong additive effect of 1,25-dihydroxycholecalciferol and cyclosporine A but not tacrolimus in rat lung allotransplantation

^a Division of General Thoracic Surgery, University Hospital Berne, CH-3010 Berne, Switzerland
^b Department of Pathology, University Hospital, Berne, Switzerland
^c Division of Thoracic Surgery, Regional Hospital, Szczecin-Zdunowo, Poland

Received 27 September 2002; received in revised form 9 April 2003; accepted 26 April 2003.

^* Corresponding author. Tel.: +41-31-632-2330; fax: +41-31-632-2327
e-mail: ralph.schmid{at}insel.ch

Objectives: 1,25-Dihydroxycholecalciferol (calcitriol, vitamin D3) has immunosuppressive properties. This study evaluates the effect of calcitriol in combination with either cyclosporine A or tacrolimus on acute lung allograft rejection in a rat model of unilateral left lung allotransplantation. Methods: Unilateral left lung transplantation was performed in male rats (Brown–Norway to Fischer F344, 200–250 g body weight). For immunosuppression, the following subtherapeutic doses were used: calcitriol 0.5 µg/kg/day, cyclosporine A 2.5 mg/kg/day i.p., and tacrolimus 40 µg/kg i.m. Five groups (n=5) were analyzed: cyclosporine A; cyclosporine A and calcitriol; calcitriol; tacrolimus and calcitriol; and tacrolimus. The injections were performed for 5 days starting from the day of transplantation. Recipients were sacrificed on day 5 post-transplant. The contralateral right main bronchus and pulmonary artery were occluded for 5 min and blood was drawn for blood gas analysis. The grafts were excised, fixed in formaline and embedded in paraffin. Histological evaluation was done in blinded fashion (ISHLT 1999/rank scale). The mean and standard error of the mean (PaO₂) or the median and range (rejection grading) are given. ANOVA followed by planned comparison for the PaO₂ and Kruskal–Wallis ANOVA for rejection grading were applied, p<0.05 considered significant. Results: Arterial PaO₂ on day 5 was very low in animals treated with subtherapeutic dosages of either cyclosporine A (48±10 mmHg), calcitriol (51±3) or tacrolimus (86±22). Combined treatment with cyclosporine A and calcitriol revealed a significant improvement (248±78; p<0.05 vs. other groups), whereas the combination of tacrolimus with calcitriol did not reveal any benefit (65±9). Rejection grading with these subtherapeutic doses did not show any significant difference between groups. Conclusions: Our data indicate that cyclosporine A, but not tacrolimus, has a strong additive effect with calcitriol on acute rat lung allograft rejection.

Key Words: Lung transplantation • Immunosuppression • Vitamin D3 • Cyclosporine A