LAUSR

RATIONALE Donor brain death-induced lung injury may compromise graft function after transplantation. Establishing strategies to attenuate lung damage remains a challenge because the underlying mechanisms remain uncertain. OBJECTIVES The effects of tacrolimus pretreatment were evaluated in an experimental model of brain death-induced lung injury. METHODS Brain death was induced by slow intracranial infusion of blood in anesthetized pigs after randomization to tacrolimus (orally administered at 0.25 mg. kg-1 BID the day before the experiment and intravenously at 0.05 mg. kg-1 one hour before the experiment; n=8) or placebo (n=9) pretreatment. Hemodynamic measurements were performed 1, 3, 5 and 7 hours after brain death. After euthanasia of the animals, lung tissue was sampled for pathobiological and histological analysis, including lung injury scoring (LIS). MEASUREMENTS AND MAIN RESULTS Tacrolimus pretreatment prevented increases in pulmonary artery pressure, pulmonary vascular resistance and pulmonary capillary pressure and decreases in systemic artery pressure and thermodilution cardiac output associated with brain death. After brain death, the ratio of the partial arterial O2 pressure to the inspired O2 fraction (PaO2/FiO2) decreased, which was prevented by tacrolimus. Tacrolimus pretreatment prevented increases in the interleukin (IL)-6-to-IL-10 ratio, vascular cell adhesion molecule-1, circulating levels of IL-1β, IL-6-to-IL-10 ratio and glycocalyx-derived molecules. Tacrolimus partially decreased apoptosis [Bax-to-Bcl2 ratio (p=0.07) and the number of apoptotic cells in the lungs (p<0.05)] but failed to improve LIS. CONCLUSIONS Immunomodulation through tacrolimus pretreatment prevented pulmonary capillary hypertension as well as the activation of inflammatory and apoptotic processes in the lungs after brain death; however, LIS did not improve.