Tacrolimus Prevents Mechanical and Humoral Alterations in Brain Death–induced Lung Injury in Pigs

Abstract

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 Á kg 21 twice daily the day before the experiment and intravenously at 0.05 mg Á kg 21 1 h 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 score (LIS).Measurements and Main Results: Tacrolimus pretreatment prevented increases in pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary capillary pressure and decreases in systemic arterial pressure and thermodilution cardiac output associated with brain death. After brain death, the ratio of Pa O 2 to FI O 2 decreased, which was prevented by tacrolimus. Tacrolimus pretreatment prevented increases in the ratio of IL-6 to IL-10, VCAM1 (vascular cell adhesion molecule 1), circulating concentrations of IL-1b, and glycocalyx-derived molecules. Tacrolimus partially decreased apoptosis (Bax [Bcl2associated X apoptosis regulator]-to-Bcl2 [B-cell lymphoma-2] ratio [P = 0.07] and 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.

Calcineurin Inhibitors in Lung Donors to Attenuate Ischemia–Reperfusion Injury in Recipients: Next Steps?

“…The present work by Belhaj and colleagues ( 12 ) found that tacrolimus pretreatment attenuated adverse physiologic, inflammatory, and histologic effects of brain death on the lung. This study builds on earlier evidence from animal models that CNIs may reduce the risk of IR injury in neurologically deceased donors and improve graft function ( 10 , 11 , 14 ).…”

“…In this issue of the Journal , Belhaj and colleagues (pp. 584–595 ) evaluated the effects of CNI (tacrolimus) preconditioning in a randomized experimental pig model of brain death–induced lung injury ( 12 ). The investigators administered intravenous tacrolimus ( n = 8) or placebo ( n = 9) before inducing brain death through the infusion of autologous blood.…”

“…This would not translate to the usual clinical scenario of organ donation, where the timing of this neurologic event is unpredictable, and, more importantly, clinicians in most jurisdictions wait until after brain death to initiate specific organ donor management. As Belhaj and colleagues ( 12 ) highlight in their conclusions, however, CNIs should be tested shortly after brain death (alone or in combination with other pharmacological strategies) to further elucidate the pathophysiological effects on the donor lungs. The present study focused on pathogenic effects within 7 hours of brain death, and longer follow-up of the pulmonary and systemic effects are now of interest, including future study designs to monitor effects after graft implementation.…”

Calcineurin Inhibition in Deceased Organ Donors: A Systematic Review and Meta-analysis of Preclinical Studies

“…In a preclinical study of 18 neurologically deceased pigs, tacrolimus (2.5 mg/kg BID) compared with placebo reduced donor pulmonary artery pressure and pulmonary vascular resistance, thus reducing donor pulmonary edema. 53 The translation of our findings to clinical care should proceed carefully. The absence of comorbidities (eg, hypertension, diabetes, hypercholesterolemia) and the predominance of males in animal models of ischemic preconditioning has been suggested as a possible explanation for translational failure in human studies.…”

“…In a preclinical study of 18 neurologically deceased pigs, tacrolimus (2.5 mg/kg BID) compared with placebo reduced donor pulmonary artery pressure and pulmonary vascular resistance, thus reducing donor pulmonary edema. 53 …”