Effects of 3,3',5-triiodothyronine supplementation during ex vivo lung perfusion on ischemia/reperfusion injury in rat lungs.

BACKGROUND

Ischemia/reperfusion injury (IRI) still represents a major determinant of both early and late complications of lung transplantation. Increasing evidence indicates that ischemia-induced molecular damage and energetic impairment are established before ex vivo lung perfusion (EVLP) and continue to progress over perfusion. Thyroid hormones support mitochondrial metabolism and cellular energetics and show multiple protective effects in different models of lung injury. We investigated, for the first time, the potential effects of 3,3',5-triiodothyronine (T3) supplementation during experimental EVLP.

METHODS

An established rat model of EVLP was used. After procurement, lungs were either immediately perfused for 3 h (n = 10) or exposed to 2 h of ischemia (1 h-warm + 1 h-cold), followed by 3 h of EVLP (n = 10). In each condition, T3 (EVLP + T3 and Ischemia + EVLP + T3, n = 5 each) or an equal volume of saline (EVLP and Ischemia + EVLP, n = 5 each) were directly added to the perfusion fluid. Lung hemodynamics and airway pressure were monitored throughout the procedure. Perfusate samples were collected at time intervals to assess gas pressures, electrolyte balance, biomarkers of cell damage, and mitochondrial DNA (mtDNA) release. Biopsies were taken at the end of EVLP for cellular energetics evaluation and selected gene expression profiling. Samples collected from rats in resting conditions were used as reference (Native, n = 5).

RESULTS

T3 supplementation was associated with reduced pulmonary artery pressure and vascular resistance in uninjured lungs, while ischemic lungs showed improved CO₂ clearance. However, at the molecular level, T3-treated lungs showed no significant advantage compared to the corresponding control groups. Indeed, T3 administration was associated with an increased mtDNA release into the perfusate and induction of pro-apoptotic signaling. Moreover, T3 failed to restore the ATP depletion induced by ischemia and did not improve cell energy charge. Gene expression analysis showed only modest transcriptional modulation of stress and inflammatory pathways, without evidence of a protective molecular signature.

CONCLUSION

Despite promising results in several lung injury models, our evidence indicates that T3 administration during EVLP does not exert protective effects but could rather exacerbate mitochondrial stress in lungs exposed to ischemia. These results suggest caution when considering T3-based interventions for organ reconditioning during EVLP.