Ex-vivo lung perfusion (EVLP) and immune/inflammatory signaling profile

The Manchester group⁽⁴⁾ report that warm EVLP alters the inflammatory signalling profile of the pig donor lung prior to transplantation with a global cell survival and anti-apoptotic signature when compared with lungs undergoing standard transplantation. This signature includes increased phosphorylation of downstream pro-signalling kinases. During the first 24 hours after transplantation, they found up-regulated expression of several anti-apoptotic proteins with down-regulation of apoptosis inducing mitochondrial associated molecules.

A study from Duke⁽⁵⁾, in which EVLP was performed on rat lungs for three hours, indicated that during EVLP, donor leukocytes are flushed from the graft and T cells and B cells are enriched in the perfusate. The authors also suggested that cell death of donor leukocytes contributes to the accumulation of damage-associated molecular patterns (DAMPs) they observed during EVLP. The inference is that these molecules would not reach the recipient, with the potential benefit of less host immune activation.

Another approach is the addition of agents to the EVLP perfusate. Two recent studies from Pittsburgh have looked at opportunities to suppress inflammatory cascades and thus improve outcomes in transplanted lung.

Haam et al⁽⁶⁾ found that adding Cyclosporine A (CyA) to the perfusate can have a preconditioning effect through both its anti-inflammatory and mitochondrial protective properties. This leads to improved lung graft preservation, which may result in enhanced graft quality after transplantation. The authors added CyA to the perfusate during four-hour EVLP sessions in rat lungs, and assessed the grafts two hours after reperfusion. Lung grafts on EVLP with CyA exhibited significantly better functional and physiological parameters, compared to those without CyA treatment. The authors conclude that CyA administration attenuated proinflammatory changes and prohibited glucose consumption during EVLP through mitigating mitochondrial dysfunction in lung grafts.

In another study, Burki et al⁽⁷⁾ looked at the impact of Triptolide, also an anti-inflammatory agent, added to the EVLP Steen solution perfusate in the same rat lung model.

With Triptolide, too, graft glucose consumption was significantly attenuated on ex vivo lung perfusion due to the inhibition of hypoxia signaling: this resulted in improved mitochondrial function and reduced oxidative stress. Intragraft inflammation was also markedly lower in triptolide-treated lungs because of the inhibition of nuclear factor-κB signaling. Furthermore, post-transplant graft function and inflammatory events were significantly improved in the triptolide group compared with the untreated group.

The rat EVLP approach is probably useful for screening potential interventions, but has important differences from full-sized animal models: lower flows are used and there are limited parallels to EVLP of the human donor lung.

References:

4. Stone JP et al, Ex-Vivo Lung Perfusion Improves the Inflammatory Signalling Profile of the Porcine Donor Lung Following Transplantation. Transplantation. 2020 Jun 2 . Online ahead of print. (link to abstract)

5. Davis RP et al, Donor Leukocyte Trafficking and Damage-associated Molecular Pattern Expression During Ex Vivo Lung Perfusion. Transplant Direct. 2020 Feb 10;6(3):e532 (link to abstract)

6. Haam S et al, Cyclosporin A Administration During Ex Vivo Lung Perfusion Preserves Lung Grafts in Rat Transplant Model. Transplantation. 2020 Mar 20 -online ahead of print. (link to abstract)

7. Burki S et al, Impact of Triptolide During Ex Vivo Lung Perfusion on Grafts After Transplantation in a Rat Model. J Thorac Cardiovasc Surg. 2020 Jan 23;S0022-5223(20)30191-4 (link to abstract)

Xvivo Insights PB-2020-06-31