Key words : Lung conditioning, Lung preservation, Lung transplant, Chromic lung allograft dysfunction

Dear Editor:

This letter is a comment about a previously published paper, titled “Do we need to cool the lung graft after an ex vivo lung perfusion? A preliminary study”.¹

Lung transplant is the main therapeutic strategy for patients with end-stage pulmonary failure. Recently, ex vivo lung perfusion (EVLP) was introduced as a major strategy for graft conditioning before transplant. However, graft rejection and development of bronchiolitis obliterans are major problems complicating lung transplant, which are included within a big category of complication recently termed chronic lung allograft dysfunction-CLAD. Accordingly, an important target of graft conditioning is to decrease immune stimulation and cytokine production within the graft.2 Recent findings showed increased production of interleukin 8, interleukin 1-β (IL-1β), and interleukin 6 (IL-6) within the graft during EVLP. In addition, IL-1β was reported to induce other proinflammatory cytokines, including IL-6.^1,3

The cytokine IL-1β and other proinflammatory cytokines are activated mainly by stimulation of complex intracellular macromolecules called inflammasomes, which are stimulated after various pul-monary and nonpulmonary insults such as pulmonary viral infections, cigarette smoking, and myocardial infarction. This activation leads to initiation of immune reactions.⁴ The mechanisms by which inflammasomes are activated are related to oxidative stress, decreased potassium ion channel activity, and potassium ion efflux.⁴ Cold static graft preservation is associated with increased production of reactive oxygen species, inhibited potassium ion channel activity and increased potassium ion efflux. This leads to inflammasome activation and increased cytokine production. However, effective graft per-fusion and reconditioning might abate these effects.

Following this sequence, repeat exposure of the graft to ischemia (especially cold static) should result in increased cytokine production, with subsequent hazards on the transplant. However, post-EVLP ischemia might follow another model, which is the exposure to ischemia after ischemic preconditioning (ischemia-reperfusion). This preconditioning may be the basis for tolerating post-EVLP ischemia in both cold preservation and normothermic groups, and many mediators could be involved such as adenosine triphosphate reserve, nitric oxide, oxygen free radicals, and potassium ion channel activity. Various paracrine factors might be involved in differential activation and inhibition of molecular pathways.⁵

Consideration of this model for post-EVLP ischemia would be of value, so that the previously achieved knowledge regarding ischemic condition-ing could be applied to EVLP:

• The protective role of ischemic preconditioning may last for 2 to 3 hours.⁵
• Drugs that mimic the ischemic conditioning (such as agonists of adenosine triphosphate sensitive potassium channels) could be used to improve and prolong graft protection.⁶

Therefore, I believe that the work of the addressed paper should be supplemented with further assessment of the possible mediators of ischemic preconditioning and assessment of inflammasome activation in bigger study groups with cold and warm post-EVLP ischemia.

Key words: Lung conditioning, Lung preservation, Lung transplant, Chromic lung allograft dysfunction

References:

1. Stanzi A, Neyrinck A, Somers J, et al. Do we need to cool the lung graft after ex vivo lung perfusion? A preliminary study. J Surg Res. 2014;192(2):647-655.
   CrossRef - PubMed
2. Van Raemdonck D, Neyrinck A, Cypel M, Keshavjee S. Ex-vivo lung perfusion. Transpl Int. 2014 Mar 15. doi: 10.1111/tri.12317. [Epub ahead of print].
   CrossRef - PubMed
3. Sadaria MR, Smith PD, Fullerton DA, et al. Cytokine expression profile in human lungs undergoing normothermic ex-vivo lung perfusion. Ann Thorac Surg. 2011;92(2):478-484.
   CrossRef - PubMed 71
4. Triantafilou K, Triantafilou M. Ion flux in the lung: virus-induced inflammasome activation. Trends Microbiol. 2014;22(10):580-588.
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5. Muscari C, Giordano E, Bonafè F, Govoni M, Pasini A, Guarnieri C. Molecular mechanisms of ischemic preconditioning and postconditioning as putative therapeutic targets to reduce tumor survival and malignancy. Med Hypotheses. 2013;81(6):1141-1145.
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6. Hu X, Yang Z, Yang M, et al. Remote ischemic preconditioning mitigates myocardial and neurological dysfunction via K(ATP) channel activation in a rat model of hemorrhagic shock. Shock. 2014;42(3):228-233.
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