The potential of ex vivo lung perfusion on improving organ quality and ameliorating ischemia reperfusion injury

Abstract

Allogeneic lung transplantation (LuTx) is considered the treatment of choice for a broad range of advanced, progressive lung diseases resistant to conventional treatment regimens. Ischemia reperfusion injury (IRI) occurring upon reperfusion of the explanted, ischemic lung during implantation remains a crucial mediator of primary graft dysfunction (PGD) and early allo‐immune responses. Ex vivo lung perfusion (EVLP) displays an advanced technique aiming at improving lung procurement and preservation. Indeed, previous clinical trials have demonstrated a reduced incidence of PGD following LuTx utilizing EVLP, while long‐term outcomes are yet to be evaluated. Mechanistically, EVLP may alleviate donor lung inflammation through reconditioning the injured lung and diminishing IRI through storing the explanted lung in a non‐ischemic, perfused, and ventilated status. In this work, we review potential mechanisms of EVLP that may attenuate IRI and improve organ quality. Moreover, we dissect experimental treatment approaches during EVLP that may further attenuate inflammatory events deriving from tissue ischemia, shear forces or allograft rejection associated with LuTx.

Mesenchymal Stromal/Stem Cells and Their Products as a Therapeutic Tool to Advance Lung Transplantation

“…However, there is growing evidence that EVLP could also serve for normally accepted lungs. EVLP can reduce ischemia-reperfusion injury (IRI), with the potential to improve organ quality and to reduce primary graft dysfunction (PGD) [ 62 ]. Interestingly, the idea of EVLP as a therapeutic platform to reduce inflammation, edema, and infection in allografts is very promising.…”

Experimental Models of Ischemic Lung Damage for the Study of Therapeutic Reconditioning During Ex Vivo Lung Perfusion

“…Most notably, lung ischemia-reperfusion injury is a crucial pathophysiological mechanism of lung damage and dysfunction during lung transplantation, which may be treated by targeted interventions during EVLP. 16 In this respect, we assessed several ex vivo models of rat lung ischemia-reperfusion and evaluated their impact on major end points of EVLP (lung mechanics, edema and oxygenation capacity, and injury and oxidative/ nitro-oxidative stress). Three distinct variables were incorporated in our models, namely, CI or WI preservation, various Rat lungs exposed to only CI (3 h) did not develop any overt signs of damage and dysfunction after 3 h EVLP, whereas they inflated at a FiO 2 of 0.21 or 0.5 to foster the generation of oxygen-derived oxidants and free radicals.…”

Novel approaches for long-term lung transplant survival

“…EVLP offers several advantages over cold static preservation, including 1) the opportunity for evaluation of marginal donor lungs prior to transplantation, 2) safe extension of preservation time, and 3) the potential to improve both marginal and standard grafts through targeted administration of therapeutics ( 61 ). EVLP provides insight into the function of a marginal donor organ by enabling assessment of physiological parameters including pulmonary vascular pressures, perfusate oxygen content (PaO2), lung edema, and PaO2:FiO2 ratios, as well as novel parameters such as interstitial fluid metabolite composition ( 62 ).…”

“…Perhaps the most significant advantage of EVLP relates to its use as a therapeutic platform for administration of localized, targeted lung-specific therapies ( 61 , 65 , 66 ). Even without modifications, EVLP is associated with alterations in the donor lung environment from diminished release of inflammatory mediators and augmentation of anti-inflammatory signaling pathways ( 67 – 70 ).…”