Primary Graft Dysfunction: The Role of Aging in Lung Ischemia-Reperfusion Injury

Abstract

Transplant centers around the world have been using extended criteria donors to remedy the ongoing demand for lung transplantation. With a rapidly aging population, older donors are increasingly considered. Donor age, at the same time has been linked to higher rates of lung ischemia reperfusion injury (IRI). This process of acute, sterile inflammation occurring upon reperfusion is a key driver of primary graft dysfunction (PGD) leading to inferior short- and long-term survival. Understanding and improving the condition of older lungs is thus critical to optimize outcomes. Notably, ex vivo lung perfusion (EVLP) seems to have the potential of reconditioning ischemic lungs through ex-vivo perfusing and ventilation. Here, we aim to delineate mechanisms driving lung IRI and review both experimental and clinical data on the effects of aging in augmenting the consequences of IRI and PGD in lung transplantation.

Primary graft dysfunction after lung transplantation

“…Previous work has established that PGD occurs in two phases: an early phase modulated by donor lung macrophages and lymphocytes, and a later phase regulated by recipient neutrophils and lymphocytes [2]. In response to acute inflammation, reactive oxygen species (ROS) are generated and accelerate the pace of injury by disturbing cellular function, activating proteolytic enzymes and increasing autophagy [12 ▪ ,13 ▪ ,14 ▪▪ ]. The transcriptional signature of this process of ischemia-reperfusion injury is the upregulation of genes involved in cell survival, cell surface signalling and oxidative stress response [4 ▪ ].…”

“…Recognized donor specific risk factors for the development of PGD relate to both the manner of death and donor management preceding organ procurement. Inherent risk factors related to the donor include increased age (>45), tobacco use (smoking history >20 pack years), chronic alcohol use, female sex and African–American race [2,12 ▪ ]. Recent evidence suggests that increasing organ age augments the damage related to ischemia due to impaired tolerance against damaging stress [12 ▪ ].…”

“…Inherent risk factors related to the donor include increased age (>45), tobacco use (smoking history >20 pack years), chronic alcohol use, female sex and African–American race [2,12 ▪ ]. Recent evidence suggests that increasing organ age augments the damage related to ischemia due to impaired tolerance against damaging stress [12 ▪ ]. In a similar way, prior donor tobacco or alcohol use is thought to contribute to the development of PGD by alterations in the redox state [4 ▪ ].…”

Preserving and rejuvenating old organs for transplantation: novel treatments including the potential of senolytics

“…As an inevitable consequence of solid organ transplantation, IRI affects both short-and longterm outcomes [19,[36][37][38][39]. Although effects on clinical outcomes have not been entirely delineated, there is strong experimental evidence that aging enhances the susceptibility of IRI in clinical transplantation [40,41]. Despite the minimal morphologic changes with age, older livers have significantly reduced intracellular energy content after IRI linked to a reduced capacity of mitochondrial ATP production [42].…”

cGAS–STING pathway in ischemia-reperfusion injury: a potential target to improve transplantation outcomes

“…Surgical blood reperfusion can lead to severe oxidative damage and an inflammatory response following reoxygenation. This series of events aggravates allograft injury and may lead to primary graft dysfunction, which is associated with high mortality and morbidity ( 8 , 9 ). The cellular and molecular events that occur during IRI are complex and involve innate immune system activation and programmed cell death (PCD) ( 10 , 11 ).…”