The Post-Lung Transplant Impact of Alveolar Macrophage Senescence in Aged Donor Lungs - PROJECT SUMMARY Lung transplantation (LTx) has become a well-established therapy for patients with end-stage lung disease whose condition has not improved on maximal medical therapy. As procedures and access to LTxhave improved over recent years, there has been an increase in the number of patients considered to be suitable candidates for the procedure. Concurrent with the advances in LTx, the population of older adults (age 60+) has also dramatically increased, and these patients are increasingly occupyingslots on the waitlist. To meet the increased demand for LTx, the transplant community has begun looking toward the use of “extended criteria donors”, including a significant increase in the use of donor lungs from older adults, to make up for the shortage of donor organs available for transplant. However, aged lungs from older adult donors are associated with higher rates of rejection, graft failure, and poorer long-term outcomes, hampering their utility. Similar results have been observed in studies from other transplantation fields, including cardiac and kidney. While these poor outcomes from aged lungs are thought largely to be associated with patient comorbidities such as cigarette smoke exposure, infections, and age-related decline in function, the precise underlying mechanisms driving these outcomes remain largely unknown. However, recent studies in aging and immunosenescence have identified pathological phenomena in older adults characterized by a pro-inflammatory milieu, commonly referred to as inflamm-aging . While the underlying process is poorly understood, inflamm-aging produces a persistent inflammatory state that results in improper responses to cellular interactions. Current literature implicates senescent lung macrophages in the pathophysiology of acute and chronic lung diseases, however there are no data on the impact of cellular senescence in the context of LTx. This proposal will address this critical gap in knowledge by determining the role of senescent alveolar macrophages (AM) in the increased rate of graft failure and poor outcomes associated with aged donor lungs. AM constitute 90-95% of the alveolar cellular content, and previous work has shown that senescent AM undergo a shift from a tolerogenic self-renewing resident macrophage population to a monocyte-derived macrophage population, suggesting a phenotypically distinct AM population in aged lungs, which may in fact be pro-inflammatory and a key driver of immunosenescent changes. Specifically, this proposal will 1) determine the effects of advanced donor age on ischemia-reperfusion injury (IRI) and acute rejection (AR); 2) determine the role of senescent AMpopulations in chronic rejection and chronic lung allograft dysfunction(CLAD); and 3) determine the roleof senescentAMpopulations in IRI and alloimmunity. The results of this work will provide crucial insights into the mechanisms driving poor outcomes associated with aged donor lungs, identifying therapeutic targets to successfully increase their utility, and increasing the number and quality of available organs available to LTx recipients.
