Sterile inflammation in thoracic transplantation

Abstract

The life-saving benefits of organ transplantation can be thwarted by allograft dysfunction due to both infectious and sterile inflammation post-surgery. Sterile inflammation can occur after necrotic cell death due to the release of endogenous ligands [such as damage-associated molecular patterns (DAMPs) and alarmins], which perpetuate inflammation and ongoing cellular injury via various signaling cascades. Ischemia-reperfusion injury (IRI) is a significant contributor to sterile inflammation after organ transplantation and is associated with detrimental short- and long-term outcomes. While the vicious cycle of sterile inflammation and cellular injury is remarkably consistent amongst different organs and even species, we have begun understanding its mechanistic basis only over the last few decades. This understanding has resulted in the developments of novel, yet non-specific therapies for mitigating IRI-induced graft damage, albeit with moderate results. Thus, further understanding of the mechanisms underlying sterile inflammation after transplantation is critical for identifying personalized therapies to prevent or interrupt this vicious cycle and mitigating allograft dysfunction. In this review, we identify common and distinct pathways of post-transplant sterile inflammation across both heart and lung transplantation that can potentially be targeted.

Keywords: Adaptive immunity; Cell death; Ferroptosis; Innate immunity; Ischemia–reperfusion injury; Necroptosis; Primary graft dysfunction.

Fig. 1

General schema of sterile inflammation occurring in the context of thoracic organ transplantation. Risk factors such as brain death and prolonged cold ischemia contribute to programmed cell death pathways such as ferroptosis, necroptosis and/or pyroptosis. These processes result in the release of extracellular and intracellular triggers, which activate signaling pathways, ultimately resulting in graft injury. Ongoing tissue injury propagates cell death, setting up a vicious cycle. ATP (extracellular) adenosine triphosphate, FPR1 formyl peptide receptor 1, HMGB1 High Mobility Group Box 1, IL1R interleukin-1 receptor, mtDNA mitochondrial DNA, P2XR purinergic 2 receptor, RAGE receptor for advanced glycated end products, TLR Toll-like receptors. Created with Biorender.com