The Role of Ischemia Reperfusion Injury in Lung Allograft Rejection

Washington University, Saint Louis MO

Investigators

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Abstract

Abstract The success of lung transplantation is limited by ischemia reperfusion injury-mediated primary graft dysfunction and allograft rejection, two processes that we have shown are immunologically linked. Current strategies to reduce graft rejection and improve survival are mostly based on targeting adaptive immune cell populations in the recipient. These approaches are only modestly effective and carry high risks of life-threatening infections and development of malignancies. We have shown that neutrophilic graft infiltration during ischemia reperfusion injury is a major driver major driver of alloreactivity. Therefore, a complementary approach to prevent rejection is to target innate immune pathways that are activated during ischemia and reperfusion. The ability to dampen the initial immune response following lung transplantation represents a promising avenue to increase allograft tolerance and improve clinical outcomes. Our recent work has identified that necroptosis, a non-apoptotic form of inflammatory cell death mediates the early inflammatory response after reperfusion of pulmonary grafts. Recent work has suggested that the removal of apoptotic neutrophils by macrophages, a process referred to as efferocytosis, induces synthesis of specialized pro-resolving mediators pointing to mechanistic targets to prevent ischemia reperfusion injury. Also, we have generated new data that selectively inducing metabolic stress in neutrophil apoptosis triggers innate immune responses that limit ischemia reperfusion injury. We have additionally reported that treatment with Resolvin D1, an endogenous pro-resolving lipid mediator, inhibits neutrophil recruitment, downregulates inflammatory pathways and reduces ischemia reperfusion injury. In this proposal, we will use state-of-the-art techniques, including intravital microscopy, single cell RNA sequencing, oxidative lipidomics, multi-omics imaging mass spectrometry and novel mouse strains to perform studies that will 1) define mechanisms and impact of cell death (Aim 1), 2) define mechanisms that contribute to the endogenous production of specialized proresolving lipid mediators after lung transplantation (Aim 2) and 3) define mechanisms of action and immunological impact of specialized pro-resolving mediators (Aim 3) in driving innate inflammatory and alloimmune responses after lung transplantation. Our studies will lay the foundation for novel therapy that will improve outcomes after pulmonary transplantation.