Review: Ischemia Reperfusion Injury-A Translational Perspective in Organ Transplantation

Abstract

Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI.

Keywords: RNA interference; cell death; cell metabolism; hypoxia; innate immunity; ischemia reperfusion injury.

Figure 1

Cellular events involved in ischemia/reperfusion injury (IRI). (1) Hypoxia following death of the donor induces metabolic stress, vascular permeability, and cellular apoptosis. (2) In the ischemic graft, danger signaling pathways are potential therapeutic targets for optimization. (3) IRI generates a sterile inflammatory response in the recipient due to the events present in (2). Treatments based on the use of complement and (Tumor Necrosis Factor) TNF inhibitors are used to decrease the immune response, as well as cell therapy with myeloid-derived suppressor cells (MDSCs) and hematopoietic stem cells (HSCs), which are important in controlling this response.

Figure 2

Signaling pathways involved in ischemia/reperfusion injury (IRI). (1) Damage-associated molecular patterns (DAMPs), released by injured and necrotic cells during IRI, are recognized by pattern recognition receptors (PRRs), such as Toll-like receptors (TLR), and Interleukin-1 receptor (IL1-R). The activation of PRRs results into the induction of nuclear factor-κB (NF-κB), which is a key regulator of DNA transcription, cytokine production, and pro-inflammatory signaling. As a result, DNA acquires epigenetic marks, and an immune response is initiated. (2) During IRI, T cells recognize specific antigens (Ags) through the T cell receptor (TCR), activating NF-κB and initiating an immune response without antigen-presenting cells. (3) The recognition of DAMPs or Ags leads to an increase of Nicotinamide Adenine Dinucleotide Phosphate Hydrogen (NADPH) oxidase activity in mitochondria, generating reactive oxygen species (ROS), which maintain the immune activation. Abbreviation: ECM, extracellular matrix; PKC, protein kinase C; CARMA, CARD motif of a subfamily of membrane-associated guanylate kinase (MAGUK) proteins called CARD-MAGUKs; MALT1, paracaspase MLT.