Minimizing Ischemia Reperfusion Injury in Xenotransplantation

Patel, Parth M.; Connolly, Margaret; Coe, Taylor M.; Calhoun, Anthony; Pollok, Franziska; Markmann, James F.; Burdorf, Lars; Azimzadeh, Agnes M.; Madsen, Joren C.; Pierson, Richard N.

doi:10.3389/fimmu.2021.681504

Cited by 16 publications

(15 citation statements)

References 349 publications

(532 reference statements)

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“…26,46 Intriguingly, IRI is also critical for primary xenograft function and the expression of HO-1 is likewise associated with improved primary graft function and long-term survival in xenotransplantation. 47,48 This indicates that HO-1 is a key therapeutic target for protection against hepatic IRI in allo-and xenotransplantation. However, none of the aforementioned stimulators of HO-1 is clinically applicable yet.…”

Section: Discussionmentioning

confidence: 99%

Prolyl Hydroxylase Inhibition Mitigates Allograft Injury During Liver Transplantation

et al. 2022

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Background. Ischemia and reperfusion injury (IRI) determines primary allograft function after liver transplantation (LT). Primary graft dysfunction (PGD) is associated with increased morbidity and impaired graft survival and can eventually progress to graft failure requiring retransplantation. Hypoxia-inducible transcription factor–prolyl hydroxylase containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors, which control the adaptive hypoxia response through the hypoxia-inducible factor (HIF). In this study, we have investigated pharmacological activation of the HIF pathway through inhibition of PHDs as a strategy to reduce PGD after LT. Methods. Primary rat hepatocytes were isolated and the impact of the pan-PHD small-molecule inhibitor ethyl-3,4-dihydroxybenzoate (EDHB) on HIF-1 and its downstream target gene expression assessed. Subsequently, various rodent models of segmental warm liver ischemia and reperfusion and orthotopic LT were applied to study the impact of EDHB on normothermic or combined cold and warm liver IRI. Liver enzyme levels and histology were analyzed to quantify hepatic IRI. Results. In vitro, EDHB induced HIF-1 signaling and significantly upregulated its downstream target heme-oxygenase 1 in primary rat hepatocytes. In vivo, after establishment of the optimal EDHB pretreatment conditions in a murine IRI model, EDHB pretreatment significantly mitigated hepatic IRI after warm segmental liver ischemia and reperfusion and allograft injury after orthotopic LT in rats. Mechanistically, EDHB stabilized HIF-1 in the liver and subsequently increased hepatoprotective heme-oxygenase 1 levels, which correlated with reduced hepatic IRI in these models. Conclusions. This proof-of-concept study establishes a strong therapeutic rationale for targeting PHDs with small-molecule inhibitors to mitigate PGD after LT.

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Section: Discussionmentioning

confidence: 99%

Prolyl Hydroxylase Inhibition Mitigates Allograft Injury During Liver Transplantation

et al. 2022

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“…As part of the events during reperfusion, calcium overload and the excessive ROS generation trigger both, apoptosis and necrosis causing a further release of ROS, proinflammatory cytokines and damage-associated molecular patterns (DAMPs) consisting of peptides, proteins and nucleotide fragments ( 78 ). DAMPs represent endogenous danger signals that are normally carefully prevented from release to the extracellular space and differ from microorganism derived pathogen associated molecular patterns (PAMPs) ( 79 , 80 ). Both PAMPs and DAMPs are mainly recognized by their pattern recognition receptors including Tolllike receptors that play an important role in the induction of innate immune responses ( 81 – 83 ).…”

Section: Lung Ischemia Reperfusion Injurymentioning

confidence: 99%

“…This inflammatory milieu leads to pulmonary neutrophil infiltration, further exacerbating and maintaining lung inflammation and injury ( 85 , 86 ). Released ROS and inflammatory cytokines upregulate and activate adhesion molecules including ICAM-1, CD18 and P-selectin on leukocytes and endothelial cells ( 79 , 87 ). The activation of adhesion molecules facilitates the migration of neutrophils from their intravascular location to the lung interstitium where they release more ROS and proteolytic enzymes resulting into the destruction of cellular and extracellular matrix ( 88 ).…”

Section: Lung Ischemia Reperfusion Injurymentioning

confidence: 99%

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

et al. 2022

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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.

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“…Reperfusion of the allograft will initiate a complex interplay of pathological processes, the degree of which will determine the amount of immediate muscle damage, and predispose the heart to further pathological processes such as acute rejection [30] and development of cardiac allograft vasculopathy (CAV). Ischemia reperfusion injury (IRI) involves a complex coordinated interplay of fibroblasts, leukocytes, endothelial cells, pericytes, and cardiomyocytes [31] (Figure 1). In myocyte damage, the process will lead to the replacement of tissue by scarring.…”

Section: Ischemia-reperfusion Injury-early Event Long-term Consequencesmentioning

confidence: 99%

“…In addition to immune activation, EC vasoconstriction is promoted by upregulation of endothelin-1 expression and downregulation of nitric oxide (NO) expression. The simultaneous vasoconstriction, upregulation of procoagulant genes and platelet activation create a prothrombotic environment [31].…”

Section: Endothelial Cells (Ecs)mentioning

confidence: 99%

Failing Heart Transplants and Rejection—A Cellular Perspective

Hurskainen

Ainasoja

Lemström

2021

JCDD

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The median survival of patients with heart transplants is relatively limited, implying one of the most relevant questions in the field—how to expand the lifespan of a heart allograft? Despite optimal transplantation conditions, we do not anticipate a rise in long-term patient survival in near future. In order to develop novel strategies for patient monitoring and specific therapies, it is critical to understand the underlying pathological mechanisms at cellular and molecular levels. These events are driven by innate immune response and allorecognition driven inflammation, which controls both tissue damage and repair in a spatiotemporal context. In addition to immune cells, also structural cells of the heart participate in this process. Novel single cell methods have opened new avenues for understanding the dynamics driving the events leading to allograft failure. Here, we review current knowledge on the cellular composition of a normal heart, and cellular mechanisms of ischemia-reperfusion injury (IRI), acute rejection and cardiac allograft vasculopathy (CAV) in the transplanted hearts. We highlight gaps in current knowledge and suggest future directions, in order to improve cellular and molecular understanding of failing heart allografts.

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Minimizing Ischemia Reperfusion Injury in Xenotransplantation

Cited by 16 publications

References 349 publications

Prolyl Hydroxylase Inhibition Mitigates Allograft Injury During Liver Transplantation

Prolyl Hydroxylase Inhibition Mitigates Allograft Injury During Liver Transplantation

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

Failing Heart Transplants and Rejection—A Cellular Perspective

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