Ischaemia-reperfusion injury in liver transplantation--from bench to bedside.
01 Feb 2013-Nature Reviews Gastroenterology & Hepatology (Nature Publishing Group)-Vol. 10, Iss: 2, pp 79-89
TL;DR: The latest mechanistic insights into innate–adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia–reperfusion are highlighted, progress in large animal experiments is discussed and efforts to minimize liver IRI in patients who have received a liver transplant are examined.
Abstract: Ischaemia-reperfusion injury (IRI) in the liver, a major complication of haemorrhagic shock, resection and transplantation, is a dynamic process that involves the two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury. This Review highlights the latest mechanistic insights into innate-adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia-reperfusion, discusses progress in large animal experiments and examines efforts to minimize liver IRI in patients who have received a liver transplant. The interlinked signalling pathways in multiple hepatic cell types, the IRI kinetics and positive versus negative regulatory loops at the innate-adaptive immune interface are discussed. The current gaps in our knowledge and the pathophysiology aspects of IRI in which basic and translational research is still required are stressed. An improved appreciation of cellular immune events that trigger and sustain local inflammatory responses, which are ultimately responsible for organ injury, is fundamental to developing innovative strategies for treating patients who have received a liver transplant and developed ischaemia-reperfusion inflammation and organ dysfunction.
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TL;DR: This Review focuses on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia–reperfusion injury and paracetamol-induced liver injury and proposes novel approaches in the treatment of inflammation in liver disease.
Abstract: Inflammation contributes to the pathogenesis of most acute and chronic liver diseases Inflammasomes are multiprotein complexes that can sense danger signals from damaged cells and pathogens and assemble to mediate caspase-1 activation, which proteolytically activates the cytokines IL-1β and IL-18 In contrast to other inflammatory responses, inflammasome activation uniquely requires two signals to induce inflammation, therefore setting an increased threshold IL-1β, generated upon caspase-1 activation, provides positive feed-forward stimulation for inflammatory cytokines, thereby amplifying inflammation Inflammasome activation has been studied in different human and experimental liver diseases and has been identified as a major contributor to hepatocyte damage, immune cell activation and amplification of liver inflammation In this Review, we discuss the different types of inflammasomes, their activation and biological functions in the context of liver injury and disease progression Specifically, we focus on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia-reperfusion injury and paracetamol-induced liver injury The application and translation of these discoveries into therapies promises novel approaches in the treatment of inflammation in liver disease
420 citations
TL;DR: It is shown that NETs form in the sinusoids of ischemic liver lobes in vivo and inhibition of NET formation is found by the peptidyl‐arginine‐deiminase 4 inhibitor and that DNase I reduces High Mobility Group Box 1 and histone‐mediated liver I/R injury.
331 citations
Cites background from "Ischaemia-reperfusion injury in liv..."
...Neutrophil infiltration and accumulation in the ischemic liver lobe further contribute to the inflammation-associated damage by releasing reactive oxygen species, numerous inflammatory mediators, as well as various proteolytic enzymes.(6) In addition to the mechanisms described above, novel aspects of neutrophil biology may contribute to I/Rinduced liver injury....
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TL;DR: The relationship between factors and inflammatory pathways that characterize hepatic IRI, MMPs and current pharmacological approaches to this disease are explored.
206 citations
TL;DR: It is becoming more and more clear that no single MMP can be unequivocally labeled as 'good' or 'bad' when considering inflammation in general - the net result of proteolytic activity is dependent on context.
152 citations
Cites background from "Ischaemia-reperfusion injury in liv..."
...to find ways to ameliorate the damage and achieve organ homeostasis as quickly as possible [31]....
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TL;DR: It is demonstrated in a DCD liver transplant model that end-ischemic hypothermic oxygenated perfusion is a powerful strategy for protection against biliary injury.
151 citations
Cites background or result from "Ischaemia-reperfusion injury in liv..."
...Endothelial cell activation and T cell activation occur simultaneously aggravating the magnitude of the injury[3, 6, 24, 45] including two T cell cytokines (IL-13 and IL-17) secreted by innate immune cells, which trigger additional neutrophil sequestration [40]....
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...Our results are consistent with recent insights on reperfusion injury, which is initiated by liver parenchymal DAMPs release with later involvement of blood cells such as leucocytes and platelets and non-parenchymal liver cells, including Kupffer cells, endothelial cells, and dendritic cells[40, 41]....
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References
More filters
12,729 citations
TL;DR: Rapid progress that has recently improved the understanding of the molecular mechanisms that mediate TLR signalling is reviewed.
Abstract: One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.
7,906 citations
TL;DR: The role of PRRs, their signaling pathways, and how they control inflammatory responses are discussed.
6,987 citations
TL;DR: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea as discussed by the authors.
Abstract: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.
2,368 citations
TL;DR: This Review highlights recent advances in the newly emerging field of TLR cooperation and discusses their implications for the development of adjuvants and immunotherapies.
Abstract: The mechanisms by which the recognition of Toll-like receptor (TLR) ligands leads to host immunity remain poorly defined. It is now thought that to induce an effective immune response, microorganisms must stimulate complex sets of pattern-recognition receptors, both within and outside of the TLR family. The combined activation of these different receptors can result in complementary, synergistic or antagonistic effects that modulate innate and adaptive immunity. Therefore, a complete understanding of the role of TLRs in host resistance to infection requires 'decoding' of these multiple receptor interactions. This Review highlights recent advances in the newly emerging field of TLR cooperation and discusses their implications for the development of adjuvants and immunotherapies.
1,380 citations