scholarly journals Toll-like receptor 3 mediates ischaemia/reperfusion injury after cardiac transplantation

2020 ◽  
Vol 57 (5) ◽  
pp. 826-835
Author(s):  
Can Gollmann-Tepeköylü ◽  
Michael Graber ◽  
Leo Pölzl ◽  
Felix Nägele ◽  
Rafael Moling ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Transplantation ◽  
Reperfusion Injury ◽  
Cardiac Transplantation ◽  
Toll Like Receptor ◽  
Cardiac Damage ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Subsequent Activation ◽  
Tlr3 Activation

Abstract OBJECTIVES Ischaemia and subsequent reperfusion during heart transplantation inevitably result in donor organ injury. Toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viral and endogenous RNA released by injured cells. We hypothesized that ischaemia/reperfusion injury (IRI) leads to RNA release with subsequent TLR3 activation in transplanted hearts. METHODS Human endothelial cells were subjected to IRI and treated with TLR3 agonist polyinosinic–polycytidylic acid or a TLR3/double-stranded RNA complex inhibitor. TLR3 activation was analysed using reporter cells. Gene expression profiles were evaluated via next-generation sequencing. Neutrophil adhesion was assessed in vitro. Syngeneic heart transplantation of wild-type or Tlr3−/− mice was performed following 9 h of cold ischaemia. Hearts were analysed for inflammatory gene expression, cardiac damage, apoptosis and infiltrating leucocytes. RESULTS IRI resulted in RNA release with subsequent activation of TLR3. Treatment with a TLR3 inhibitor abrogated the inflammatory response upon IRI. In parallel, TLR3 stimulation caused activation of the inflammasome. Endothelial IRI resulted in TLR3-dependent adhesion of neutrophils. Tlr3−/− animals showed reduced intragraft and splenic messenger ribonucleic acid (mRNA) expression of proinflammatory cytokines, resulting in decreased myocardial damage, apoptosis and infiltrating cells. Tlr3 deficiency protected from cardiac damage, apoptosis and leucocyte infiltration after cardiac transplantation. CONCLUSIONS We uncover the release of RNA by injured cells with subsequent activation of TLR3 as a crucial pathomechanism of IRI. Our data indicate that TLR3 represents a novel target in the prevention of IRI in solid organ transplantation.

Dual modulation of nitric oxide production in the heart during ischaemia/reperfusion injury and inflammation

2010 ◽  
Vol 104 (08) ◽  
pp. 200-206 ◽  
Author(s):  
Alessandra de Prati ◽  
Bruno Podesser ◽  
Giuseppe Faggian ◽  
Tiziano Scarabelli ◽  
Alessandro Mazzucco ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Reperfusion Injury ◽  
Critical Role ◽  
Inos Expression ◽  
Functional Adaptation ◽  
No Production ◽  
Cardiac Damage ◽  
Ischaemia Reperfusion Injury ◽  
Early Reperfusion ◽  
Ischaemia Reperfusion

SummaryNitric oxide (NO) homeostasis maintained by neuronal/endothelial nitric oxide (NO) synthase (n/eNOS) contributes to regulate cardiac function under physiological conditions. At the early stages of ischaemia, NO homeostasis is disturbed due to Ca2+-dependent e/nNOS activation. In endothelial cells, successive drop in NO concentration may occur due to both uncoupling of eNOS and/or successive inhibition of nNOS catalytic activity mediated by arachidonic acid-induced tyrosine phosphorylation of this enzyme. The reduced NO bioavailability triggers nuclear factor (NF)-κB activation followed by the induction of inducible NOS (iNOS) expression. In cardiomyocytes ischaemia also triggers the induction of iNOS expression during reperfusion. The massive amounts of NO which are subsequently produced following iNOS induction may exert on cardiomyocytes and the other cell types of cells of the heart, such as endothelial and smooth muscle cells, macrophages and neutrophils, opposing effects, either beneficial or toxic. The balance between these two double-faced actions may contribute to the final clinical outcomes, determining the degree of functional adaptation of the heart to ischaemia/reperfusion injury. In the light of this new vision on the critical role played by the cross-talk between n/eNOS and iNOS as well as the non enzymatic NO production by nitrite, we have reason to believe that new pharmacological measurements or experimental interventions, such as ischaemic preconditioning, aimed at counteracting the drop in NO levels beyond the normal range of NO homeostasis during early reperfusion can represent an efficient strategy to reduce the extent of functional impairment and cardiac damage in the heart exposed to ischaemia/reperfusion injury.

Gene Silencing using siRNA for Preventing Liver Ischaemia-Reperfusion Injury

2018 ◽  
Vol 24 (23) ◽  
pp. 2692-2700 ◽  
Author(s):  
H. Susana Marinho ◽  
Paulo Marcelino ◽  
Helena Soares ◽  
Maria Luísa Corvo
Keyword(s):  
Gene Silencing ◽  
Reperfusion Injury ◽  
Therapeutic Potential ◽  
Major Complication ◽  
Ischaemia Reperfusion Injury ◽  
Small Interference Rna ◽  
Ischaemia Reperfusion ◽  
Promising Therapeutic Approach ◽  
Sirna Therapy

Background: Ischaemia-reperfusion injury (IRI), a major complication occurring during organ transplantation, involves an initial ischemia insult, due to loss of blood supply, followed by an inflammation-mediated reperfusion injury. A variety of molecular targets and pathways involved in liver IRI have been identified. Gene silencing through RNA interference (RNAi) by means of small interference RNA (siRNA) targeting mediators of IRI is a promising therapeutic approach. Objective: This study aims at reviewing the use of siRNAs as therapeutic agents to prevent IRI during liver transplantation. Method: We review the crucial choice of siRNA targets and the advantages and problems of the use of siRNAs. Results: We propose possible targets for siRNA therapy during liver IRI. Moreover, we discuss how drug delivery systems, namely liposomes, may improve siRNA therapy by increasing siRNA stability in vivo and avoiding siRNA off-target effects. Conclusion: siRNA therapeutic potential to preclude liver IRI can be improved by a better knowledge of what molecules to target and by using more efficient delivery strategies.

Pretreatment by Hyperoxia - A Tool to Reduce Ischaemia-Reperfusion Injury in the Myocardium

2010 ◽  
Vol 5 (2) ◽  
pp. 125-132 ◽  
Author(s):  
Inga Karu ◽  
Peeter Tahepold ◽  
Arno Ruusalepp ◽  
Joel Starkopf
Keyword(s):  
Reperfusion Injury ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion

scholarly journals Protective Effects of GYY4137 on Renal Ischaemia/Reperfusion Injury through Nrf2-Mediated Antioxidant Defence

2021 ◽  
pp. 1-9
Author(s):  
Hongmei Zhao ◽  
Yun Qiu ◽  
Yichen Wu ◽  
Hong Sun ◽  
Sumin Gao
Keyword(s):  
Oxidative Stress ◽  
Reperfusion Injury ◽  
Nuclear Translocation ◽  
Organ Damage ◽  
Related Factor ◽  
Protective Effects ◽  
Ischaemia Reperfusion Injury ◽  
Renal Ischaemia ◽  
Ischaemia Reperfusion ◽  
Renal Histology

<b><i>Introduction/Aims:</i></b> Hydrogen sulfide (H<sub>2</sub>S) is considered to be the third most important endogenous gasotransmitter in organisms. GYY4137 is a long-acting donor for H<sub>2</sub>S, a gas transmitter that has been shown to prevent multi-organ damage in animal studies. We previously reported the effect of GYY4137 on cardiac ischaemia reperfusion injury (IRI) in diabetic mice. However, the role and mechanism of GYY4137 in renal IRI are poorly understood. The aims of this study were to determine whether GYY4137 can effectively alleviate the injury induced by renal ischaemia reperfusion and to explore its possible mechanism. <b><i>Methods:</i></b> Mice received right nephrectomy and clipping of the left renal pedicle for 45 min. GYY4137 was administered by intraperitoneal injection for 2 consecutive days before the operation. The model of hypoxia/reoxygenation injury was established in HK-2 cells, which were pre-treated with or without GYY4137. Renal histology, function, apoptosis, and oxidative stress were measured. Western blot was used to measure the target ­protein after renal IRI. <b><i>Results:</i></b> The results indicated that GYY4137 had a clear protective effect on renal IRI as reflected by the attenuation of renal dysfunction, renal tubule injury, and apoptosis. Moreover, GYY4137 remarkably reduced renal IRI-induced oxidative stress. GYY4137 significantly elevated the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2) and the expression of antioxidant enzymes regulated by Nrf2, including SOD, HO-1, and NQO-1. <b><i>Conclusions:</i></b> GYY4137 alleviates ischaemia reperfusion-induced renal injury through activating the antioxidant effect mediated by Nrf2 signalling.

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