Normothermic ex vivo heart perfusion with NLRP3 inflammasome inhibitor Mcc950 treatment improves cardiac function of circulatory death hearts after transplantation

Xu, Liang‐Guo; Zeng, Zifeng; Niu, Chuanjie; Liu, Deshen; Lin, Shaoyan; Liu, Xiu; Szabó, Gábor; Lu, Jun; Zheng, Shaoyi; Zhou, Pengyu

doi:10.3389/fcvm.2023.1126391

Cited by 6 publications

(3 citation statements)

References 32 publications

(30 reference statements)

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“…Pyroptosis has been shown to play a role in various transplanted organs, including kidneys and the heart [ 193 , 194 ]. In a porcine liver transplantation model, the comparison of cold storage vs. different protocols of machine perfusion strongly suggests a role for NLRP3- and IL-18-related pathways [ 195 , 196 , 197 ].…”

Section: Cell Death In Liver Diseasementioning

confidence: 99%

Cell Death in Liver Disease and Liver Surgery

Stoess,

Choi,

Onyuru

et al. 2024

Biomedicines

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Cell death is crucial for maintaining tissue balance and responding to diseases. However, under pathological conditions, the surge in dying cells results in an overwhelming presence of cell debris and the release of danger signals. In the liver, this gives rise to hepatic inflammation and hepatocellular cell death, which are key factors in various liver diseases caused by viruses, toxins, metabolic issues, or autoimmune factors. Both clinical and in vivo studies strongly affirm that hepatocyte death serves as a catalyst in the progression of liver disease. This advancement is characterized by successive stages of inflammation, fibrosis, and cirrhosis, culminating in a higher risk of tumor development. In this review, we explore pivotal forms of cell death, including apoptosis, pyroptosis, and necroptosis, examining their roles in both acute and chronic liver conditions, including liver cancer. Furthermore, we discuss the significance of cell death in liver surgery and ischemia-reperfusion injury. Our objective is to illuminate the molecular mechanisms governing cell death in liver diseases, as this understanding is crucial for identifying therapeutic opportunities aimed at modulating cell death pathways.

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Section: Cell Death In Liver Diseasementioning

confidence: 99%

Cell Death in Liver Disease and Liver Surgery

Stoess,

Choi,

Onyuru

et al. 2024

Biomedicines

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“…NLRP3 activation has been shown to significantly contribute to cardiac IRI ( 93 , 94 ). Specifically, in donation after circulatory death (DCD) heart transplantation models, inhibiting the NLRP3-inflammasome has been shown to protect the donor allograft against pyroptosis and apoptosis alike ( 95 ). CD38 inhibition also has the potential to prevent the NLRP3-inflammasome formation and have similar effects on mechanisms of programmed cell-death.…”

Section: Clinical Applications Of Cd38 Mediated Iri and Modulationmentioning

confidence: 99%

The role of CD38 in ischemia reperfusion injury in cardiopulmonary bypass and thoracic transplantation: a narrative review

Gouchoe,

Vijayakumar,

Aly

et al. 2023

J Thorac Dis

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Background and Objective Ischemia reperfusion injury (IRI) is often the underlying cause of endothelium breakdown and damage in cardiac or transplantation operations, which can lead to disastrous post-operative consequences. Recent studies of cluster of differentiation 38 (CD38) have identified its critical role in IRI. Our objective is to provide a comprehensive overview of CD38-mediated axis, pathways, and potential CD38 translational therapies for reducing inflammation associated with cardiopulmonary bypass (CPB) or thoracic transplantation and IRI. Methods We conducted a review of the literature by performing a search of the PubMed database on 2 April 2023. To find relevant publications on CD38, we utilized the MeSH terms: “CD38” AND “Ischemia” OR “CD38” AND “Transplant” OR “CD38” AND “Heart” from 1990–2023. Additional papers were included if they were felt to be relevant but were not captured in the MeSH terms. We found 160 papers that met this criterion, and following screening, exclusion and consensus a total of 36 papers were included. Key Content and Findings CD38 is most notably a nicotine adenine dinucleotide (NAD) + glycohydrolase (NADase), and a generator of Ca 2+ signaling secondary messengers. Ultimately, the release of these secondary messengers leads to the activation of important mediators of cellular death. In the heart and during thoracic transplantation, this pathway is intimately involved in a wide variety of injuries; namely the endothelium. In the heart, activation generally results in vasoconstriction, poor myocardial perfusion, and ultimately poor cardiac function. CD38 activation also prevents the accumulation of atherosclerotic disease. During transplantation, intracellular activation leads to infiltration of recipient innate immune cells, tissue edema, and ultimately primary graft dysfunction (PGD). Specifically, in heart transplantation, extracellular activation could be protective and improve allograft survival. Conclusions The knowledge gap in understanding the molecular basis of IRI has prevented further development of novel therapies and treatments. The possible interaction of CD38 with CD39 in the endothelium, and the modulation of the CD38 axis may be a pathway to improve cardiovascular outcomes, heart and lung donor organ quality, and overall longevity.

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“…76 Furthermore, NLRP3 (NOD-, LRR-and pyrin domain-containing 3) inflammasome inhibitors have demonstrated significant therapeutic effects in combating ROS and mitigating oxidative stress in myocardial cells. In a study by Xu et al 77 using donor-heart rats to investigate IR injury in hearts donated after circulatory death (DCD), it was found that intravenous administration of the NLRP3 inhibitor MCC950 in rats could reduce the inflammatory response and oxidative stress levels in DCD hearts preserved with normothermic ex vivo heart perfusion, effectively countering cardiac IR injury. Research by Sun et al 78 revealed that MCC950 treatment markedly reduced the myocardial infarct area, alleviated pathological changes in myocardial tissue, increased left ventricular development pressure, and improved the levels of the maximum rise/decrease rate of left ventricular pressure.…”

Section: Mechanisms Of Macrophage Involvement In Myocardial Ischemia-...mentioning

confidence: 99%

Macrophage Heterogeneity and Its Impact on Myocardial Ischemia-Reperfusion Injury: An Integrative Review

Xu,

et al. 2023

JIR

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The coronary reperfusion following acute myocardial infarction can paradoxically trigger myocardial ischemia-reperfusion (IR) injury. This complex phenomenon involves the intricate interplay of different subsets of macrophages. These macrophages are crucial players in the post-infarction inflammatory response and subsequent myocardial anti-inflammatory repair. However, their diverse functions can lead to both beneficial and detrimental effects. On one hand, these macrophages play a crucial role in orchestrating the inflammatory response, aiding in the clearance of cellular debris and initiating tissue repair mechanisms. On the other hand, their excessive infiltration and activation can contribute to the perpetuation of the inflammatory cascade, leading to additional myocardial injury and adverse cardiac remodeling. Multiple mechanisms contribute to the IR injury mediated by macrophages, including oxidative stress, apoptosis, and autophagy. These processes further exacerbate the damage to the already vulnerable myocardial tissue. To address this delicate balance, therapeutic strategies aiming to target and modulate macrophage polarization and function are being explored. By fine-tuning the immune inflammatory response, such interventions hold promise in mitigating post-infarction myocardial injury and fostering a more favorable environment for myocardial healing and recovery. Through advancements in this area of research, potential anti-inflammatory interventions may pave the way for improved clinical outcomes and better management of patients after acute myocardial infarction.

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Normothermic ex vivo heart perfusion with NLRP3 inflammasome inhibitor Mcc950 treatment improves cardiac function of circulatory death hearts after transplantation

Cited by 6 publications

References 32 publications

Cell Death in Liver Disease and Liver Surgery

Cell Death in Liver Disease and Liver Surgery

The role of CD38 in ischemia reperfusion injury in cardiopulmonary bypass and thoracic transplantation: a narrative review

Macrophage Heterogeneity and Its Impact on Myocardial Ischemia-Reperfusion Injury: An Integrative Review

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