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Cells
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Molecular Mechanisms of Ischemia-Reperfusion Injury and Hepatoprotection
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Molecular Mechanisms of Ischemia-Reperfusion Injury and Hepatoprotection

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 9446

Special Issue Editor

Dr. Rita Carini

E-Mail Website
Guest Editor
Department of Health Science, University of Piemonte Orientale, Novara, Italy
Interests: hepatoprotection; molecular mechanisms of liver preconditioning; hepatotoxicity; ischemia-reperfusion; NAFLD and NASH; intracellular ionic alteration and hepatocyte death

Special Issue Information

Dear Colleagues,

Hepatic ischemia-reperfusion injury (IRI) is the phenomenon during which hepatocellular damage, caused by hypoxia, is paradoxically exacerbated after the restoration of oxygen delivery. IRI is implicated in all conditions causing a transient fall in the blood flow to the liver such as shock, trauma, hepatic surgery or transplantation. Fatty liver infiltration, the most common hepatic pathology in Western countries, significantly increases IRI. Although IRI represents a main clinical alteration, no specific therapeutic treatments are available.

IRI occurs as the sum of the intracellular alterations occurring during the ischemic and reperfusion phases in parenchymal and non-parenchymal liver cells. Such molecular and cellular alterations are further affected and/or exacerbated by activation of immune-inflammatory reactions at reperfusion. A complete understanding of the specific molecular and cellular events underlaying IRI is essential to establish opportune interventions to attenuate or prevent IRI.

In this Special Issue of Cells, I invite you to contribute original research articles, reviews or commentaries on all aspects related to the theme of “Molecular Mechanisms of Ischemia-Reperfusion Injury and Hepatoprotection”.

The aim of this Special Issue is to cover and discuss the different features of experimental hepatic IRI at the biochemical, cellular, functional and translational levels. The latest research on potentially druggable targets or on protective strategies such as pharmacological or ischemic preconditioning, able to inhibit single or multifaced damaging aspects of IRI, will be highly appreciated.

Dr. Rita Carini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hepatocytes
  • liver endothelial cells
  • Kupffer cell
  • immune-inflammation
  • cytotoxic pathways
  • survival signal mediators
  • preconditioning
  • liver transplantation
  • liver steatosis
  • hypoxia
  • microbiota

Published Papers (3 papers)

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Research

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12 pages, 1832 KiB  
Article
Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation
by Elisa Alchera, Bangalore R. Chandrashekar, Nausicaa Clemente, Ester Borroni, Renzo Boldorini and Rita Carini
Cells 2021, 10(11), 3171; https://doi.org/10.3390/cells10113171 - 15 Nov 2021
Cited by 8 | Viewed by 2010
Abstract
Hepatic ischemia/reperfusion injury (IRI) is aggravated by steatosis and is a main risk factor in fatty liver transplantation. Adenosine receptors (ARs) are emerging as therapeutic targets in liver diseases. By using cellular and in vivo systems of hepatic steatosis and IRI, here we [...] Read more.
Hepatic ischemia/reperfusion injury (IRI) is aggravated by steatosis and is a main risk factor in fatty liver transplantation. Adenosine receptors (ARs) are emerging as therapeutic targets in liver diseases. By using cellular and in vivo systems of hepatic steatosis and IRI, here we evaluated the effects of pharmacological A2AR and A1R activation. The A2AR agonist CGS21680 protected the primary steatotic murine hepatocyte from IR damage and the activation of ASK1 and JNK. Such an effect was attributed to a phosphatidylinositol-3-kinase (PI3K)/Akt-dependent inhibition of ASK1. By contrast, the A1R agonist CCPA enhanced IR damage, intracellular steatosis and oxidative species (OS) production, thereby further increasing the lipid/OS-dependent ASK1-JNK stimulation. The CGS2680 and CCPA effects were nullified by a genetic ASK1 downregulation in steatotic hepatoma C1C7 cells. In steatotic mice livers, CGS21680 protected against hepatic IRI and ASK1/JNK activation whereas CCPA aggravated hepatic steatosis and IRI, and enhanced ASK1 and JNK stimulation. These results evidence a novel mechanism of CGS21680-mediated hepatoprotection, i.e., the PI3K/AKT-dependent inhibition of ASK1, and they show that CGS21680 and CCPA reduces and enhances the IRI of fatty liver, respectively, by preventing or increasing the activation of the cytotoxic ASK1/JNK axis. They also indicate the selective employment of A2AR agonists as an effective therapeutic strategy to prevent IRI in human fatty liver surgery. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia-Reperfusion Injury and Hepatoprotection)
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Review

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15 pages, 1035 KiB  
Review
A Potential Route to Reduce Ischemia/Reperfusion Injury in Organ Preservation
by Marc Micó-Carnero, Mohamed Amine Zaouali, Carlos Rojano-Alfonso, Cristina Maroto-Serrat, Hassen Ben Abdennebi and Carmen Peralta
Cells 2022, 11(17), 2763; https://doi.org/10.3390/cells11172763 - 05 Sep 2022
Cited by 6 | Viewed by 2491
Abstract
The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context [...] Read more.
The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context of organ shortages, most organs come from extended criteria donors (ECDs), which are more sensitive to IRI. The main objective of organ preservation solutions is to protect against IRI through the application of specific, nonphysiological components, under conditions of no blood or oxygen, and then under conditions of metabolic reduction by hypothermia. The composition of hypothermic solutions includes osmotic and oncotic buffering components, and they are intracellular (rich in potassium) or extracellular (rich in sodium). However, above all, they all contain the same type of components intended to protect against IRI, such as glutathione, adenosine and allopurinol. These components have not changed for more than 30 years, even though our knowledge of IRI, and much of the relevant literature, questions their stability or efficacy. In addition, several pharmacological molecules have been the subjects of preclinical studies to optimize this protection. Among them, trimetazidine, tacrolimus and carvedilol have shown the most benefits. In fact, these drugs are already in clinical use, and it is a question of repositioning them for this novel use, without additional risk. This new strategy of including them would allow us to shift from cold storage solutions to cold preservation solutions including multitarget pharmacological components, offering protection against IRI and thus protecting today’s more vulnerable organs. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia-Reperfusion Injury and Hepatoprotection)
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12 pages, 995 KiB  
Review
Role of Immuno-Inflammatory Signals in Liver Ischemia-Reperfusion Injury
by Christof Kaltenmeier, Ronghua Wang, Brandon Popp, David Geller, Samer Tohme and Hamza O. Yazdani
Cells 2022, 11(14), 2222; https://doi.org/10.3390/cells11142222 - 17 Jul 2022
Cited by 34 | Viewed by 4486
Abstract
Ischemia reperfusion injury (IRI) is a major obstacle in liver resection and liver transplantation. The initial step of IRI is mediated through ischemia which promotes the production of reactive oxygen species in Kupffer cells. This furthermore promotes the activation of pro-inflammatory signaling cascades, [...] Read more.
Ischemia reperfusion injury (IRI) is a major obstacle in liver resection and liver transplantation. The initial step of IRI is mediated through ischemia which promotes the production of reactive oxygen species in Kupffer cells. This furthermore promotes the activation of pro-inflammatory signaling cascades, including tumor necrosis factor-alpha, IL-6, interferon, inducible nitric oxide synthase, TLR9/nuclear-factor kappa B pathway, and the production of damage-associated molecular patterns (DAMPs), such as ATP, histone, high mobility group box 1 (HMGB1), urate, mitochondrial formyl peptides and S100 proteins. With ongoing cell death of hepatocytes during the ischemic phase, DAMPs are built up and released into the circulation upon reperfusion. This promotes a cytokines/chemokine storm that attracts neutrophils and other immune cells to the site of tissue injury. The effect of IRI is further aggravated by the release of cytokines and chemokines, such as epithelial neutrophil activating protein (CXCL5), KC (CXCL1) and MIP-2 (CXCL2), the complement proteins C3a and C5a, mitochondrial-derived formyl peptides, leukotriene B4 and neutrophil extracellular traps (NETs) from migrating neutrophils. These NETs can also activate platelets and form Neutrophil-platelet microthrombi to further worsen ischemia in the liver. In this review we aim to summarize the current knowledge of mediators that promote liver IRI, and we will discuss the role of neutrophils and neutrophil extracellular traps in mediating IRI. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Ischemia-Reperfusion Injury and Hepatoprotection)
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