Abstract
Ischemia / reperfusion injury (IRI) during the course of liver transplantation enhances the immunogenicity of allografts and thus impacts overall graft outcome. This sterile inflammatory insult is known to activate innate immunity and propagate organ damage through the recognition of damage-associate molecular pattern (DAMP) molecules. The purpose of the present study was to investigate the role of mitochondrial DAMPs (MTDs) in the pathogenesis of hepatic IRI. Using in vitro models we observed that levels of MTDs were significantly higher in both transplantation-associated and warm IR, and that co-culture of MTDs with human and rat hepatocytes significantly increased cell death. MTDs were also released in an in vivo rat model of hepatic IRI and associated with increased secretion of inflammatory cytokines (TNF-α, IL-6, and IL-10) and increased liver injury compared to the sham group. Our results suggest that hepatic IR results in a significant increase of MTDs both in vitro and in vivo suggesting that MTDs may serve as a novel marker in hepatic IRI. Co-culture of MTDs with hepatocytes showed a decrease in cell viability in a concentration dependent manner, which indicates that MTDs is a toxic mediator participating in the pathogenesis of liver IR injury.
Highlights
Ischemia reperfusion injury (IRI) is a phenomenon whereby cellular damage in a hypoxic organ is exacerbated following the restoration of oxygen delivery [1]
mitochondrial damage-associated molecular patterns (DAMPs) (MTDs) express at least two molecular signatures, formyl peptides and mitochondrial DNA that act on formyl peptide receptors (FPRs) and Toll-like receptors (TLRs), respectively [21,22]
To determine whether mitochondrial DAMPs play a role in hepatic organ damage after cold IR or warm IR, we used a Modular Incubator Chamber to simulate hypoxia at 4°C or at 37°C followed by transferring to a normoxic, humidified incubator at 37°C
Summary
Ischemia reperfusion injury (IRI) is a phenomenon whereby cellular damage in a hypoxic organ is exacerbated following the restoration of oxygen delivery [1]. The ongoing donor organ shortage has led to the increased use of extended criteria donor organs, i.e. those from older or steatotic donors, or from donors after cardiocirculatory death, as well as organs that have been subjected to prolonged periods of cold ischemia. These organs are more susceptible to IRI. An improved understanding of the mechanisms underlying hepatic IRI may lead to more effective therapeutic interventions to minimize liver dysfunction and improve transplant outcomes
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