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Acid Ceramidase Protects Against Hepatic Ischemia/Reperfusion Injury by Modulating Sphingolipid Metabolism and Reducing Inflammation and Oxidative Stress.

ABSTRACT: Ceramide is a bioactive signaling lipid involved in the pathogenesis of numerous diseases. It also plays an important role in ischemia reperfusion (IR) injury via activation of inflammatory/oxidative stress-stimulated signaling pathways, resulting in tissue damage. Acid ceramidase is a lipid hydrolase that modulates the levels of ceramide, and as such has a potential therapeutic role in many human diseases where ceramide has been implicated. Here we investigated the therapeutic potential of recombinant acid ceramidase in a murine model of hepatic IR injury. Serum ALT, AST, and LDH activities, as well as oxidative stress (MDA) and inflammatory (MCP-1) markers, were increased in mice subjected to IR compared to a sham group. In contrast, these elevations were significantly lower in an IR group pretreated with a single injection of acid ceramidase. Histological examination by two different assessment criteria also revealed that acid ceramidase pretreatment alleviated IR-induced hepatocyte damage, including reduced evidence of cell death and necrosis. In addition, elevated ceramide and sphingosine levels were observed in the IR group compared to sham, and were markedly reduced when pretreated with acid ceramidase. In contrast, the levels of the protective signaling lipid, sphingosine-1-phosphate (S1P), were reduced following IR and elevated in response to acid ceramidase pretreatment. These changes in sphingolipid levels could be correlated with changes in the activities of several sphingolipid-metabolizing enzymes. Overall, these results indicated that sphingolipid changes were an important pathologic component of hepatic IR injury, and that acid ceramidase administration ameliorated these lipid changes and other downstream pathologic changes.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC8134688 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionSurgery, a crucial therapeutic modality in the treatment of solid tumors, can induce sterile inflammatory processes which can result in metastatic progression. Liver ischemia and reperfusion (I/R) injury, an inevitable consequence of hepatic resection of metastases, has been shown to foster hepatic capture of circulating cancer cells and accelerate metastatic growth. Efforts to reduce these negative consequences have not been thoroughly investigated. Drag reducing polymers (DRPs) are blood-soluble macromolecules that can, in nanomolar concentrations, increase tissue perfusion, decrease vascular resistance and decrease near-wall microvascular concentration of neutrophils and platelets thereby possibly reducing the inflammatory microenvironment. We hypothesize that DRP can potentially be used to ameliorate metastatic capture of tumor cells and tumor growth within the I/R liver.MethodsExperiments were performed utilizing a segmental ischemia model of mice livers. Five days prior or immediately prior to ischemia, murine colon adenocarcinoma cells (MC38) were injected into the spleen. DRP (polyethylene oxide) or a control of low-molecular-weight polyethylene glycol without drag reducing properties were administered intraperitoneally at the onset of reperfusion.ResultsAfter three weeks from I/R, we observed that liver I/R resulted in an increased ability to capture and foster growth of circulating tumor cells; in addition, the growth of pre-existing micrometastases was accelerated three weeks later. These effects were significantly curtailed when mice were treated with DRPs at the time of I/R. Mechanistic investigations in vivo indicated that DRPs protected the livers from I/R injury as evidenced by significant decreases in hepatocellular damage, neutrophil recruitment into the liver, formation of neutrophil extracellular traps, deposition of platelets, formation of microthrombi within the liver sinusoids and release of inflammatory cytokines.ConclusionsDRPs significantly attenuated metastatic tumor development and growth. DRPs warrant further investigation as a potential treatment for liver I/R injury in the clinical setting to improve cancer-specific outcomes.

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Acid Ceramidase Protects Against Hepatic Ischemia/Reperfusion Injury by Modulating Sphingolipid Metabolism and Reducing Inflammation and Oxidative Stress.

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