Dataset Information

Augmenter of Liver Regeneration Reduces Ischemia Reperfusion Injury by Less Chemokine Expression, Gr-1 Infiltration and Oxidative Stress.

ABSTRACT: Hepatic ischemia reperfusion injury (IRI) is a major complication in liver resection and transplantation. Here, we analyzed the impact of recombinant human augmenter of liver regeneration (rALR), an anti-oxidative and anti-apoptotic protein, on the deleterious process induced by ischemia reperfusion (IR). Application of rALR reduced tissue damage (necrosis), levels of lipid peroxidation (oxidative stress) and expression of anti-oxidative genes in a mouse IRI model. Damage associated molecule pattern (DAMP) and inflammatory cytokines such as HMGB1 and TNF?, were not affected by rALR. Furthermore, we evaluated infiltration of inflammatory cells into liver tissue after IRI and found no change in CD3 or ??TCR positive cells, or expression of IL17/IFN? by ??TCR cells. The quantity of Gr-1 positive cells (neutrophils), and therefore, myeloperoxidase activity, was lower in rALR-treated mice. Moreover, we found under hypoxic conditions attenuated ROS levels after ALR treatment in RAW264.7 cells and in primary mouse hepatocytes. Application of rALR also led to reduced expression of chemo-attractants like CXCL1, CXCL2 and CCl2 in hepatocytes. In addition, ALR expression was increased in IR mouse livers after 3 h and in biopsies from human liver transplants with minimal signs of tissue damage. Therefore, ALR attenuates IRI through reduced neutrophil tissue infiltration mediated by lower expression of key hepatic chemokines and reduction of ROS generation.

SUBMITTER: Weiss TS

PROVIDER: S-EPMC6912457 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Augmenter of Liver Regeneration Reduces Ischemia Reperfusion Injury by Less Chemokine Expression, Gr-1 Infiltration and Oxidative Stress.

Weiss Thomas S TS Lupke Madeleine M Dayoub Rania R Geissler Edward K EK Schlitt Hans J HJ Melter Michael M Eggenhofer Elke E

Cells 20191112 11

Hepatic ischemia reperfusion injury (IRI) is a major complication in liver resection and transplantation. Here, we analyzed the impact of recombinant human augmenter of liver regeneration (rALR), an anti-oxidative and anti-apoptotic protein, on the deleterious process induced by ischemia reperfusion (IR). Application of rALR reduced tissue damage (necrosis), levels of lipid peroxidation (oxidative stress) and expression of anti-oxidative genes in a mouse IRI model. Damage associated molecule pat ...[more]

PMID: 31718093

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Project description:BackgroundAcute renal injury (AKI) secondary to ischemia reperfusion (IR) injury continues to be a significant perioperative problem and there is no effective treatment. Mindin belongs to the mindin/F-spondin family and involves in inflammation, proliferation, and cell apoptosis. Previous studies have explored the biological functions of mindin in liver and brain ischemic injury, but its role in AKI is unknown.MethodTo investigate whether mindin has a pathogenic role, mindin knockout (KO) and wild-type (WT) mice were used to establish renal IR model. After 30 min of ischemia and 24 h of reperfusion, renal histology, serum creatinine, and inflammatory response were examined to assess kidney injury. In vitro, proinflammatory factors and inflammatory signaling pathways were measured in mindin overexpression or knockdown and vector cells after hypoxia/reoxygenation (HR).ResultsFollowing IR, the kidney mindin level was increased in WT mice and deletion of mindin provided significant protection for mice against IR-induced renal injury as manifested by attenuated the elevation of serum creatinine and blood urea nitrogen along with less severity for histological alterations. Mindin deficiency significantly suppressed inflammatory cell infiltration, TNF-α and MCP-1 production following renal IR injury. Mechanistic studies revealed that mindin deficiency inhibits TLR4/JNK/NF-κB signaling activation. In vitro, the expression levels of TNF-α and MCP-1 were increased in mindin overexpression cells compared with vector cells following HR. Moreover, TLR4/JNK/NF-κB signaling activation was elevated in the mindin overexpression cells in response to HR stimulation while mindin knockdown inhibited the activation of TLR4/JNK/ NF-κB signaling after HR in vitro. Further study showed that mindin protein interacted directly with TLR4 protein. And more, mindin protein was confirmed to be expressed massively in renal tubule tissues of human hydronephrosis patients.ConclusionThese data demonstrate that mindin is a critical modulator of renal IR injury through regulating inflammatory responses. TLR4/JNK/NF-κB signaling most likely mediates the biological function of mindin in this model of renal ischemia.

Project description:Mitochondrial inner membrane protein (Mitofilin or Mic60) is a mitochondria-shaping protein that plays a key role in maintaining mitochondrial cristae structure and remodeling. We recently showed that Mitofilin knockdown in H9c2 myoblasts induces mitochondrial structural damage resulting in mitochondrial dysfunction that is responsible for cell death via apoptosis. Here, we investigated the role of Mitofilin regulation in ischemia/reperfusion (I/R) injury and studied the relationship between Mitofilin and Cyclophilin (CypD), a key regulator of mitochondrial permeability transition pore (mPTP) opening. C57Bl6 male mice hearts were subjected to different ischemia times (15, 30, or 45 min) followed by a 2 h reperfusion period, or 45 min ischemia followed by 0, 15, 30, 60, or 120 min reperfusion to determine the impact of ischemia or reperfusion times on Mitofilin levels and its interaction with CypD. We found that the increase in myocardial infarct size and the reduction of mitochondrial calcium retention capacity were concomitant with Mitofilin reduction as a function of ischemic duration. We also found that 15 min reperfusion after 45 min ischemia was sufficient to cause a reduction of Mitofilin levels compared to sham, while 45 min ischemia alone was not enough to cause a significant decrease of Mitofilin. We revealed that the c-terminus coiled-coiled domain of Mitofilin is important for its interaction with CypD and the deletion of this identified sequence resulted in a loss of Mitofilin-CypD link, dissipation of mitochondrial membrane potential and increase in cell death. A decrease of the levels of Mitofilin was also associated with mitochondrial structural integrity damage, increased reactive oxygen species (ROS) production, and calpain activity. Our results indicate that Mitofilin physically binds to CypD in the inner mitochondrial membrane and the disruption of this interaction may play a critical role in the increase of mitochondrial dysfunction and initiation of myocytes' death after I/R injury.

Dataset Information

Augmenter of Liver Regeneration Reduces Ischemia Reperfusion Injury by Less Chemokine Expression, Gr-1 Infiltration and Oxidative Stress.

Publications

Augmenter of Liver Regeneration Reduces Ischemia Reperfusion Injury by Less Chemokine Expression, Gr-1 Infiltration and Oxidative Stress.

Similar Datasets

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