Inhibition of macrophage migration inhibitory factor (MIF) suppresses apoptosis signal-regulating kinase 1 to protect against liver ischemia/reperfusion injury

Abstract

Background: Hepatic ischemia–reperfusion (I/R) injury is a major complication leading to surgical failures in liver resection, transplantation, and hemorrhagic shock. The role of cytokine macrophage migration inhibitory factor (MIF) in hepatic I/R injury is unclear.Methods: We examined changes of MIF expression in mice after hepatic I/R surgery and hepatocytes challenged with hypoxia–reoxygenation (H/R) insult. Subsequently, MIF global knock-out mice and mice with adeno-associated-virus (AAV)-delivered MIF overexpression were subjected to hepatic I/R injury. Hepatic histology, the inflammatory response, apoptosis and oxidative stress were monitored to assess liver damage. The molecular mechanisms of MIF function were explored in vivo and in vitro.Results: MIF was significantly upregulated in the serum whereas decreased in liver tissues of mice after hepatic I/R injury. MIF knock-out effectively attenuated I/R -induced liver inflammation, apoptosis and oxidative stress in vivo and in vitro, whereas MIF overexpression significantly aggravated liver injury. Via RNA-seq analysis, we found a significant decreased trend of MAPK pathway in MIF knock-out mice subjected hepatic I/R surgery. Using the apoptosis signal-regulating kinase 1 (ASK1) inhibitor NQDI-1 we determined that, mechanistically, the protective effect of MIF deficiency on hepatic I/R injury was dependent on the suppressing of the ASK1-JNK/P38 signaling pathway. Moreover, we found MIF inhibitor ISO-1 alleviate hepatic I/R injury in mice.Conclusion: Our results confirm that MIF deficiency suppresses the ASK1-JNK/P38 pathway and protects the liver from I/R -induced injury. Our findings suggest MIF as a novel biomarker and therapeutic target for the diagnosis and treatment of hepatic I/R injury.

ASK1 inhibitor NQDI‑1 decreases oxidative stress and neuroapoptosis via the ASK1/p38 and JNK signaling pathway in early brain injury after subarachnoid hemorrhage in rats

“…NQDI-1 is a specific inhibitor of ASK1 and its functional role has been previously demonstrated using in vitro kinase assays (11,33). in a mouse model of acute pancreatitis, nQdi-1 decreases pancreatic follicular cell necrosis through decrease of roS production and receptor interacting serine/threonine kinase 3 and p-mixed lineage kinase domain-like pseudokinase protein expression levels (34).…”

Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

“…We constructed a partial (70%) liver IRI model as previously described 18 . In brief, mice were fasted but drank freely for 12 h before the operation.…”

“…Hematoxylin and eosin (H&E) and IHC staining were performed using paraffin‐embedded liver sections as previously reported 18 . Liver tissues were sectioned serially at a 5‐μm thickness.…”

“…We constructed a partial (70%) liver IRI model as previously described. 18 In brief, mice were fasted but drank freely for 12 h before the operation. Mice were anesthetized by intraperitoneal injection of pentobarbital sodium (50 mg/kg, Sigma, St. Louis, MO, USA).…”

“…Hematoxylin and eosin (H&E) and IHC staining were performed using paraffin-embedded liver sections as previously reported. 18 Liver tissues were sectioned serially at a 5-μm thickness. Sections were stained with H&E to visualize necrotic areas after deparaffinization and rehydration.…”