Abstract
Hepatic ischemia/reperfusion injury (IRI) is an unavoidable course in liver transplantation, during which the immune response of inflammation plays a leading part. MicroRNA-450b-5p (miR-450b-5p), which has been reported to participate in several inflammatory diseases, was investigated in this study. The purpose of this study is to identify the potential function of miR-450b-5p toward remission of hepatic IRI and elucidate the specific mechanism. Herein we found that expression of miR-450b-5p, interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 was stimulated in hepatic IRI. Inhibition of miR-450b-5p could remarkably alleviate mouse hepatic IRI and improve liver function measured by hematoxylin–eosin (HE) staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), and enzyme-linked immunosorbent assay (ELISA). We further assessed protein expression undergoing Western blot and immunofluorescence, and discovered that miR-450b-5p suppressed alpha B-crystallin (CRYAB), thus restraining the inhibitory κB kinase (IKK) β-mediated canonical nuclear factor-κB (NF-κB) signaling, instead of the noncanonical path guided by IKKα in hepatic IRI. In addition, we demonstrated CRYAB as an activator of M2 polarization through protein kinase B (Akt) 1/mammalian target of rapamycin (mTOR), thus resulting in relief of liver IRI. Combination treatment containing both paths revealed a better antidamage efficacy than adjusting either path alone, suggesting that the joint therapy might be a promising solution in hepatic IRI.
Highlights
Liver transplantation has gradually become one of the most effective treatments for various end-stage liver diseases, during which the hepatic ischemia/reperfusion injury (IRI) is an inevitable pathological process that can lead to liver dysfunction and graft loss[1,2]
Expression of miR-450b-5p and nuclear factor-κB (NF-κB) pathway-associated protein was increased in hepatic IRI accompanied by downregulation of CRYAB H/R model as a classic in vitro model of hepatic IRI was constructed to examine the possible role of miR-450b-5p and CRYAB
Hepatic IRI is a constitutive process during liver transplantation, and some hepatectomies, the mechanism of which has been so far manifested to include inflammation, oxidative stress, and apoptosis, remain not fully explored[26,27]
Summary
Liver transplantation has gradually become one of the most effective treatments for various end-stage liver diseases, during which the hepatic ischemia/reperfusion injury (IRI) is an inevitable pathological process that can lead to liver dysfunction and graft loss[1,2]. The whole molecular mechanism of hepatic IRI remains to be unfolded[3,4]. Occurrence of inflammation induced by NF-κB plays a critical part among these disparate pathogeneses[5,6,7]. As an important member of small heat-shock protein, CRYAB displays a proper role with identification of the anti-inflammatory effect[12,13]. Recent studies indicated that CRYAB could serve as a potential target in response to stimulation of inflammatory cytokines, through suppression of IKK in intestinal mucosal inflammation[14]. Given the pivotal role of IKK in the initiation of NF-κB signaling, CRYAB is likely to control the occurrence and progress of inflammation in hepatic IRI to some extent, the specific molecular mechanism of which needs an indepth exploration[8,15]
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