Abstract
The purpose of this study was to investigate the protective mechanism of HDAC2 inhibitor CAY10683 on intestinal mucosal barrier in acute liver failure (ALF). In order to establish ALF-induced intestinal epithelial barrier disruption models, D-galactosamine/LPS and LPS were, respectively, used with rats and NCM460 cell and then administrated with CAY10683. Transepithelial electrical resistance (TEER) was measured to detect the permeability of cells. Real-time PCR and Western blotting were employed to detect the key mRNA and protein levels. The intestinal epithelial tissue pathology was detected. After interfering with CAY10683, the mRNA and protein levels of TLR4, MyD88, TRIF, and TRAF6 were decreased compared with model group (P < 0.05), whereas the levels of ZO-1 and occluding were elevated (P < 0.05). The permeability was elevated in CAY10683-interfered groups, when compared with model group (P < 0.05). And the degree of intestinal epithelial tissue pathological damage in CAY10683 group was significantly reduced. Moreover, CAY10683 significantly decreased the TLR4 staining in animal tissue. The HDAC2 inhibitor CAY10683 could promote the damage of intestinal mucosal barrier in ALF through inhibiting LPS/TLR4/MyD88 pathway.
Highlights
Acute liver failure (ALF), caused by a large area of hepatocyte necrosis, is a serious clinical syndrome and characterized by the rapid progress of hepatic encephalopathy and severe liver damage associated with high mortality [1]
After interfering with CAY10683, the mRNA and protein levels of TLR4, myeloid differentiation primary response gene 88 (MyD88), toll-interleukin-1 receptor domain-containing adaptor inducing interferon β (TRIF), and TNF-α receptor association factor 6 (TRAF6) were decreased compared with model group (P < 0 05), whereas the levels of ZO-1 and occluding were elevated (P < 0 05)
Endotoxin is a lipopolysaccharide component located in gram-negative bacterial cell wall that passes through the damaged intestinal mucosal barrier
Summary
Acute liver failure (ALF), caused by a large area of hepatocyte necrosis, is a serious clinical syndrome and characterized by the rapid progress of hepatic encephalopathy and severe liver damage associated with high mortality [1]. Systemic and intestinal immune system in the early stage of ALF showed the inhibited state, so the removal of bacterial capacity decreased and the displacement of bacteria could break through the limitations of mesenteric lymph nodes to migrate and colonize to the other body tissues and organs, which could result intestinal mucosal barrier dysfunction, increased permeability, intestinal bacterial translocation, and intestinal endotoxemia, and the result in inflammatory response can further cause systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) [3]. LPS could aggravate the inflammatory injury of the intestinal mucosal barrier, promote the migration of bacteria and endotoxin, and format a vicious cycle.
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