Quercetin protects against intestinal barrier disruption and inflammation in acute necrotizing pancreatitis through TLR4/MyD88/p38 MAPK and ERS inhibition

Pancreatology. 2018 Oct;18(7):742-752. doi: 10.1016/j.pan.2018.08.001. Epub 2018 Aug 6.

Abstract

Objective: To investigate the effects of quercetin on intestinal barrier disruption and inflammation in acute necrotizing pancreatitis (ANP) in rats, and its possible mechanism.

Methods: ANP was established by retrograde injection of 3.5% sodium taurocholate into the biliopancreatic duct, and quercetin (50 mg/kg × 3) was administered by intraperitoneal injection prior to and after ANP induction. Pancreatitis was assessed by pancreatic histopathology, plasma amylase, pancreatic myeloperoxidase (MPO) activity, IL-1β, TNFα and IL-6 levels. Injury of the distal ileum was assessed by histological evaluation. The ultrastructural changes of ileal epithelial cells were examined by transmission electron microscope (TEM). Intestinal barrier function was estimated by plasma diamine oxidase (DAO), d-lactate, endotoxin; and intestinal tight junction proteins including zonula occludens-1 (ZO-1), claudin 1, occludin; and bacterial translocation. Intestinal inflammation was determined by IL-1β, TNFα and IL-17 A expression. TLR4, MyD88, pp38 MAPK, and endoplasmic reticulum stress (ERS)-related molecules (Bip, p-IRE1α, sXBP1, p-eIF2α, ATF6) were measured by immunohistochemistry and WB.

Results: Quercetin intervention attenuated pancreatic and ileal pathological damages in ANP (P < 0.05), ameliorated intestinal barrier disruption and inflammation (P < 0.05). Meantime, QE significantly suppressed intestinal TLR4/MyD88/p38 MAPK pathway and ERS activation.

Conclusions: Quercetin plays a protective role against intestinal barrier disruption and inflammation in ANP, probably partly by inhibiting TLR4/MyD88/p38 MAPK and ERS activation.

Keywords: Acute necrotizing pancreatitis; Endoplasmic reticulum stress; Ileum; Quercetin; TLR4/MyD88/p38 MAPK pathway.

MeSH terms

  • Endoplasmic Reticulum Stress / drug effects
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation / prevention & control*
  • Intestines / drug effects
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • Pancreatitis, Acute Necrotizing / chemically induced
  • Pancreatitis, Acute Necrotizing / drug therapy*
  • Quercetin / pharmacology*
  • Taurocholic Acid / toxicity
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Myd88 protein, rat
  • Myeloid Differentiation Factor 88
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Taurocholic Acid
  • Quercetin
  • p38 Mitogen-Activated Protein Kinases