Effect of dexmedetomidine on intestinal barrier function in mice with traumatic brain injury and the role of Nrf2/HO-1 signaling pathway / 中华麻醉学杂志

ABSTRACT

Objective:To evaluate the effect of dexmedetomidine on intestinal barrier function in mice with traumatic brain injury (TBI) and the role of nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway.Methods:Thirty ICR male wild-type (WT) and 30 Nrf2 knockout (Nrf2-KO) mice, aged 6-8 weeks, weighing 20-25 g, were divided into 3 groups ( n=10 each) using a random number table method: control group (group C), TBI group (group T) and TBI+ dexmedetomidine group (group T+ D). A 100 g of stainless steel impactor was used to produce a free fall acceleration strike on the head from 12 cm height in anesthetized animals.Dexmedetomidine 30 μg/kg was intraperitoneally injected at 30 min before TBI in group T+ D, while the equal volume of normal saline was given instead in C and TBI groups.The mouse bladder was emptied at 18 h after TBI, the test solution 200 μl containing 13.3 mg lactulose and 10.1 mg mannitol was given via a gastric tube.Urine was collected at 24 h after TBI, and the ratio of lactulose to mannitol was measured to estimate the intestinal barrier permeability.Blood samples were collected from heart to measure the concentration of lipopolysaccharide in plasma.Then the mice were sacrificed, and the tissues of ileum were collected to detect the contents of tumor necrosis factor-alpha(TNF-α), interleukin-1beta(IL-1β), IL-6 and 8-iso-prostaglandin F 2α (8-iso-PGF 2α) (by enzyme-linked immunosorbent assay), contents of superoxide dismutase (SOD) and catalase (CAT) (by hydroxylamine method and ammonium molybdate colorimetric method, respectively), content of malondialdehvde (MDA) (by thibabituric acid method), and expression of Nrf2 and HO-1 (by Western blot). Results:For WT mice Compared with group C, the intestinal barrier permeability, concentration of LPS in plasma, and contents of TNF-α, IL-1β, IL-6, MDA and 8-iso-PGF 2α were significantly increased, the activities of intestinal CAT and SOD were decreased, and the expression of Nrf2 and HO-1 was up-regulated in T and T+ D groups ( P<0.05). Compared with group T, the intestinal barrier permeability, concentration of LPS in plasma, and contents of TNF-α, IL-1β, IL-6, MDA and 8-iso-PGF 2α were significantly decreased, the activities of intestinal CAT and SOD were increased, and the expression of Nrf2 and HO-1 was up-regulated in group T+ D ( P<0.05). For Nrf2-KO mice Compared with group C, the intestinal barrier permeability, concentration of LPS in plasma, and contents of TNF-α, IL-1β, IL-6, MDA and 8-iso-PGF 2α were significantly increased, and no significant change was found in the activities of intestinal CAT and SOD in T and T+ D groups( P>0.05). There was no significant difference in the expression of HO-1 among the three groups ( P>0.05). Conclusion:Dexmedetomidine can improve the intestinal barrier dysfunction in mice with TBI, and the mechanism is related to activating Nrf2/HO-1 signaling pathway.