Dexmedetomidine Alleviates Gut-Vascular Barrier Damage and Distant Hepatic Injury Following Intestinal Ischemia/Reperfusion Injury in Mice

Abstract

BACKGROUND: Intestinal ischemia/reperfusion (I/R) challenge often results in gut barrier dysfunction and induces distant organ injury. Dexmedetomidine has been shown to protect intestinal epithelial barrier against I/R attack. The present study aims to investigate the degree to which intestinal I/R attack will contribute to gut-vascular barrier (GVB) damage, and to examine the ability of dexmedetomidine to minimize GVB and liver injuries in mice. METHODS: In vivo, intestinal ischemic challenge was induced in mice by clamping the superior mesenteric artery for 45 minutes. After clamping, the mice were subjected to reperfusion for either 2, 4, 6, or 12 hours. Intraperitoneal injection of dexmedetomidine 15, 20, or 25 μg•kg -1 was performed intermittently at the phase of reperfusion. For the in vitro experiments, the challenge of oxygen-glucose deprivation/reoxygenation (OGD/R) was established in cultured vascular endothelial cells, and dexmedetomidine (1 nM) was used to treat the cells for 24 hours. Moreover, in vivo and in vitro, SKL2001 (a specific agonist of β-catenin) or XAV939 (a specific inhibitor of β-catenin) was applied to determine the role of β-catenin in the impacts provided by dexmedetomidine. RESULTS: The attack of intestinal I/R induced GVB damage. The greatest level of damage was observed at 4 hours after intestinal reperfusion. There was a significant increase in plasmalemma vesicle-associated protein-1 (PV1, a specific biomarker for endothelial permeability) expression (5.477 ± 0.718 vs 1.000 ± 0.149; P < .001), and increased translocation of intestinal macromolecules and bacteria to blood and liver tissues was detected (all P < .001). Liver damages were observed. There were significant increases in histopathological scores, serum parameters, and inflammatory factors (all P < .001). Dexmedetomidine 20 μg•kg -1 reduced PV1 expression (0.466 ± 0.072 vs 1.000 ± 0.098; P < .001) and subsequent liver damages (all P < .01). In vitro, dexmedetomidine significantly improved vascular endothelial cell survival (79.387 ± 6.447% vs 50.535 ± 1.766%; P < .001) and increased the productions of tight junction protein and adherent junction protein (all P < .01) following OGD/R. Importantly, in cultured cells and in mice, β-catenin expression significantly decreased (both P < .001) following challenge. Dexmedetomidine or SKL2001 upregulated β-catenin expression and produced protective effects (all P < .01). However, XAV939 completely eliminated the protective effects of dexmedetomidine on GVB (all P < .001).

Improvement of gut-vascular barrier by terlipressin reduces bacterial translocation and remote organ injuries in gut-derived sepsis

“…β-catenin is essential for reducing the vascular permeability and bacterial penetration (Spadoni, Zagato et al, 2015;Mouries, Brescia et al, 2019;Zhang, Chang et al, 2022). Several studies demonstrated that upregualtion of β-catenin could improve GVB in pathologic conditions (Birdsey, Shah et al, 2015;Mouries, Brescia et al, 2019;Zhang, Chang et al, 2022). When we knocked down β-catenin in endothelial monolayer, the increased TER, tight and adhesin junction proteins and decreased permeability across HUVEC monolayers conferred by terlipressin sharply changed (Figure 6).…”

“…The sample size analysis was performed based on our literature (Zhang, Chang et al, 2022) and the Power and Sample Size online software (http://powerandsamplesize. com/Calculators/).…”

“…The current application of terlipressin increased p-GSK-3β and βcatenin expression, but decreased p-β-catenin in intestinal tissues (Figure 5). β-catenin is essential for reducing the vascular permeability and bacterial penetration (Spadoni, Zagato et al, 2015;Mouries, Brescia et al, 2019;Zhang, Chang et al, 2022). Several studies demonstrated that upregualtion of β-catenin could improve GVB in pathologic conditions (Birdsey, Shah et al, 2015;Mouries, Brescia et al, 2019;Zhang, Chang et al, 2022).…”

Bibliometric and visual analysis of intestinal ischemia reperfusion from 2004 to 2022

“…As for intestinal injury mechanisms, dexmedetomidine may inhibit p38MAPK, and TLR4/MyD88/NF-κB signaling pathways and activate Jak/STAT signaling pathways, attenuating intestinal injury ( 74 – 76 ). Reportedly, dexmedetomidine pretreatment alleviates intestinal vascular barrier injury and is clarified to attenuate distal liver injury ( 77 ).…”

Dexmedetomidine prevents PDIA3 decrease by activating α2-adrenergic receptor to alleviate intestinal ischemia/reperfusion in mice

“…DEX has been reported to be a potential drug for the prevention and treatment of intestinal I/R injury ( 7 , 9 , 16 , 18 , 19 ). Our results elaborated that the protection from DEX in mice with intestinal I/R injury evidenced with an inhibition of inflammation, ER stress-dependent apoptosis, and oxidative stress in the intestinal mucosa.…”