Molecular mechanism mediating enteric bacterial translocation after severe burn: the role of cystic fibrosis transmembrane conductance regulator

Xinzhu Liu; Yu Chen; Bo You; Yuan Peng; Yajie Chen; Zichen Yang; Yixin Zhang; Jing Chen

doi:10.1093/burnst/tkaa042

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Molecular mechanism mediating enteric bacterial translocation after severe burn: the role of cystic fibrosis transmembrane conductance regulator

更新时间：2022-06-14

- Molecular mechanism mediating enteric bacterial translocation after severe burn: the role of cystic fibrosis transmembrane conductance regulator
- Burns & Trauma Vol. 9, Issue 1, (2021)
- 作者机构：
  
  1. State Key Laboratory of Trauma
  2. Department of Burn and Plastic Surgery
  3. Department of Plastic and Reconstructive Surgery
- 作者简介：
- 基金信息：
- DOI：10.1093/burnst/tkaa042
  CLC：
- Published：2021，
  
  Published Online：15 January 2021，
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Xinzhu Liu, Yu Chen, Bo You, Yuan Peng, Yajie Chen, Zichen Yang, Yixin Zhang, Jing Chen, Molecular mechanism mediating enteric bacterial translocation after severe burn: the role of cystic fibrosis transmembrane conductance regulator, Burns & Trauma, Volume 9, 2021, tkaa042, https://doi.org/10.1093/burnst/tkaa042
DOI：

Xinzhu Liu, Yu Chen, Bo You, Yuan Peng, Yajie Chen, Zichen Yang, Yixin Zhang, Jing Chen, Molecular mechanism mediating enteric bacterial translocation after severe burn: the role of cystic fibrosis transmembrane conductance regulator, Burns & Trauma, Volume 9, 2021, tkaa042, https://doi.org/10.1093/burnst/tkaa042 DOI：

摘要

Abstract

BackgroundGut ischemia and hypoxia post severe burn leads to breakdown of intestinal epithelial barrier and enteric bacterial translocation (EBT)

resulting in serious complications

such as systemic inflammatory response syndrome

sepsis and multiple organ failure. Cystic fibrosis transmembrane conductance regulator (CFTR) is known to be downregulated by hypoxia and modulate junctional complexes

which are crucial structures maintaining the intestinal barrier. This study aimed to investigate whether CFTR plays a role in both regulating the intestinal barrier and mediating EBT post severe burn

as well as the signaling pathways involved in these processes.MethodsAn in vitro Caco-2 cell model subjected to hypoxic injury and an in vivo mouse model with a 30% total body surface area full-thickness dermal burn were established. DF 508 mice (mice with F508del CFTR gene mutation) were used as an in vivo model to further demonstrate the role of CFTR in maintaining normal intestinal barrier function. QRT-PCR

western blot

ELISA

TER assay and immunofluorescence staining were used to detect the expression and localization of CFTR and tight junction proteins

as well as the function of tight junctions.ResultsOur data indicated that

in Caco-2 cells

the hypoxia condition significantly reduced CFTR expression; activated extracellular signal-regulated kinase and nuclear factor-κB signaling; elevated secretion of inflammatory factors (tumor necrosis factor-α

interleukin-1β and interleukin-8); downregulated zonula occludens-1

occludin and E-cadherin expression; decreased transepithelial electrical resistance values; and led to a cellular mislocation of ZO-1. More importantly

knockdown of CFTR caused similar alterations. The upregulation of inflammatory factors and downregulation of tight junction proteins (ZO-1 and occludin) induced by knockdown of CFTR could be reversed by specific extracellular signal-regulated kinase or nuclear factor-κB inhibition. In support of the in vitro data

exuberant secretion of pro-inflammatory mediators and EBT was observed in the intestine of severely burnt mice in vivo. EBT occurred in DF508 mice (mice with the F508del CFTR gene mutation)

accompanied by augmented tumor necrosis factor-α

interleukin-1β and interleukin-8 levels in the ileum compared to wildtype mice. In addition

vitamin D3 was shown to protect the intestinal epithelial barrier from hypoxic injury.ConclusionsCollectively

the present study illustrated that CFTR and downstream signaling were critical in modulating the intestinal epithelial junction and EBT post severe burn.

关键词

Keywords

Burn InflammationIntestinal junctionEnteric bacterial translocationVitamin D3Bacterial translocationCystic fibrosis transmembrane

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