| First Author | Feng Y | Year | 2013 |
| Journal | J Physiol | Volume | 591 |
| Issue | 15 | Pages | 3709-23 |
| PubMed ID | 23753529 | Mgi Jnum | J:212137 |
| Mgi Id | MGI:5578112 | Doi | 10.1113/jphysiol.2013.253518 |
| Citation | Feng Y, et al. (2013) Tumour necrosis factor--induced loss of intestinal barrier function requires TNFR1 and TNFR2 signalling in a mouse model of total parenteral nutrition. J Physiol 591(Pt 15):3709-23 |
| abstractText | Tumour necrosis factor-alpha (TNF-alpha) has been reported to play a central role in intestinal barrier dysfunction in many diseases; however, the precise role of the TNF-alpha receptors (TNFRs) has not been well defined using in vivo models. Our previous data showed that enteral nutrient deprivation or total parenteral nutrition (TPN) led to a loss of intestinal epithelial barrier function (EBF), with an associated upregulation of TNF-alpha and TNFR1. In this study, we hypothesized that TNF-alpha plays an important role in TPN-associated EBF dysfunction. Using a mouse TPN model, we explored the relative roles of TNFR1 vs. TNFR2 in mediating this barrier loss. C57/BL6 mice underwent intravenous cannulation and were given enteral nutrition or TPN for 7 days. Tumour necrosis factor-alpha receptor knockout (KO) mice, including TNFR1KO, TNFR2KO or TNFR1R2 double KO (DKO), were used. Outcomes included small intestine transepithelial resistance (TER) and tracer permeability, junctional protein zonula occludens-1, occludin, claudins and E-cadherin expression. In order to address the dependence of EBF on TNF-alpha further, exogenous TNF-alpha and pharmacological blockade of TNF-alpha (Etanercept) were also performed. Total parenteral nutrition led to a loss of EBF, and this was almost completely prevented in TNFR1R2DKO mice and partly prevented in TNFR1KO mice but not in TNFR2KO mice. The TPN-associated downregulation of junctional protein expression and junctional assembly was almost completely prevented in the TNFR1R2DKO group. Blockade of TNF-alpha also prevented dysfunction of the EBF and junctional protein losses in mice undergoing TPN. Administration of TPN upregulated the downstream nuclear factor-B and myosin light-chain kinase (MLCK) signalling, and these changes were almost completely prevented in TNFR1R2DKO mice, as well as with TNF-alpha blockade, but not in TNFR1KO or TNFR2KO TPN groups. Tumour necrosis factor-alpha is a critical factor for TPN-associated epithelial barrier dysfunction, and both TNFR1 and TNFR2 are involved in EBF loss. Nuclear factor-B and MLCK signalling appear to be important downstream mediators involved in this TNF-alpha signalling process. |
