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Background & Aims: Our previous studies have provided evidence that p38 mitogen-activated protein kinase (MAPK) is involved in total parenteral nutrition (TPN)-associated complications, but its exact effects and mechanisms have not been fully understood. This study aimed to evaluate the roles of p38 MAPK inhibitor SB203580 in the TPN-induced loss of intestinal barrier function and liver disease., Methods: A rodent model of TPN was used to analyze the roles of SB203580 in TPN-associated complications.Intestinal barrier function was evaluated by transepithelial electrical resistance (TER) and paracellular permeability in Caco-2 cells. The palmitic acid (PA) was used to induce hepatic lipoapoptosis in vitro. The lipoapoptosis was detected using Caspase-3/7 and lipid staining., Results: In the present study, we showed that SB203580 treatment significantly suppressed TPN-mediated intestinal permeability in rats. SB203580 treatment significantly inhibited IL-1β-induced an increase in tight junction permeability of Caco-2 cells via repressing the p38/ATF-2 signaling. Unexpectedly, SB203580 treatment enhanced hepatic lipoapoptosis in the model of TPN. Palmitic acid (PA)-induced hepatic lipoapoptosis in human liver cells was significantly augmented by the SB203580 treatment., Conclusions: We demonstrate that the p38 MAPK inhibitor SB203508 ameliorates intestinal barrier function but promotes hepatic lipoapoptosis in model of TPN., (© 2017 The Author(s)Published by S. Karger AG, Basel.)

The cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) have been implicated as important mediators of the inflammatory reaction in patients with intestinal inflammation. The present study was designed to investigate the roles of these cytokines on mucosal barrier function in a mouse model of acute colitis with using anti-cytokine strategies. Mice received 3% dextran sulfate sodium (DSS) in their drinking water for 7days showed morphological alteration of mucosa and increase of intestinal permeability. Administration of IL-6 monoclonal antibody (mAb) or TNF-α mAb significantly attenuated intestinal permeability. IL-6 mAb and TNF-α mAb treatment also effectively suppressed the expression of claudin-2 and myosin light chain kinase (MLCK). Taken together, we indicated that anti-IL-6 and anti-TNF-α therapy prevent intestinal permeability induced by intestinal inflammation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To initially investigate the expressing regularity and effect of enterocyte NOD like receptors on gut mucosal barrier during early phase of acute intra-abdominal infection., Methods: Sprague-Dawley (SD) rats were randomly allocated into control group (n=6) and experimental group (n=24). Acute intra-abdominal infection model was induced by cecal ligation and puncture (CLP). The level of NOD2 and NOD like receptor 3 (NLRP3) mRNA expression in gut mucosa was determined using fluorescent polymerase chain reaction (PCR); the expression of caspase-1 and tight junction protein was determined by Western blotting; the activity of nuclear factor-ΚB (NF-ΚB) was determined by electrophoretic mobility shift assay (EMSA); the level of serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was determined by enzyme linked immunosorbent assay (ELISA). The dead cell percentage of enterocyte was observed by terminal deoxynucleotidyl transferase mediated nick end labeling, and the gut mucosal permeability using an in situ loop preparation of gut with fluorescence isothiocyanate-conjugated dextran was determined., Results: NOD2 mRNA expression was quickly increased to a very high apex at 2 hours after operation, compared with the control group, the difference was statistically significant (75.50±13.03 vs. 1.00±0.00, P<0.01), and quickly descended at 6 hours, and then slowing descended. The expression of NLRP3 mRNA was decreased at 2 hours after the operation, then increased gradually, and peaked at 12 hours, which was significantly higher than that in control group (4.03±0.71 vs. 1.00±0.00,P<0.05). The level of caspase-1 was significantly higher than that in control group at 2 hours (3.56±0.14 vs. 2.10±0.11,P<0.01) and then gradually increased. The levels of Occludin, ZO-1 and Claudin-4 were obviously lowered than that in control group at 2-6 hours (2 hours Occludin: 7.24±1.13 vs. 12.72±1.34, 6 hours ZO-1: 0.47±0.09 vs. 1.57±0.17, 2 hours Claudin-4: 1.63±0.28 vs. 3.40±0.34, P<0.05 or P<0.01), and then all slowly decreased. The activity of NF-ΚB was quickly increased at 2 hours, obviously higher than that in control group (24.85±0.57 vs. 12.42±0.73, P<0.01), and then slowly decreased at a state of high expression. The expression of IL-6 in experimental group had a peak at 6 hours (compared with the control group, 3088.07±330.03 vs. 26.19±7.58,P<0.01), and then slowly decreased. The level of TNF-α was significantly higher than that in control group at 2 hours (110.75±19.18 vs. 7.86±3.58,P<0.01), and then gradually increased. The percentage of dead enterocyte was higher than that in control group with infection progress (0.12±0.02 vs. 0.03±0.01,P<0.05), and then gradually increased, so mucosal permeability was gradually increased too. Compared with the control group, the difference was statistically significant through 2 hours [glucosans: (35.75±4.66)% vs. (2.84±0.35)%, P<0.01]. The relevance analysis showed that NLRP3 have a little higher correlation with mucosal permeability and caspase-1 protein expression than other targets. Caspase-1 had a strong correlation with the percentage of dead cell, TNF-α and gut mucosal permeability. Gut mucosal permeability had highest correlation with the expression of caspase-1 protein., Conclusions: The data of our study suggested that NOD2 and NLRP3 take role in early phase of intra-abdominal infection, the huge wave of the expression level of NOD2 hinted that it was feed backed by some accurate mechanism in case of its express was too strong or too weak. The correlation of NLRP3, caspase-1, and percentage of dead cell imply they maybe have some extent of causation, and the percentage of dead cell in gut mucosa was as important as tight junction protein in maintaining the function of intestinal mucosal barrier.