P38 MAPK Pharmacological Inhibitor SB203580 Alleviates Total Parenteral Nutrition-Induced Loss of Intestinal Barrier Function but Promotes Hepatocyte Lipoapoptosis

Abstract

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.

The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis

“…This may be an advantage of the peptide over classical inhibitors of p38 MAP kinase signaling, which exert significant side effects from off-target effects in the central nervous system and the immune system. 54,55 A potential concern is that ENaC activation in the distal nephron can contribute to hypertension, 41 but in our study, TIP peptide, which activates ENaC, 20,22 does not increase b a s i c r e s e a r c h MAP in mice on standard chow or on high salt diet and does not further increase MAP in NTN mice. This suggests that the active peptide does not reach the distal tubules in the inner medullary collecting ducts or that the distal nephron regulatory capacity is sufficient to maintain close to normal ENaC activity.…”

Neuronal MAP kinase p38α inhibits c-Jun N-terminal kinase to modulate anxiety-related behaviour

“…Previous reports have shown increased activation of JNK in different cell types lacking p38α 17 – 19 , 29 , suggesting a regulation of JNK activity by p38α. This increased JNK activity has been shown to have diverse functional consequences in these cell types 17 , 19 , 30 .…”

Milk Fat Globule Membrane Inhibits NLRP3 Inflammasome Activation and Enhances Intestinal Barrier Function in a Rat Model of Short Bowel

“…Regarding the 2 downstream inflammatory cytokines of NLRP3 pathway, supplementation of MFGM showed decreased levels of IL‐1β but higher levels of IL‐18 in ileum tissues compared with the SBS group. Previous studies found that IL‐1β release induced T‐cell differentiation into a proinflammatory phenotype, while inhibition of IL‐1β resulted in reduced intestinal permeability, possibly through p38 mitogen‐activated protein kinase signaling way . Zaki et al found that administration of exogenous recombinant IL‐18 protected against colitis in inflammasome‐deficient mice, indicating IL‐18 as a crucial mediator of mucosal barrier repair and protection .…”

“…Previous studies found that IL-1β release induced T-cell differentiation into a proinflammatory phenotype, 38 while inhibition of IL-1β resulted in reduced intestinal permeability, possibly through p38 mitogen-activated protein kinase signaling way. 39 Zaki et al found that administration of exogenous recombinant IL-18 protected against colitis in inflammasome-deficient mice, indicating IL-18 as a crucial mediator of mucosal barrier repair and protection. 40 As a complex compound of various bioactive nutrients, including phospholipids and proteins, MFGM might exert regulating effects on NLRP3 inflammasome activation through different mechanisms.…”