scholarly journals Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis

2009 ◽  
Vol 297 (3) ◽  
pp. G471-G479 ◽  
Author(s):  
Jessica A. Clark ◽  
Heng Gan ◽  
Alexandr J. Samocha ◽  
Amy C. Fox ◽  
Timothy G. Buchman ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Intestinal Permeability ◽  
Cecal Ligation ◽  
Intestinal Barrier ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Septic Peritonitis ◽  
Epidermal Growth

Systemic administration of epidermal growth factor (EGF) decreases mortality in a murine model of septic peritonitis. Although EGF can have direct healing effects on the intestinal mucosa, it is unknown whether the benefits of systemic EGF in peritonitis are mediated through the intestine. Here, we demonstrate that enterocyte-specific overexpression of EGF is sufficient to prevent intestinal barrier dysfunction and improve survival in peritonitis. Transgenic FVB/N mice that overexpress EGF exclusively in enterocytes ( IFABP-EGF) and wild-type (WT) mice were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability, expression of the tight junction proteins claudins-1, -2, -3, -4, -5, -7, and -8, occludin, and zonula occludens-1; villus length; intestinal epithelial proliferation; and epithelial apoptosis were evaluated. A separate cohort of mice was followed for survival. Peritonitis induced a threefold increase in intestinal permeability in WT mice. This was associated with increased claudin-2 expression and a change in subcellular localization. Permeability decreased to basal levels in IFABP-EGF septic mice, and claudin-2 expression and localization were similar to those of sham animals. Claudin-4 expression was decreased following CLP but was not different between WT septic mice and IFABP-EGF septic mice. Peritonitis-induced decreases in villus length and proliferation and increases in apoptosis seen in WT septic mice did not occur in IFABP-EGF septic mice. IFABP-EGF mice had improved 7-day mortality compared with WT septic mice (6% vs. 64%). Since enterocyte-specific overexpression of EGF is sufficient to prevent peritonitis-induced intestinal barrier dysfunction and confers a survival advantage, the protective effects of systemic EGF in septic peritonitis appear to be mediated in an intestine-specific fashion.

scholarly journals Lactobacillus casei and Epidermal Growth Factor Prevent Osmotic Stress-Induced Tight Junction Disruption in Caco-2 Cell Monolayers

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3578
Author(s):  
Geetha Samak ◽  
Rupa Rao ◽  
Radhakrishna Rao
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Osmotic Stress ◽  
Tight Junction ◽  
Lactobacillus Casei ◽  
Kinase Inhibitor ◽  
Adherens Junction ◽  
Barrier Dysfunction ◽  
Cell Monolayers ◽  
Epidermal Growth

Osmotic stress plays a crucial role in the pathogenesis of many gastrointestinal diseases. Lactobacillus casei and epidermal growth factor (EGF) effects on the osmotic stress-induced epithelial junctional disruption and barrier dysfunction were investigated. Caco-2 cell monolayers were exposed to osmotic stress in the presence or absence of L. casei or EGF, and the barrier function was evaluated by measuring inulin permeability. Tight junction (TJ) and adherens junction integrity were assessed by immunofluorescence confocal microscopy. The role of signaling molecules in the L. casei and EGF effects was determined by using selective inhibitors. Data show that pretreatment of cell monolayers with L. casei or EGF attenuates osmotic stress-induced TJ and adherens junction disruption and barrier dysfunction. EGF also blocked osmotic stress-induced actin cytoskeleton remodeling. U0126 (MEK1/2 inhibitor), the MAP kinase inhibitor, blocked EGF-mediated epithelial protection from osmotic stress. In contrast, the L. casei-mediated epithelial protection from osmotic stress was unaffected by U0126, AG1478 (EGFR tyrosine kinase inhibitor), SP600125 (JNK1/2 inhibitor), or SB202190 (P38 MAP kinase inhibitor). On the other hand, Ro-32-0432 (PKC inhibitor) blocked the L. casei-mediated prevention of osmotic stress-induced TJ disruption and barrier dysfunction. The combination of EGF and L. casei is more potent in protecting the barrier function from osmotic stress. These findings suggest that L. casei and EGF ameliorate osmotic stress-induced disruption of apical junctional complexes and barrier dysfunction in the intestinal epithelium by distinct signaling mechanisms.

scholarly journals Centella Asiatica Ameliorates Radiation-induced Epithelial Barrier Dysfunction by Secreting Epidermal Growth Factor in Endothelial Cells.

2021 ◽  
Author(s):  
Seo Young Kwak ◽  
Sehwan Shim ◽  
Won Il Jang ◽  
Seung Bum Lee ◽  
Min-Jung Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Centella Asiatica ◽  
Epithelial Barrier ◽  
Therapeutic Effects ◽  
Barrier Dysfunction ◽  
Radiation Induced ◽  
Epidermal Growth ◽  
Epithelial Barrier Dysfunction

Abstract BackgroundRadiation-induced intestinal damage is frequently observed following radiotherapy for abdominal and pelvic cancer or occurs due to radiation exposure in a nuclear accident. In an effort to overcome radiation-induced normal tissue damage, a variety of radio-mitigator candidates have been investigated. The loss of the epithelium and its barrier function leads to ‘leaky gut’, so recovery of damaged epithelium is an important strategy in therapeutic trials. Centella asiatica (CA), a traditional herbal medicine in Chinese culture, is widely used for wound healing by protecting against endothelial damage. In this study, we investigated the radio-mitigating effect of CA, focusing on crosstalk between endothelial and epithelial cells.ResultsCA treatment attenuated radiation-induced endothelial dysfunction in human umbilical vein endothelial cells and mitigated radiation-induced enteropathy in a mouse model. In particular, treatment of the conditioned media from CA-treated irradiated endothelial cells recovered loss of epithelial integrity by regulating zonula occludens 1 and desmoglein 2 in radiation exposure. We also determined that epidermal growth factor (EGF) is a critical factor secreted by CA-treated irradiated endothelial cells. Treatment with EGF, which can mimic the effect of CA-induced secretion in irradiated endothelial cells, effectively improved the radiation-induced epithelial barrier dysfunction. In addition, blockade of EGF in CA-induced endothelial secretome impeded epithelial barrier recovery. Finally, we identified the therapeutic effects of CA-induced endothelial secretome in a radiation-induced enteropathy mouse model with epithelial barrier restoration.ConclusionsWe have shown therapeutic effects of CA on radiation-induced enteropathy, with the recovery of endothelial and epithelial dysfunction, focusing on the crosstalk between endothelial cells and epithelial cells. Thus, our finding suggest that CA is an effective radio-mitigator against radiation-induced enteropathy.

scholarly journals Protective Effects of Let-7b on the Expression of Occludin by Targeting P38 MAPK in Preventing Intestinal Barrier Dysfunction

2018 ◽  
Vol 45 (1) ◽  
pp. 343-355 ◽  
Author(s):  
Zhihua Liu ◽  
Yinghai Tian ◽  
Yanqiong Jiang ◽  
Shihua Chen ◽  
Ting Liu ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Conditional Knockout ◽  
Intestinal Barrier Function ◽  
Control Group ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Entire Study ◽  
Intestinal Barrier Dysfunction

Background/Aims: Let-7b was dramatically reduced after a dicer knockout of mice with intestinal barrier function injuries. This paper aims to investigate the molecular mechanism of let-7b by targeting p38 MAPK in preventing intestinal barrier dysfunction. Methods: A total of 186 patients were enrolled, with 93 in the control group and 93 in the PRO group. Only 158 patients completed the entire study, whereas the others either did not meet the inclusion criteria or refused to participate. To further verify the role of let-7b, intestinal epithelial conditional knockout (IKO) mice of mmu-let-7b model were established. Serum let-7b, zonulin, IL-6, and TNF-α concentrations were measured by ELISA or quantitative RT-PCR. Permeability assay was done by ussing chamber. The apoptotic cells were identified using an In Situ Cell Death Detection Kit. Protein was detected by western blot. Results: Probiotics can lower infection-related complications, as well as increase the serum and tissue let-7b levels. P38 MAPK was identified as the target of let-7b, as verified by NCM460 cells. P38 MAPK expression was increased, whereas tight-junction (TJ) proteins were significantly decreased in let-7b IKO mice (both P<0.05). Negative regulation of p38 MAPK molecular signaling pathways was involved in the protective effects of let-7b on intestinal barrier function. Conclusion: Let-7b was identified as a novel diagnosis biomarker or a potential treatment target for preventing intestinal barrier dysfunction.

scholarly journals Epidermal growth factor upregulates serotonin transporter in human intestinal epithelial cells via transcriptional mechanisms

2011 ◽  
Vol 300 (4) ◽  
pp. G627-G636 ◽  
Author(s):  
Ravinder K. Gill ◽  
Arivarasu Natarajan Anbazhagan ◽  
Ali Esmaili ◽  
Anoop Kumar ◽  
Saad Nazir ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Serotonin Transporter ◽  
Egf Receptor ◽  
Transport Processes ◽  
Mrna Levels ◽  
Protective Effects ◽  
Exon 2 ◽  
Basolateral Side ◽  
Epidermal Growth

Serotonin transporter (SERT) regulates extracellular availability of serotonin and is a potential pharmacological target for gastrointestinal disorders. A decrease in SERT has been implicated in intestinal inflammatory and diarrheal disorders. However, little is known regarding regulation of SERT in the intestine. Epidermal growth factor (EGF) is known to influence intestinal electrolyte and nutrient transport processes and has protective effects on intestinal mucosa. Whether EGF regulates SERT in the human intestine is not known. The present studies examined the regulation of SERT by EGF, utilizing Caco-2 cells grown on Transwell inserts as an in vitro model. Treatment with EGF from the basolateral side (10 ng/ml, 24 h) significantly stimulated SERT activity (∼2-fold, P < 0.01) and mRNA levels compared with control. EGF increased the activities of the two alternate promoter constructs for human SERT gene: SERT promoter 1 (hSERTp1, upstream of exon 1a) and SERT promoter 2 (hSERTp2, upstream of exon 2). Inhibition of EGF receptor (EGFR) tyrosine kinase activity by PD168393 (1 nM) blocked the stimulatory effects of EGF on SERT promoters. Progressive deletions of the SERT promoter indicated that the putative EGF-responsive elements are present in the −672/−472 region of the hSERTp1 and regions spanning −1195/−738 and −152/+123 of hSERTp2. EGF markedly increased the binding of Caco-2 nuclear proteins to the potential AP-1 cis-elements present in EGF-responsive regions of hSERTp1 and p2. Overexpression of c-jun but not c-fos specifically transactivated hSERTp2, with no effects on hSERTp1. Our findings define novel mechanisms of transcriptional regulation of SERT by EGF via EGFR at the promoter level that may contribute to the beneficial effects of EGF in gut disorders.

scholarly journals P011 Dysbiosis and Goblet cells depletion triggers early intestinal barrier dysfunction that precedes gut inflammation in IL-10 deficient mice (IL-10−/−)

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S135-S135 ◽  
Author(s):  
B López Cauce ◽  
M Puerto ◽  
J J García ◽  
J Miranda-Bautista ◽  
J Vaquero ◽  
...  
Keyword(s):  
Intestinal Permeability ◽  
Goblet Cell ◽  
Intestinal Barrier ◽  
Goblet Cells ◽  
Interleukin 10 ◽  
Length Ratio ◽  
Barrier Dysfunction ◽  
Gut Inflammation ◽  
Intestinal Barrier Dysfunction

Abstract Background Interleukin-10 deficient mouse (IL-10−/−) is a widely used model of spontaneous ileocolitis that resembles human inflammatory bowel disease (IBD); intestinal barrier dysfunction is an early pathophysiological event, but its underlying mechanisms are still unknown. The objective of this work is to study the natural history of ileocolitis in IL-10−/−, and unravel the influence of intestinal barrier dysfunction and dysbiosis in the development of overt inflammation. Methods Wild-type (WT) and IL-10−/− mice were followed until sacrifice at 3, 5, 10, 20, 57 and 70 weeks of life. Bodyweight, colonic weight/length ratio and in vivo intestinal permeability (measured by rectal administration of FITC-dextran) were registered. After the sacrifice, the colon was harvested and the evaluation of the expression of inflammatory (interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), inducible nitric synthase (iNOS) and cyclooxygenase-2 (COX-2) and epithelial permeability (ZO-1, E-cadherin, Occludin, Claudins 2 and 7, and Reticulon-4B (RTN-4B) markers was performed by qPCR; expression of mucin-2 (MUC-2) and molecules involved in goblet cell maturation such as interleukin-18 (IL-18) and WAP Four-Disulphide Core Domain 2 (WFDC2), as well as the endoplasmic reticulum stress marker X-box-binding protein (Xbp)-1) by qPCR were also analysed. We also used colon slices for histologic evaluation with haematoxylin-eosin and alcian blue stainings. The microbiota composition was studied by sequencing of the V3-V4 regions of ribosomal 16S from faecal samples of all these mice. Results Compared with WT, IL-10−/− mice showed lower weight gain at all ages and a higher colonic weight/length ratio and histological evidence of inflammation at weeks 20 and 57. iNOS and IL-1b gene expression in the colon were significantly higher in IL-10−/− mice at weeks 10 and 20, respectively. Nevertheless, increased intestinal permeability was observed from week 10; the number of goblet cells and expression of MUC-2, IL-18, WFDC2 and XBP-1 were significantly lower in knockout mice from week 10. Moreover, dysbiosis in IL-10−/− mice began at week 5, increasing at 10 and showing the lowest diversity and appearance of pathogenic families at 20 weeks of age. Conclusion Dysbiosis and goblet cell depletion in the colon of IL-10−/− mice are associated with early intestinal barrier dysfunction, and precede overt gut inflammation in this animal model of IBD.

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