epidermal-growth-factor and Enteritis

Epidermal growth factor (EGF) promotes gastrointestinal mucosal recovery by stimulating the mitogenic activity of intestinal crypt epithelial cells. The aim of this study was to determine the effects of EGF on atrophic enteritis induced in piglets by experimental infection with porcine epidemic diarrhoea virus (PEDV) strain Dr13. Two groups of 12 conventional, colostrum-deprived, 1-day-old, large White-Duroc cross breed piglets were inoculated orally with PEDV (3 x 10(5) 50% tissue culture infective doses), with or without EGF (10 microg/kg/day, intraperitoneally once daily for 4 days after infection) and compared to 12 uninfected, untreated control piglets. PEDV+EGF piglets had less severe clinical signs than PEDV only piglets at 48 and 60 h post-infection (hpi). Histologically, the ratio of villous height:crypt depth of PEDV+EGF piglets was significantly higher than PEDV only piglets at 36 and 48 hpi. Immunohistochemistry for Ki67 demonstrated increased proliferation in intestinal crypt epithelial cells of PEDV+EGF piglets compared to PEDV only piglets at 36, 48 and 60 hpi. EGF stimulates proliferation of intestinal crypt epithelial cells and promotes recovery from atrophic enteritis in PEDV-infected piglets.

Topics: Animals; Coronavirus Infections; Enteritis; Epidermal Growth Factor; Immunohistochemistry; Jejunum; Ki-67 Antigen; Porcine epidemic diarrhea virus; Recombinant Proteins; Swine

Radiation-induced enteritis is frequently observed following radiotherapy for cancer or occurs due to radiation exposure in a nuclear accident. The loss of the epithelial integrity leads to 'leaky gut', so recovery of damaged epithelium is an important strategy in therapeutic trials.

Topics: Animals; Centella; Endothelial Cells; Enteritis; Epidermal Growth Factor; Mice; Phytotherapy; Radiation Injuries

Wound healing of the gastrointestinal mucosa is essential for the maintenance of gut homeostasis and integrity. Enteric glial cells play a major role in regulating intestinal barrier function, but their role in mucosal barrier repair remains unknown. The impact of conditional ablation of enteric glia on dextran sodium sulfate (DSS)-induced mucosal damage and on healing of diclofenac-induced mucosal ulcerations was evaluated in vivo in GFAP-HSVtk transgenic mice. A mechanically induced model of intestinal wound healing was developed to study glial-induced epithelial restitution. Glial-epithelial signaling mechanisms were analyzed by using pharmacological inhibitors, neutralizing antibodies, and genetically engineered intestinal epithelial cells. Enteric glial cells were shown to be abundant in the gut mucosa, where they associate closely with intestinal epithelial cells as a distinct cell population from myofibroblasts. Conditional ablation of enteric glia worsened mucosal damage after DSS treatment and significantly delayed mucosal wound healing following diclofenac-induced small intestinal enteropathy in transgenic mice. Enteric glial cells enhanced epithelial restitution and cell spreading in vitro. These enhanced repair processes were reproduced by use of glial-conditioned media, and soluble proEGF was identified as a secreted glial mediator leading to consecutive activation of epidermal growth factor receptor and focal adhesion kinase signaling pathways in intestinal epithelial cells. Our study shows that enteric glia represent a functionally important cellular component of the intestinal epithelial barrier microenvironment and that the disruption of this cellular network attenuates the mucosal healing process.

Topics: Analysis of Variance; Animals; Caco-2 Cells; Cell Shape; Coculture Techniques; Culture Media, Conditioned; Dextran Sulfate; Diclofenac; Disease Models, Animal; Enteritis; Epidermal Growth Factor; Epithelial Cells; ErbB Receptors; Focal Adhesion Kinase 1; Glial Fibrillary Acidic Protein; Humans; Intestinal Mucosa; Intestine, Small; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuroglia; Paracrine Communication; Peptic Ulcer; Phosphorylation; Protein Precursors; Rats; RNA Interference; Signal Transduction; Simplexvirus; Thymidine Kinase; Time Factors; Transfection; Wound Healing

Several growth factors are trophic for the gastrointestinal tract and able to reduce the degree of intestinal damage caused by cytotoxic agents. However, studies of epidermal growth factor (EGF) for chemotherapy-induced intestinal injury are conflicting. The development of a transgenic mouse that specifically overexpresses EGF in the small intestine provided a unique opportunity to assess the contribution of EGF in mucositis. After a course of fluorouracil, transgenic mice fared no better than control mice. Weight recovery was inferior, and mucosal architecture was not preserved. Apoptosis was not decreased and proliferation was not increased in the crypts. To corroborate the findings in transgenic mice, ICR mice were treated with exogenous EGF after receiving fluorouracil. Despite ileal upregulation of native and activated EGF receptor, the mice were not protected from intestinal damage. No benefits were observed with different EGF doses or schedules or routes of EGF administration. Finally, mucositis was induced in mutant mice with specific defects of the EGF signaling axis. Compared with control mice, clinical and histological parameters of intestinal injury after fluorouracil were no different in waved-2 mice, which have functionally diminished EGF receptors, or waved-1 mice, which lack transforming growth factor-alpha, another major ligand for the EGF receptor. These findings do not support a critical role for EGF or its receptor in chemotherapy-induced intestinal injury.

Topics: Animals; Antineoplastic Agents; Enteritis; Epidermal Growth Factor; ErbB Receptors; Fluorouracil; Gene Expression; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Microvilli; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor alpha

The effect of phospholipase A2 (PLA2) on intestinal epithelial cell migration was investigated using an in vitro wounding model of confluent monolayers of IEC-6. PLA2 (0.001-2 U/ml) enhanced IEC-6 cell migration in a dose dependent manner. Addition of 4-bromophenacyl bromide (BPB) (a PLA2 inhibitor) to PLA2 completely blocked the migration-promoting effect. However, addition of piroxicam (a cyclooxygenase inhibitor) or nordihydroguaiaretic acid (a lipoxygenase inhibitor) had no influence on the effect. Lysophosphatidylcholine (lysoPC) (0.01-5,000 ng/ml), one of the products of phosphatidylcholine by PLA2, dose-dependently enhanced IEC-6 cell migration as well. A combination of PsLA2 (1 U/ml) and lysoPC (1,000 ng/ml) had no additive effect or migration. Moreover, the migration-promoting effect of PLA2 that was blocked by BPB was recovered by lysoPC. After pretreatment of IEC-6 cells with replication-inhibiting doses of mitomycin C, the enhanced migration induced by PLA2 or lysoPC was still observed. These observations suggest that PLA2 may, independently of proliferation, enhance intestinal epithelial cell migration mainly via lysoPC.

Topics: Acetophenones; Animals; Cell Division; Cell Movement; Cells, Cultured; Dinoprostone; Enteritis; Epidermal Growth Factor; Intestine, Small; Lysophosphatidylcholines; Lysophospholipids; Masoprocol; Mitomycin; Phospholipases A; Phospholipases A2; Piroxicam; Rats