Induction of mitogen-activated protein kinase signal transduction pathway during gastric ulcer healing in rats

doi:10.1016/S0016-5085(98)70584-0

Gastroenterology

Volume 114, Issue 4, April 1998, Pages 706-713

https://doi.org/10.1016/S0016-5085(98)70584-0 Get rights and content

Abstract

Background & Aims: Previous studies have shown that gastric ulceration stimulates epithelial cell proliferation and overexpression of epidermal growth factor (EGF) and EGF receptor (EGF-R) in the mucosa bordering necrosis. The aim of this study was to investigate whether extracellular signal-regulated kinase (ERK) cascade is involved in the healing of experimental gastric ulcers. Methods: We studied EGF-R levels, EGF-R phosphorylation levels, and ERK1 and ERK2 activity in normal and ulcerated rat gastric mucosa. We also examined the effect of Tyrphostin A46 (potent inhibitor of EGF-R and EGF-R kinase–dependent proliferation) on the above parameters. Results: During the initial stages of healing (3 and 7 days), ulcerated mucosa showed significant increase (vs. controls) in protein tyrosine kinase activity, EGF-R levels (510% and 550%), EGF-R phosphorylation levels, ERK1 activity (430% and 880%), and ERK2 activity (550% and 990%). Tyrphostin A46 treatment significantly inhibited ulcer healing and reduced EGF-R levels, EGF-R phosphorylation, and ERK1 and ERK2 activity. Conclusions: These findings indicate that experimental gastric ulcer healing involves activation of EGF-R–ERK signal transduction pathway.

GASTROENTEROLOGY 1998;114:706-713

Section snippets

Animals

This study was approved by the Subcommittee for Animal Studies of the Long Beach (CA) Department of Veterans Affairs Medical Center. Two hundred twenty-two male Sprague–Dawley rats (weighing 225–250 g) were used in the experiments. Rats were kept individually in wire-bottom cages with free access to a standard rat chow (Rodent Diet No. 8504; Harlan Teklad, Madison, WI) and water. The animal room was illuminated on 12-hour light-dark cycles. Room temperature was kept at 18–22°C and humidity at

PTK activity

To determine whether intrinsic tyrosine kinases are affected during the early stages of ulcer healing, tyrosine kinase activity in the membranes was determined 1, 3, and 7 days after ulcer induction. As shown in Figure 1, a significant increase in PTK activity was observed after 3 and 7 days (but not at 1 day) after ulcer induction.

. Total tyrosine kinase activity in the membranes of gastric specimens from sham-operated rats and in membranes from 1-, 3-, and 7-day ulcers. ct, controls. Membrane

Discussion

The present study shows that gastric ulceration activates the EGF-R/ERK signaling cascade as reflected by increase in tyrosine kinase activity, EGF-R, EGF-R phosphorylation, and ERK1 and ERK2 activity and their phosphorylation levels. Gastric epithelial cells isolated from the ulcer margins showed significant increase in ERK1 and ERK2 activity, which clearly indicates that ERK1 and ERK2 activation is attributable to the epithelial cells. Furthermore, this study showed that treatment with

Acknowledgements

The authors thank Dr. B. V. Bassa for helpful technical advice with MAPK assays and Dr. E. Sasaki (visiting scientist from Osaka City University, Osaka, Japan) for expert technical assistance with isolation of gastric epithelial cells.

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Citation Excerpt :
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^☆: Address requests for reprints to: Andrzej S. Tarnawski, M.D., D.Sc., Gastroenterology Section (111G), DVA Medical Center, 5901 East Seventh Street, Long Beach, California 90822.

^☆☆: Supported by the Medical Research Service of the Department of Veterans Affairs.

^★: Dr. Ohta was a visiting scientist from Department of Surgery II, Kyushu University, Fukuoka, Japan, and was the recipient of the Uehara Memorial Foundation (Tokyo, Japan) postdoctoral research fellowship.

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Alimentary TractInduction of mitogen-activated protein kinase signal transduction pathway during gastric ulcer healing in rats☆,☆☆,★

Abstract

Section snippets

Animals

PTK activity

Discussion

Acknowledgements

Gastroenterology

Gastroenterology

J Biol Chem

Cell

J Lab Clin Med

Cell Biol Int

Cell

J Biol Chem

Curr Opin Cell Biol

J Biol Chem

Exp Cell Res

Gastric ulceration

Vascular and microvascular changes: key factors in the development of acetic acid–induced gastric ulcers in rats

J Clin Gastroenterol

Quality of gastric ulcer healing: a new emerging concept

J Clin Gastroenterol

Cellular mechanisms of gastric ulcer healing

Regulation of gastrointestinal growth

Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells

Nature

Immunoreactivities for epidermal growth factor (EGF) and for EGF receptors in rats with gastric ulcer

Cell Tissue Res

Inhibition of epidermal growth factor-mediated DNA synthesis by specific tyrosine kinase inhibitor in vascular smooth muscle cells of the spontaneously hypertensive rat

J Hypertens Suppl

Alimentary Tract
Induction of mitogen-activated protein kinase signal transduction pathway during gastric ulcer healing in rats☆,☆☆,★