Increased expression of transforming growth factor-alpha and epidermal growth factor receptors in rat chronic reflux esophagitis.
OBJECTIVE
Transforming growth factor-alpha (TGF-alpha), which binds to epidermal growth factor receptors (EGF-R), stimulates esophageal epithelial cell proliferation, enabling rapid repair after mucosal injury. The aim of the present study was to examine epithelial proliferation and dynamics of TGF-alpha and EGF-R gene and protein expression in rat chronic acid reflux esophagitis.


METHODS
Gastric acid reflux esophagitis was induced in Wistar rats by ligating the transitional region between the forestomach and the glandular portion, and by covering the duodenum near the pyloric ring with a small piece of an 18Fr Nélaton catheter. Epithelial cell proliferation was assessed by bromodeoxyuridine (BrdU) uptake. Expression of TGF-alpha and EGF-R mRNA and protein was assessed by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry.


RESULTS
Esophageal lesions were observed in the lower and middle esophagus. Histologically, a significant increase in mucosal thickening with elongation of lamina propria papillae and basal cell hyperplasia was observed. The BrdU labeling index was significantly increased from 2.7 +/- 1.0 in normal mucosa and 2.8 +/- 1.2 in background mucosa adjacent to the esophageal lesion, to 60.3 +/- 32.7 in the lesions of chronic esophagitis. Expression of TGF-alpha and EGF-R mRNA in the esophageal lesion significantly increased compared to those in the control and background tissue, whereas treatment with rabeprazole significantly inhibited increases in TGF-alpha and EGF-R mRNA expression. According to immunohistochemical study, TGF-alpha and EGF-R revealed strong expression in esophageal lesions compared with control and background mucosa. The superficial layer of the esophagus was strongly positive for TGF-alpha and most cells in regions of basal hyperplasia had a positive reaction for EGF-R in the esophagitis lesion.


CONCLUSIONS
Epithelial proliferation and expression of TGF-alpha and EGF-R were significantly increased in rat chronic reflux esophagitis. Activation of TGF-alpha and EGF-R genes in response to acid reflux may facilitate rapid mucosal healing by stimulating epithelial proliferation. These results suggest that TGF-alpha and EGF-R play crucial roles in rat chronic reflux esophagitis.
Fujiwara
Yasuhiro
Y
Department of Gastroenterology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. yasu@med.osaka-cu.ac.jp
Higuchi
Kazuhide
K
Hamaguchi
Masaki
M
Takashima
Takashi
T
Watanabe
Toshio
T
Tominaga
Kazunari
K
Oshitani
Nobuhide
N
Matsumoto
Takayuki
T
Arakawa
Tetsuo
T
D000595:Amino Acid Sequence; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000096:biosynthesis*; D004942:Esophagitis, Peptic / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D006471:Gastrointestinal Hemorrhage / Q000209:etiology / Q000473:pathology; D015870:Gene Expression; D007124:Immunoenzyme Techniques; D008026:Ligation; D008297:Male; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis*
D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors