Involvement of oxidative stress in experimentally induced reflux esophagitis and Barrett's esophagus: clue for the chemoprevention of esophageal carcinoma by antioxidants.
Oxidative damage has long been related to mucosal damages of gastrointestinal tracts and their ensuing carcinogenesis. In spite of treatment with anti-secretory medications for reflux esophagitis, considerable portions of patient did not achieve the complete mucosal healings or suffered from sustaining symptoms or development of dread complication like Barrett's esophagus, suggesting other damaging factors or impaired mucosal resistance are also involved in their pathogenesis. The present study was designed either to evaluate the oxidative stress as the major pathogenic factor of reflux esophagitis or to find out the usefulness of antioxidant in the treatment of reflux esophagitis and the prevention of development of Barrett's esophagus. Acute or chronic reflux esophagitis was induced through either narrowing the third portion of duodenal lumen or performing myotomy of lower esophageal sphincter in rats, respectively. DA-9601, a new phytopharmaceutical possessing antioxidative properties, significantly attenuated the gross and histopathologic scores of acute reflux esophagitis in a dose-dependent manner compared to those treated with ranitidine alone. Only scattered erosions were observed in antioxidant pre-treated group, but acid suppression by ranitidine was not so effective in decreasing the severity of reflux esophagitis. Significantly increased amounts of malondialdehyde (MDA), increased NF-kappa B activations, and depletions of reduced glutathione (GSH) were observed in experimentally induced reflux esophagitis, but DA-9601 pre-treatment attenuated the decrement of mucosal GSH levels and decreased MDA formations significantly. DA-9601 treatment showed significant reductions in the activation of NF-kappa B transcription factor. DA-9601 significantly decreased the proliferating cell nuclear antigen-labeling index (PCNA-LI) of esophagus (P<0.05) in chronic reflux esophagitis model and prevented the development of Barrett's esophagus. In conclusion, reflux esophagitis provoked considerable levels of oxidative stress in the esophageal mucosa. Antioxidant treatment seems to be the first line therapeutics in the prevention or treatment of reflux esophagitis. Moreover, antioxidant possibly played the chemopreventive role through preventing the development of Barrett's esophagus.
Lee
J S
JS
College of Pharmacy, Seoul National University, Seoul, South Korea.
Oh
T Y
TY
Ahn
B O
BO
Cho
H
H
Kim
W B
WB
Kim
Y B
YB
Surh
Y J
YJ
Kim
H J
HJ
Hahm
K B
KB
D000208:Acute Disease; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D000975:Antioxidants / Q000627:therapeutic use*; D001471:Barrett Esophagus / Q000150:complications*; D002277:Carcinoma / Q000209:etiology / Q000517:prevention & control*; D018890:Chemoprevention; D002908:Chronic Disease; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000209:etiology / Q000517:prevention & control*; D004942:Esophagitis, Peptic / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008679:Metaplasia / Q000473:pathology / Q000517:prevention & control; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000897:Anti-Ulcer Agents; D000975:Antioxidants; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D008315:Malondialdehyde; D011899:Ranitidine; D005978:Glutathione