The molecular mechanisms responsible for the progression of malignant transformation in Barrett's esophagus (BE) are still poorly understood. This study was undertaken (1) to investigate the gene and protein expression of cyclooxygenase-2 (COX-2), peroxisome proliferator-activated receptor-gamma (PPARgamma), interleukin-8 (IL-8), hepatocyte growth factor (HGF), gastrin, and its receptor (CCK-2) in the Barrett's epithelium; (2) to analyze the activity of NFkappaB in Barrett's esophagus with low-grade dysplasia; and (3) to assess the effects of PPARgamma ligand (ciglitazone) and gastrin on cell proliferation in the cell line derived from esophageal adenocarcinoma (OE-33). COX-2, PPARgamma, IL-8, HGF, gastrin, and CCK-2 expression levels relative to the control gene encoding GAPDH were analyzed by RT-PCR and Western blot in specimens of BE with low-grade dysplasia (n = 20) and compared with that in the normal squamous esophageal mucosa from the middle portion of the esophagus (n = 20). In vitro experiments included the incubation of cell line OE-33 with ciglitazone (1-15 microM) and gastrin (100 nM). NFkappaB activity in biopsies specimens was measured by highly sensitive ELISA. COX-2, PPARgamma, IL-8, HGF, gastrin, and CCK-2 expressions were significantly increased in BE compared with normal squamous esophageal mucosa. NFkappaB activity was significantly upregulated in BE. Ciglitazone inhibited cell proliferation of OE-33 cells as assessed by BrdU and this effect was attenuated partly by gastrin. (1) COX-2, PPARgamma, HGF, gastrin, and its receptor are significantly upregulated in BE, suggesting a possible role for these factors in Barrett's carcinogenesis; (2) the increased NFkappaB activity is probably linked to increased IL-8 and COX-2 expression; and (3) PPARgamma ligands might be useful as a new therapeutic option in the prevention and treatment of Barrett's carcinoma.

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Abstract. Peroxisome proliferator-activated receptor g (PPARg) is a ligand-dependent transcription factor involved in various processes including the inflammation and carcinogenesis. The aim of the present study was 1) to examine the mRNA and protein expression of PPARg in gastric cancer (GC); 2) to evaluate the effect of PPARg ligand (ciglitazone) on the proliferation and apoptosis of GC cell line; and 3) to assess the levels of gastric tissue proinflammatory cytokines, IL-1b and IL-8, and plasma gastrin in GC patients before and after Helicobacter pylori (H. pylori) eradication. The trial material included 30 H. pylori-negative controls and 30 sex-and age-matched GC patients without or with H. pylori before and after its eradication. Expression of tissue PPARg, tissue levels of IL-1b and IL-8, and plasma concentration of gastrin were significantly higher in H. pylori-positive GC compared to controls, but H. pylori eradication significantly reduced these parameters. Kato III cells incubated with alive H. pylori upregulated PPARg expression and ciglitazone inhibited cell proliferation and induced apoptosis. PPARg, proinflammatory cytokines and plasma gastrin appear to be implicated in H. pylori-related gastric carcinogenesis and PPARg agonists may have potential in cancer therapy.

Reflux esophagitis is a common clinical entity in western countries with approximately 30% of the population experiencing the symptoms at least once every month. The imbalance between the protective and aggressive factors leads to inflammation and damage of the esophageal mucosa. We compared the effect of exogenous melatonin and melatonin derived endogenously from L-tryptophan with that of pantoprazole or ranitidine in acid reflux esophagitis due to ligation of the rat pylorus and the limiting ridge between the forestomach and the corpus. Four hours after the induction of gastric reflux, an increase in mucosal lesions associated with edema of the submucosa and with the infiltration of numerous neutrophils and the fall in esophageal blood flow (EBF) were observed. Both melatonin and L-tryptophan or pantoprazole significantly reduced the lesion index (LI) and raised the EBF. Pinealectomy that significantly decreased plasma melatonin levels aggravated LI and these effects were reduced by melatonin and L-tryptophan. Luzindole, the MT2 receptor antagonist, abolished the melatonin-induced reduction in LI and the rise in EBF. L-NNA and capsaicin that augmented LI and decreased EBF, also significantly reduced melatonin-induced protection and hyperemia; both were restored with L-arginine and calcitonin gene-related peptide (CGRP) added to melatonin. Upregulation of IL-1β and TNF-α mRNAs and plasma IL-1β and TNF-α levels were significantly attenuated by melatonin and L-tryptophan. We conclude that melatonin protects against acid reflux-induced damage via activation of MT2 receptors mediated by NO and CGRP released from sensory nerves and the suppression of expression and release of TNF-α and IL-1β.

Background/Aim: Nitric oxide (NO) releasing nonsteroidal anti-inflammatory drugs do not cause gastric mucosal damage, despite inhibition of the cyclooxygenase activity to a similar extent as conventional nonsteroidal anti-inflammatory drugs that induce such damage. We compared the effects of native aspirin (ASA) with those of NO-releasing ASA (NO-ASA) on the development and healing of acute gastric lesions induced by water immersion and restraint stress (WRS) and the mucosal expression of heat shock protein 70 (HSP70). Methods: Wistar rats received: (1) vehicle; (2) ASA (40 mg/kg i.g), and (3) NO-ASA (2.5–40 mg/kg i.g.), followed 0.5 h later by 3.5 h of WRS with or without glyceryl trinitrate, the donor of NO, and carboxy-PTIO, a NO scavenger. Healing of WRS lesions was assessed 0–24 h after termination of WRS. Number of gastric lesions, gastric mucosal blood flow (GBF), malondialdehyde (MDA) content, and RT-PCR expression of HSP70 mRNA were determined. Results: WRS caused typical bleeding erosions that were aggravated by aspirin and this was accompanied by a fall in the GBF and a significant rise in the mucosal MDA concentrations. In contrast, NO-ASA, which raised significantly the luminal content of NO_x, reduced number of WRS lesions and mucosal MDA levels while increasing significantly the GBF. These protective and hyperemic effects of NO-ASA against WRS lesions were mimicked by addition of glyceryl trinitrate to native ASA and significantly attenuated by carboxy-PTIO added to NO-ASA. HSP70 mRNA was significantly upregulated by WRS, and this was significantly attenuated by ASA, but not by NO-ASA. NO-ASA decreased significantly the MDA content and induced overexpression of HSP70 mRNA during healing of WRS lesions.Conclusion: NO-ASA exhibits mucosal protective and healing effects against WRS-induced gastric lesions due to the release of NO, which induces gastric hyperemia, and the attenuation of lipid peroxidation and counteracts the inhibition of HSP70 expression induced by native ASA.