3-nitrotyrosine and Metaplasia

The high concentration of nitric oxide (NO) around the gastro-esophageal junction (GEJ) might play an important role in the development of Barrett's esophagus (BE), a precursor of Barrett's adenocarcimona. Although previous studies revealed that the expression of caudal-type homeobox 2 (CDX2), an important marker of BE, might be induced through Epidermal Growth Factor Receptor (EGFR), the roles of NO in this signal transduction remain unclear.. First, we investigated the expressions of EGFR, CDX2 and nitrotyrosine by immunohistochemical study for BE and squamous epithelium of human specimens. Second, we studied the effect of peroxynitrite, peroxynitrite stimulator, SIN-1, or NO donor, NOC7, on the expression of phosphorylated EGFR and CDX2 in KYSE30, an EGFR-rich human esophageal squamous cell carcinoma cell-line. Specific inhibitors for EGFR, AG1478 and small interfering RNA for EGFR (EGFR-siRNA) were employed to elucidate the role of EGFR in the induction of CDX2.. The immunohistochemical study revealed that the expressions of EGFR, CDX2 and nitrotyrosine in BE were stronger than those in squamous epithelium with positive correlations. Exposure to peroxynitrite, SIN-1 or NOC7 induced EGFR phosphorylation and CDX2 expression in dose- and time-dependent manners. Both EGFR phosphorylation and CDX2 induction were significantly diminished by AG 1478 and EGFR-siRNA.. We revealed for the first time that extrinsic NO might directly induce CDX2 expression through EGFR phosphorylation. We suggested that NO had an important role in the development of BE from squamous epithelium around GEJ.

Topics: Barrett Esophagus; Carcinoma, Squamous Cell; CDX2 Transcription Factor; Cell Line, Tumor; Epithelium; ErbB Receptors; Esophagogastric Junction; Homeodomain Proteins; Humans; Immunohistochemistry; Metaplasia; Nitric Oxide; Phosphorylation; Tyrosine

Several works have reported that nitric oxide and free oxygen radicals are up-regulated in nasal polyposis. This study aimed to assess the distribution of peroxynitrite in nasal polyps from nonatopic patients. Occurrence of peroxynitrite also was analyzed in relation with eosinophil infiltration and epithelial alterations.. Hematoxylin and eosin staining was used for histologic study. Peroxynitrite was assessed by 3-nitrotyrosine immunohistochemistry. Quantitative evaluation was done by measuring the total number of eosinophils, the number of 3-nitrotyrosine-positive eosinophils, and the extension of the various epithelial alterations.. Hematoxylin and eosin staining showed that the nasal polyp epithelium is characterized by progressive disruption or squamous metaplasia. In both cases, infiltrating eosinophils were found in the epithelium and lamina propria. The regions featuring epithelial disruption exhibited 3-nitrotyrosine immunostaining in eosinophils and epithelial cells; hematoxylin-and-eosin - stained eosinophils and 3-nitrotyrosine - positive eosinophils showed conspicuous variations in number. Within the regions featuring squamous metaplasia, 3-nitrotyrosine-positive eosinophils were rarely found, and the epithelium exhibited 3-nitrotyrosine only in the superficial cells. In these regions, hematoxylin-eosin - stained eosinophils showed slight variations in number.. Peroxynitrite plays a pivotal role in the pathophysiology of nasal polyps. In fact, strong expression of peroxynitrite is associated with epithelial disruption, while poor expression of peroxynitrite is associated with squamous metaplasia. Peroxynitrite could influence afflux of eosinophils in the nasal mucosa; moreover, the total number of eosinophils is not critical in generating alterations of nasal polyp mucosa.

Topics: Adult; Epithelium; Female; Free Radicals; Gene Expression Regulation; Humans; Immunohistochemistry; Male; Metaplasia; Models, Biological; Nasal Mucosa; Nasal Polyps; Oxygen; Peroxynitrous Acid; Tyrosine

Helicobacter pylori is the main cause of gastritis and a primary carcinogen. The aim of this study was to assess oxidative damage in mucosal compartments of gastric mucosa in H. pylori positive and negative atrophic and nonatrophic gastritis.. Five groups of 10 patients each were identified according to H. pylori positive or negative chronic atrophic (Hp-CAG and CAG, respectively) and nonatrophic gastritis (Hp-CG and CG, respectively), and H. pylori negative normal mucosa (controls). Oxidative damage was evaluated by nitrotyrosine immunohistochemistry in the whole mucosa and in each compartment at baseline and at 2 and 12 months after eradication. Types of intestinal metaplasia were classified by histochemistry.. Total nitrotyrosine levels appeared significantly higher in H. pylori positive than in negative patients, and in Hp-CAG than in Hp-CG (p <.001); no differences were found between H. pylori negative gastritis and normal mucosa. Nitrotyrosine were found in foveolae and intestinal metaplasia only in Hp-CAG. At 12 months after H. pylori eradication, total nitrotyrosine levels showed a trend toward a decrease in Hp-CG and decreased significantly in Hp-CAG (p =.002), disappearing from the foveolae (p =.002), but remaining unchanged in intestinal metaplasia. Type I and II of intestinal metaplasia were present with the same prevalence in Hp-CAG and CAG, and did not change after H. pylori eradication.. Oxidative damage of the gastric mucosa increases from Hp-CG to Hp-CAG, involving the foveolae and intestinal metaplasia. H. pylori eradication induces a complete healing of foveolae but not of intestinal metaplasia, reducing the overall oxidative damage in the mucosa.

Topics: Adult; Aged; Chronic Disease; Female; Gastric Mucosa; Gastritis; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Male; Metaplasia; Middle Aged; Tyrosine