bromochloroacetic-acid and Esophagitis

Barrett's esophagus (BE) is a metaplastic condition in which normal squamous esophageal epithelium is replaced by columnar epithelium. It is proposed that one of the possible mechanisms is dedifferentiation of squamous epithelium into columnar epithelium. The pathophysiology through which this metaplasia occurs is unknown. A recent study by serial analysis of gene expression showed that bone morphogenetic protein 4 (BMP-4) is uniquely expressed in BE. In this study, the role of the BMP pathway in the metaplastic transformation of normal squamous cells into columnar cells was examined.. Tissues from patients with esophagitis and BE and in an esophagitis-BE rat model were examined for the activation of the BMP pathway. Short-term cultures of primary normal squamous esophageal cells were treated with BMP-4, and cell biological changes were examined by Western blot analysis, immunohistochemistry, and microarrays.. In both human and rat tissues, the BMP pathway proved to be activated in esophagitis and BE. Upon incubation of squamous cell cultures with BMP-4, the cytokeratin expression pattern showed a shift that was consistent with columnar epithelium. Involvement of the BMP pathway was suggested by up-regulation of Phosphorylated-Smad 1/5/8 (P-Smad 1/5/8) that was effectively blocked by Noggin, a BMP antagonist. Comparison of the gene expression profiles of squamous cells, BMP-4-treated squamous cells, and BE cells showed a significant shift in the profile of the BMP-4-treated squamous cells toward that of the cultured BE cells.. These results suggest that the BMP pathway could play a role in the transformation of normal esophageal squamous cells into columnar cells.

Topics: Adult; Aged; Aged, 80 and over; Animals; Barrett Esophagus; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Cells, Cultured; Esophagitis; Esophagus; Female; Genome, Human; Humans; Keratins; Male; Metaplasia; Microarray Analysis; Middle Aged; Phenotype; Rats; Rats, Sprague-Dawley

Intestinal metaplasia occurs in the esophagus as a consequence of gastroesophageal reflux disease and in the stomach secondary to H. pylori infection. The etiology of intestinal metaplasia limited to the gastroesophageal junction or cardia (CIM) is disputed. We hypothesized that CIM has dual etiologies: gastroesophageal reflux in some, H. pylori infection in others, and that cytokeratin immunostaining can help to differentiate between these two etiologies.. We defined CIM as the presence of intestinal metaplasia within cardiac mucosa on biopsy from an endoscopically normal-appearing gastroesophageal junction. Thirty patients with CIM who had multiple biopsy specimens taken from the esophagus, gastroesophageal junction, and stomach were identified. Tissue blocks from biopsy specimens taken at the gastroesophageal junction were sectioned and immunostained for cytokeratins 7 and 20. The cytokeratin 7/20 staining of the CIM in each patient was determined to be either a Barrett's or non-Barrett's pattern. H. pylori infection was assessed by Giemsa staining of antral biopsy specimens.. H. pylori infection was present in 16 patients. A Barrett's cytokeratin 7/20 staining pattern in the CIM was present in only 46% of the H. pylori-positive patients, as compared to 86% in the 14 patients with CIM and no H. pylori (p = 0.025). Objective evidence of reflux disease was present in 71% of patients with CIM and no H. pylori, as compared to 31% of patients with H. pylori.. The two different patterns of cytokeratin 7/20 staining found in patients with CIM support the concept of dual etiologies for CIM. A Barrett's staining pattern was associated with objective evidence of gastroesophageal reflux and the absence of H. pylori, suggesting that cytokeratin 7/20 immunostaining is useful to determine the likely etiology of CIM.

Topics: Biopsy; Esophagitis; Esophagus; Gastric Mucosa; Gastroesophageal Reflux; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Metaplasia

Sera drawn from healthy individuals, patients with squamous cell carcinoma (SCC) of the oesophagus and patients with mild active oesophagitis were examined for autoantibodies to cytoskeletal proteins extracted from the normal oesophageal keratinocyte or from 2 carcinoma cell lines, each of the latter have a simple cytoskeleton. Using a radioimmunoassay with normal oesophageal cytokeratins as bound antigen, 86 normal, 76 SCC and 14 oesophagitis sera were compared. No significant difference in autoantibody titre was found. When the bound antigen was changed to one containing predominantly simple epithelial cytokeratins a significant increase (32% P less than 0.001) was noted in the SCC category only. Western blots using simple epithelial cell extracts as antigen revealed autoantibodies to cytokeratins 8, 18 and 19 as well as to one other unidentified protein in most SCC sera, and in some normal sera. Antibodies to cytokeratin 18 predominated. Normal and SCC sera were applied using indirect immunofluorescent techniques to normal oesophageal keratinocytes, SNO oesophageal SCC cells and HeLa cells grown in vitro. Autoantibodies to oesophageal cytokeratins were, with few exceptions, barely detectable. Strong reactions were noted against SNO and HeLa cytoskeletal components, but also against nuclear membrane and nucleolar determinants. These experiments suggest that raised levels of autoantibodies to certain cytoskeletal and nuclear determinants may be a feature of oesophageal cancer.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Blotting, Western; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophagitis; Female; Fluorescent Antibody Technique; Humans; Keratins; Male; Middle Aged