Immune and Inflammatory Responses in GERD and Lansoprazole.

The exact pathophysiological mechanisms responsible for gastroesophageal reflux disease (GERD) remain unclear. Recent studies have shown that mucosal immune and inflammatory responses, characterized by specific cytokine and chemokine profiles, may underlie the diverse esophageal phenotypes of GERD. Interleukin 8 (IL-8), a representative chemokine, mediates neutrophil trafficking via its receptors, mainly CXCR-1. The IL-8 mRNA and protein levels are increased in the esophageal mucosa, not only in reflux esophagitis (RE), but also in endoscopy-negative GERD (NERD), through activation of nuclear factor-kappaB (NF-kappaB), which is a pivotal transcription factor. Mucosal IL-8 concentrations have been found to parallel the endoscopic severity of RE, implying that this cytokine is a key player in the development of GERD. The mucosal levels of the C-C chemokines, macrophage chemoattractant protein 1 (MCP-1) and regulated on activation normal T-cell-expressed and presumably secreted (RANTES), which primarily attract monocytes and lymphocytes to the site of inflammation, respectively, are also elevated in RE. The secreted levels of IL-8 and IL-1beta, a prototype of proinflammatory cytokine, are maximal at the proximal segment within Barrett esophagus (BE) tissue. The expression of the two pleiotrophic proinflammatory cytokines, IL-6 and tumor necrosis factor alpha, is enhanced in the intestinal epithelium of BE, which places this epithelium at a higher risk for developing malignancy. BE is characterized by a distinct Th-2 predominant cytokine profile (IL-4 and -10), compared to the proinflammatory nature of RE (interferone-gamma). Treatment with a proton pump inhibitor, lansoprazole reduces the mucosal levels of IL-8 mRNA and protein in GERD, including RE and NERD. This may occur in part through an anti-inflammatory action of proton pump inhibitors beyond gastric acid inhibition.

Expression of CXC receptor 1 and 2 in esophageal mucosa of patients with reflux esophagitis.

AIM: Interleukin 8 (IL-8) mediates neutrophil trafficking via its receptors. Recent studies have shown that IL-8 is likely involved in the development and progression of erosive reflux esophagitis (RE), yet little is known about the two distinct receptors, CXC receptor (CXCR)-1 and -2. The purpose of this study was to determine CXCR-1 and -2 messenger RNA expression levels in RE. METHODS: We studied 26 patients with RE and 15 asymptomatic controls. Paired biopsy samples were taken from the esophagus 3 cm above the gastroesophageal junction; one biopsy was snap frozen for measurement of CXCR-1 and -2 mRNA levels by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), and another was formalin-fixed for histopathological evaluation. We also examined the association of the expression levels of CXCR-1 and -2 mRNA with histopathological hallmarks of RE. RESULTS: The relative CXCR-1 and -2 mRNA expression levels were rather decreased in esophageal mucosa of patients with RE, compared to those in normal esophagus of controls. There were no significant difference in the relative mRNA expression levels of CXCR-1 and -2 among endoscopic grades of RE based on the Los Angeles classification. Each histopathological hallmark of GERD was not associated with the expression levels of CXCR-1 and -2 mRNA. CONCLUSION: Apart from overexpression of IL-8, the relative expression levels of CXCR-1 and -2 mRNA were rather lower than expected in the affected esophageal mucosa of patients with RE.

Enhanced expression of interleukin-8 and activation of nuclear factor kappa-B in endoscopy-negative gastroesophageal reflux disease.

OBJECTIVE: Interleukin-8 (IL-8) mediates neutrophil trafficking via its receptors. Recent studies have shown that IL-8 is likely involved in the development and progression of erosive reflux esophagitis (RE), yet little is known about its implication in endoscopy-negative gastroesophageal reflux disease (GERD). The purpose of this study was to determine IL-8 messenger ribonucleic acid (mRNA) expression levels in endoscopy-negative GERD, along with assessment of nuclear factor kappaB (NF-kappaB) activation, which upregulates IL-8 expression. METHODS: We studied 31 patients with endoscopy-negative GERD, 15 patients with erosive RE, and 15 asymptomatic controls. Paired biopsy samples were taken from the esophagus 3 cm above the gastroesophageal junction; one biopsy was snap-frozen for measurement of IL-8 mRNA levels by real-time quantitative polymerase chain reaction, and another was formalin-fixed for histopathological evaluation. In nine endoscopy-negative GERD patients, the IL-8 mRNA expression levels were measured before and 8 wk after treatment with lansoprazole. We also sampled additional specimens for NF-kappaB-DNA binding assay and immunohistochemical analyses of NF-kappaB p65 and p50 subunits, IL-8 and specific IL-8 receptor, CXCR-1. RESULTS: The relative IL-8 mRNA expression levels were significantly higher in esophageal mucosa of patients with endoscopy-negative GERD than those of the controls. The presence of basal zone hyperplasia and intraepithelial neutrophils, histopathological hallmarks of GERD, were associated with higher levels of IL-8 mRNA. Lansoprazole treatment significantly reduced the IL-8 mRNA expression levels. The esophageal epithelium of patients with GERD showed intense immunoreactivity for IL-8, and expressed CXCR-1 antigen. We found NF-kappaB activation in esophageal mucosa in GERD patients and the NF-kappaB subunits were localized predominantly in the nuclei of IL-8-expressing cells. CONCLUSIONS: Our results demonstrate enhanced mucosal expression of IL-8 in incipient GERD even without mucosal breaks. NF-kappaB activation may be implicated in the pathogenesis in GERD.

Impact of endoscopically minimal involvement on IL-8 mRNA expression in esophageal mucosa of patients with non-erosive reflux disease.

AIM: Little has been known about the pathogenesis of non-erosive reflux disease (NERD). Recent studies have implicated interleukin 8 (IL-8) in the development and progression of gastroesophogeal reflux disease (GERD). The purpose of this study was to determine IL-8 RNA expression levels in NERD patients with or without subtle mucosal changes. METHODS: We studied 26 patients with NERD and 13 asymptomatic controls. Biopsy sample was taken from the esophagus 3 cm above the gastroesophageal junction and snap frozen for measurement of IL-8 mRNA levels by real-time quantitative polymerase chain reaction (PCR). We also examined mRNA expression of IL-8 receptors, CXCR-1 and -2 by reverse transcriptase PCR. The patients were endoscopically classified into grade M (mucosal color changes without visible mucosal break) and N (neither minimal involvement nor mucosal break) of the modified Los Angeles classification. RESULTS: The relative IL-8 mRNA expression levels were significantly higher in esophageal mucosa of NERD patients than those in esophageal mucosa of the controls. There was a significant difference in IL-8 mRNA levels between grades M and N. The CXCR-1 and -2 mRNAs were constitutively expressed in esophageal mucosa. CONCLUSION: Our results suggest that high IL-8 levels in esophageal mucosa may be involved in the pathogenesis of NERD through interaction with its receptors. NERD seems to be composed of a heterogeneous population in terms of not only endoscopically minimal involvement but also immune and inflammatory processes.

Immune thrombocytopenic purpura in patients with ulcerative colitis.

Extraintestinal manifestations of ulcerative colitis (UC) are well known, but immunologically mediated hematological diseases are relatively rare. We describe two cases of immune thrombocytopenic purpura (ITP) associated with preexisting UC. Our patients had typical symptoms of UC, and endoscopy showed pancolitis. During treatment with 5-aminosalicylic acid and steroids, severe thrombocytopenia was noted. ITP was diagnosed based on a normal to high number of megakaryocytes in the bone marrow, positive autoantibody to platelet membrane antigen, and absence of splenomegaly. Medical treatment, including increased dosage of steroids, failed to control UC and ITP in both patients. In the first patient, the platelet count recovered after colectomy, while the second patient died of a cerebral hemorrhage. We stress that a diagnosis of ITP should be considered for thrombocytopenia in patients with UC, especially those showing extensive and significant colonic inflammation, and that colectomy of UC might resolve resistant ITP.

Expression of heat shock protein (Hsp) 70 and Hsp 40 in gastric cancer.

Heat shock proteins (Hsp) 70 and Hsp 40 are stress proteins that cooperate as chaperones in mammalian cells. We determined the expression of Hsp 70 and Hsp 40 in 81 gastric cancers. Immunoreactivities to Hsp 70 and Hsp 40 were detected in 67.9 and 22.2% of tumors, respectively. Immunohistochemical analysis showed enhanced Hsp 70 and Hsp 40 expression in gastric tumor tissue, relative to the surrounding normal tissue. Overexpression of Hsp 70 and Hsp 40 was also confirmed by immunoblotting. Among various clinicopathological parameters, low histopathological differentiation was associated with reduced expression of both proteins.

Expression of heat shock protein (Hsp) 70 and Hsp 40 in colorectal cancer.

Heat shock protein (Hsp) 70 and Hsp 40 are stress proteins that cooperate as chaperones in mammalian cells. The present study was designed to determine the expression levels of Hsp 70 and Hsp 40 in colorectal cancer by immunohistochemistry and Western blot analysis. Among 50 colorectal cancer tissues studied, 80% and 14% of tumors showed specific immunoreactivity to Hsp 70 and Hsp 40, respectively. Hsp 70 and Hsp 40 were overexpressed in cancer tissue samples compared with normal tissues, on both analytic sets. However, there were no significant correlations between their expression and various clinicopathological parameters of colorectal cancer. Hsp 70 and Hsp 40 may be tumor markers for colorectal cancer.

Validation of endoscopic 13C-urea breath test with nondispersive infrared spectrometric analysis in the management of Helicobacter pylori infection.

BACKGROUND/AIMS: 13C-EUBT (endoscopic 13C-urea breath test), that combines the conventional urea breath test with endoscopy, provides excellent accuracy for detection of H. pylori. Recently, a simpler, less expensive and isotope-selected nondispersive infrared spectrometer has been developed for the urea breath test. We validated the diagnostic performance of 13C-EUBT using nondispersive infrared spectrometer in the management of H. pylori infection. METHODOLOGY: EUBT was performed in 232 patients by first collecting a baseline breath sample followed by upper gastrointestinal endoscopy. A 20-mL aliquot of 13C-urea solution was sprayed over the entire stomach under endoscopic guidance. Breath samples taken 0 and 20 minutes after spraying were analyzed using nondispersive infrared spectrometer. H. pylori infection was assessed by rapid urease test and histology. The cutoff level was determined by a receiver-operating characteristic curve analysis. Forty-four samples were also analyzed by the conventional isotope ratio mass spectrometer to compare results from both analyzers. We also applied the nondispersive infrared spectrometer-based EUBT to evaluate the efficacy of eradication therapy. RESULTS: Employing 2.4 per mL as the best cutoff value, the EUBT yielded an excellent diagnostic accuracy, with a sensitivity of 99% and specificity of 99%. The sensitivity and specificity of the test for assessing eradication therapy were 94% (16/17) and 100% (57/57), respectively. There was a high linear correlation between nondispersive infrared spectrometer and isotope ratio mass spectrometer (r = 0.998, p < 0.0001). CONCLUSIONS: 13C-EUBT using nondispersive infrared spectrometer is a highly accurate and rapid method for the assessment of H. pylori eradication as well as for detecting H. pylori infection. We believe that nondispersive infrared spectrometer gives more rapid and less expensive method for the management of H. pylori infection with the EUBT.