interleukin-8 and Gastroesophageal-Reflux

Laryngopharyngeal reflux is a controversial but increasingly made diagnosis used in patients with a collection of often non-specific laryngeal symptoms. It is a clinical diagnosis, and its pathophysiology is currently poorly understood. Previous reflux research has focused on injurious agents, acid, pepsin and biomarker expression. Failure of intrinsic defences in the larynx may cause changes in laryngeal epithelia, particularly alterations in carbonic anhydrases and E-cadherin. Carbonic anhydrase III levels vary in the larynx in response to laryngopharyngeal reflux, depending on location. Expression of E-cadherin, a known tumour suppressor, is reduced in the presence of reflux. Mucin expression also varies according to the severity of reflux. Further research is required to define the clinical entity of laryngopharyngeal reflux, and to identify a definitive mechanism for mucosal injury. Understanding this mechanism should allow the development of a comprehensive model, which would enable future diagnostic and therapeutic interventions to be developed.

Topics: Adult; Bile Acids and Salts; Biomarkers; Cadherins; Carbonic Anhydrase III; Gastric Acid; Gastroesophageal Reflux; Humans; Interleukin-8; Laryngeal Mucosa; Laryngopharyngeal Reflux; Mucins; Pepsin A; Severity of Illness Index

Gastroesophageal reflux disease (GERD) is one of the most common problems in clinical practice today. It is widely believed that functional and structural abnormalities of the gastroesophageal junction as well as an abnormal exposure to gastroduodenal contents are the main contributors to its pathogenesis. Novel findings of the inflammatory process in GERD suggest a far more complex process involving multifaceted inflammatory mechanisms. This review summarizes knowledge about the expression of inflammatory mediators in GERD and their potential cellular sources and provides an integrated concept of disease pathogenesis. In addition we evaluate the contribution of inflammatory mediators to well-known complications of GERD, namely motility abnormalities, fibrosis, and carcinogenesis. Novel findings regarding the pathophysiology of esophageal inflammation should enhance our understanding of GERD and its complications and provide new treatment insights.

Topics: Animals; Endothelial Cells; Esophageal Motility Disorders; Esophageal Neoplasms; Esophagitis; Esophagogastric Junction; Fibrosis; Gastroesophageal Reflux; Gastrointestinal Motility; Humans; Inflammation Mediators; Interleukin-1; Interleukin-6; Interleukin-8; Mesoderm; Platelet Activating Factor; Reactive Oxygen Species

The mechanism of esophageal mucosal injury has gradually been understood at the microbiological level. It is particularly important that pro-inflammatory factors, such as inflammatory cytokines, leukocytes and oxidative stress, have been demonstrated to be involved in the development of gastroesophageal reflux disease (GERD) including nonerosive reflux disease (NERD). Our present study reveals that expression of IL-8 mRNA, a potent neutrophil chemotactic and activating peptide, is correlated with the endoscopic grade of esophagitis or with inflammatory cell infiltration. In addition, it has been shown that bile acids and trypsin can promote IL-8 production from human esophageal epithelial cells via NFkappaB-and AP-1-dependent mechanism. Nociceptors such as acid-sensitive vanilloid receptors, protease-activated receptors and neuropeptides such as substance P have also been implicated in the pathogenesis of neurogenic inflammation in NERD patients with esophageal hypersensitivity. The development of new therapy with antiinflammatory and anti-oxidant effects is expected to assist in the treatment of intractable NERD/GERD and the prevention of carcinogenesis.

Topics: Anti-Inflammatory Agents; Antioxidants; Cytokines; Esophagoscopy; Esophagus; Gastroesophageal Reflux; Gene Expression; Humans; Inflammation; Inflammation Mediators; Interleukin-8; Nociceptors; Oxidative Stress; RNA, Messenger; Substance P

Topics: Duodenal Ulcer; Gastric Acid; Gastrins; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Humans; Interleukin-1; Interleukin-8

Recent reports have demonstrated significantly higher expression levels of interleukin-8 (IL-8) in patients with gastroesophageal reflux disease (GERD) including non-erosive reflux disease (NERD). The levels of IL-8 mRNA expression were significantly decreased after proton pump inhibitor. The esophageal expression of CINCs, rat IL-8-like chemokines, was markedly enhanced in the models of acute or chronic esophagitis in rats. The production of IL-8 from esophageal mucosal cells was enhanced by the exposure to bile acid. These results suggest that IL-8 chemokine may play a major role in the pathogenesis of esophageal inflammation in GERD.

Topics: Animals; Barrett Esophagus; Bile Acids and Salts; Chemokines, CXC; Depression, Chemical; Disease Models, Animal; Enzyme Inhibitors; Esophagitis, Peptic; Esophagus; Gastroesophageal Reflux; Gene Expression; Humans; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Interleukin-8; Mucous Membrane; Proton Pump Inhibitors; Rats; RNA, Messenger

The aim: To examine the composition of the oral microbiome in young children with laryngopharyngeal reflux (LPR) and its role the development of recurrent respiratory diseases.. Materials and methods: There were examined 38 children with physiological gastroesophageal reflux (GER), 18 children with LPR who had a medical history of recurrent bronchitis and 17 healthy children (control group). The study included the collection of anamnesis, objective examination. The qualitative and quantitative microbial composition of the upper respiratory tract was performed obtained by oropharyngeal deep swab. Salivary pepsin level and IL-8 were determined by enzyme-linked immunosorbent assay.. Results: This research showed significant alterations in the oral microbiome of patients with GER and LPR as compared to healthy control. We found that gram-negative microbiota such as Klebsiella pneumoniae, Escherichia coli, Proteus vulgaris, Proteus spp. and Candida albicans were identified in children with GER and LPR compared to the healthy control. At the same time, the amount of such a representative of the normal microbiome as Streptococcus viridans in children with LPR was sharply reduced. There were established a much higher mean salivary pepsin level of the patients with LPR than in the GER and control group. We found the association between high pepsin levels, saliva IL-8 levels and frequency of respiratory pathology in children with LPR.. Conclusions: Our study confirms that increased levels of pepsin in saliva are a risk factor for recurrent respiratory diseases in children with LPR.

Topics: Bronchitis; Child; Child, Preschool; Gastroesophageal Reflux; Gastrointestinal Microbiome; Humans; Interleukin-8; Laryngopharyngeal Reflux; Mouth; Pepsin A; Recurrence; Risk Factors; Saliva

Obesity is a known risk factor for the development of gastroesophageal reflux disease (GERD), Barrett's Esophagus (BE) and the progression to esophageal adenocarcinoma. The mechanisms by which obesity contributes to GERD, BE and its progression are currently not well understood. Recently, changes in lipid metabolism especially in the context of a high fat diet have been linked to GERD and BE leading us to explore whether fatty acid oxidation plays a role in the disease progression from GERD to esophageal adenocarcinoma. To that end, we analyzed the expression of the rate-limiting enzyme, carnitine palmytoyltransferase 1A (CPT1A), in human tissues and cell lines representing different stages in the sequence from normal squamous esophagus to cancer. We determined uptake of palmitic acid, the most abundant fatty acid in human serum, with fluorescent dye-labeled lipids as well as functional consequences of stimulation with palmitic acid relevant to Barrett's tumorigenesis, e.g., proliferation, characteristics of stemness and IL8 mediated inflammatory signaling. We further employed different mouse models including a genetic model of Barrett's esophagus based on IL1β overexpression in the presence and absence of a high fat diet and deoxycholic acid to physiologically mimic gastrointestinal reflux in the mice. Together, our data demonstrate that CPT1A is upregulated in Barrett's tumorigenesis and that experimental palmitic acid is delivered to mitochondria and associated with increased cell proliferation and stem cell marker expression.

Topics: Adenocarcinoma; Animals; Barrett Esophagus; Carcinogenesis; Carnitine; Carnitine O-Palmitoyltransferase; Cell Proliferation; Cell Transformation, Neoplastic; Deoxycholic Acid; Esophageal Neoplasms; Fluorescent Dyes; Gastroesophageal Reflux; Humans; Interleukin-8; Mice; Obesity; Palmitic Acid

The bile acid component of gastric refluxate has been implicated in inflammation of the oesophagus including conditions such as gastro-oesophageal reflux disease (GORD) and Barrett's Oesophagus (BO). Here we demonstrate that the hydrophobic bile acid, deoxycholic acid (DCA), stimulated the production of IL-6 and IL-8 mRNA and protein in Het-1A, a model of normal oesophageal cells. DCA-induced production of IL-6 and IL-8 was attenuated by pharmacologic inhibition of the Protein Kinase C (PKC), MAP kinase, tyrosine kinase pathways, by the cholesterol sequestering agent, methyl-beta-cyclodextrin (MCD) and by the hydrophilic bile acid, ursodeoxycholic acid (UDCA). The cholesterol-interacting agent, nystatin, which binds cholesterol without removing it from the membrane, synergized with DCA to induce IL-6 and IL-8. This was inhibited by the tyrosine kinase inhibitor genistein. DCA stimulated the phosphorylation of lipid raft component Src tyrosine kinase (Src). while knockdown of caveolin-1 expression using siRNA resulted in a decreased level of IL-8 production in response to DCA. Taken together, these results demonstrate that DCA stimulates IL-6 and IL-8 production in oesophageal cells via lipid raft-associated signaling. Inhibition of this process using cyclodextrins represents a novel therapeutic approach to the treatment of inflammatory diseases of the oesophagus including GORD and BO.

Topics: Barrett Esophagus; beta-Cyclodextrins; Bile Acids and Salts; Caveolin 1; Cell Line, Tumor; Cholesterol; Cytokines; Deoxycholic Acid; Esophagus; Gastroesophageal Reflux; Gene Expression; Humans; Inflammation; Interleukin-6; Interleukin-8; Lipids; Membrane Microdomains; Neoplasms; NF-kappa B; Phosphorylation; Signal Transduction; src-Family Kinases

Gastroesophageal reflux is a common gastrointestinal issue that can lead to aspiration and contribute to respiratory problems. Little is known about how reflux can alter the respiratory microenvironment. We aimed to determine if the presence of gastric pepsinogen in the trachea was associated with changes in the microbial and inflammatory microenvironment. A pediatric cohort at high risk of reflux aspiration was prospectively recruited, and the tracheal microenvironment was examined. Pepsinogen A3 (PGA3) and cytokines were measured. The microbiome (bacterial and fungal) was profiled using 16S rRNA and internal transcribed spacer 2 (ITS2) amplicon sequencing. Increased bacterial richness and an altered composition driven by an enrichment of

Topics: Adolescent; Candida; Chemokine CXCL10; Child; Child, Preschool; Cohort Studies; Cytokines; Female; Gastroesophageal Reflux; Gastrointestinal Microbiome; Humans; Infant; Inflammation; Interleukin-1; Interleukin-1beta; Interleukin-8; Male; Pepsinogen A; Prevotella; Respiratory Aspiration; RNA, Ribosomal, 16S; Trachea

Activation of protease-activated receptor-2 (PAR2) is involved in the mucosal immune pathogenesis of gastroesophageal reflux disease (GERD) that is characterized by proinflammatory cytokines such as interleukin-8 (IL-8). PAR2 activation on epithelial cells induces epithelial IL-8 secretion and initiates mucosal inflammation.. A human primary esophageal epithelial cell model was established to investigate the effects of repeated stimulation with weakly acidic solutions and subsequent PAR2 activation. After creating a monolayer, cells were incubated under weakly acidic conditions for 7 h followed by 17 h at pH 7.4. This short-term exposure was repeated once. After weakly acidic stimulation, PAR2 activation was achieved by a synthetic agonist at pH 7.4.. After repeated weakly acidic incubation, PAR2 transcript levels were 3.6-fold upregulated (p = 0.001) and IL-8 transcripts were 2.4-fold enhanced (p = 0.034) compared to nonstimulated controls, while IL-8 protein in the cell pellet and supernatant was not increased. Only the additional PAR2 activation upon pH stimulation led to increased IL-8 secretion into the supernatant.. We propose a 2-step mechanism in which repeated weakly acidic exposure leads to the upregulation of epithelial PAR2 expression. The subsequent activation of upregulated PAR2 contributes to the initiation of mucosal inflammation, which underlies the important role of esophageal epithelium in GERD pathogenesis.

Topics: Epithelial Cells; Esophageal Mucosa; Gastric Acid; Gastroesophageal Reflux; Humans; Interleukin-8; Primary Cell Culture; Receptor, PAR-2; Receptors, G-Protein-Coupled; RNA, Messenger; Up-Regulation

The association between gastroesophageal reflux disease (GERD) prevalence and its risk factors in an area with low Helicobacter pylori prevalence is important to clarify. We analyzed the prevalence of GERD and risk factors in an area of Indonesia with low prevalence of H. pylori infection. We recruited 104 dyspeptic patients who underwent endoscopy in Surabaya. Patients were diagnosed with GERD based on the Los Angeles classification. We evaluated gastric biopsy specimens and measured serum pepsinogen levels. Interleukin polymorphisms were evaluated by polymerase chain reaction-restriction fragment length polymorphism. Of 104 patients, 56 (53.8%) were endoscopically found to have GERD, with most categorized as grade A; 48 (46.2%) were classified as non-GERD. Higher economic status, smoking, and a history of proton-pump inhibitor use significantly increased the risk of GERD. GERD Questionnaire scores showed a positive correlation with GERD (P < 0.001). An association was found between antral atrophic gastritis and GERD (P = 0.030), and patients with GERD more frequently had severe antral atrophy than nonerosive reflux disease (P = 0.018). We found an association between pepsinogen I/II levels and GERD (P = 0.047), but with low accuracy. IL-1β -511 TT and CT were predominant among the IL-1β -511 genotypes, and IL-8-251 AT and TT were predominant among the IL-8-251 genotypes. In conclusion, we found a high prevalence of GERD in an area with low prevalence of H. pylori infection, which could be associated with acid reflux. Smoking, history of proton-pump inhibitor use, and higher economic group significantly increased the risk of GERD.

Topics: Adolescent; Adult; Aged; Biopsy; Endoscopy; Female; Gastritis; Gastroesophageal Reflux; Genotype; Helicobacter Infections; Helicobacter pylori; Humans; Interleukin-1beta; Interleukin-8; Male; Middle Aged; Pepsinogen A; Polymorphism, Single Nucleotide; Risk Factors; Smoking; Young Adult

Esophageal epithelial cells are an initiating cell type in esophageal inflammation, playing an essential role in the pathogenesis of gastroesophageal reflux disease (GERD). A new tissue-derived cytokine, interleukin-33 (IL-33), has been shown to be upregulated in esophageal epithelial cell nuclei in GERD, taking part in mucosal inflammation. Here, inflammatory cytokines secreted by esophageal epithelial cells, and their regulation by IL-33, were investigated.. In an in vitro stratified squamous epithelial model, IL-33 expression was examined using quantitative RT-PCR, western blot, ELISA, and immunofluorescence. Epithelial cell secreted inflammatory cytokines were examined using multiplex flow immunoassay. IL-33 was knocked down with small interfering RNA (siRNA) in normal human esophageal epithelial cells (HEECs). Pharmacological inhibitors and signal transducers and activators of transcription 1 (STAT1) siRNA were used to explore the signaling pathways.. Interferon (IFN)γ treatment upregulated nuclear IL-33 in HEECs. Furthermore, HEECs can produce various inflammatory cytokines, such as IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), regulated on activation normal T-cell expressed and presumably secreted (RANTES), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in response to IFNγ. Nuclear, but not exogenous IL-33, amplified IFN induction of these cytokines. P38 mitogen-activated protein kinase (MAPK) and janus protein tyrosine kinases (JAK)/STAT1 were the common signaling pathways of IFNγ-mediated induction of IL-33 and other cytokines.. Esophageal epithelial cells can actively participate in GERD pathogenesis through the production of various cytokines, and epithelial-derived IL-33 might play a central role in the production of these cytokines.

Topics: Blotting, Western; Cell Nucleus; Cells, Cultured; Cytokines; Epithelium; Esophagitis; Esophagus; Fluorescent Antibody Technique; Gastroesophageal Reflux; Humans; Interferon-gamma; Interleukin-33; Interleukin-6; Interleukin-8; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tumor Necrosis Factor-alpha

Oesophageal adenocarcinoma (OA) incidence is rising and prognosis is poor. Understanding the molecular basis of this malignancy is key to finding new prevention and treatment strategies. Gastroesophageal reflux disease is the primary cause of OA, usually managed with acid suppression therapy. However, this often does little to control carcinogenic bile acid reflux. The transcription factor nuclear factor kappa B (NF-κB) plays a key role in the pathogenesis of OA and its activity is associated with a poor response to chemotherapy, making it an attractive therapeutic target. We sought to decipher the role of different bile acids in NF-κB activation in oesophageal cell lines using short, physiologically relevant exposure times. The effect of an acidic or neutral extracellular pH was investigated concurrently, to mimic in vivo conditions associated with or without acid suppression. We found that some bile acids activated NF-κB to a greater extent when combined with acid, whereas others did so in its absence, at neutral pH. The precise composition of an individual's reflux, coupled with whether they are taking acid suppressants may therefore dictate the extent of NF-κB activation in the oesophagus, and hence the likelihood of histological progression and chemotherapy success. Regardless of pH, the kinase inhibitor of κB kinase was pivotal in mediating reflux induced NF-κB activation. Its importance was confirmed further as its increased activation was associated with histological progression in patient samples. We identified further kinases important in acid or bile induced NF-κB signalling in oesophageal cells, which may provide suitable targets for therapeutic intervention.

Topics: Adenocarcinoma; Bile Acids and Salts; Cell Line, Tumor; Esophageal Neoplasms; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; I-kappa B Kinase; Interleukin-8; NF-kappa B; Transcription Factor AP-1

Otitis media is characterized as an ongoing inflammation with accumulation of an effusion in the middle ear cleft. The molecular mechanisms underlying the pathogenesis, particularly the inflammatory response, remain largely unknown. We hypothesize that aspiration of gastric contents into the nasopharynx may be responsible for the initiation of the inflammatory process or aggravate a preexisting condition.. To investigate the correlation of gastric pepsin A with inflammatory cytokines, bacterial infection, and clinical outcomes.. Prospective study of 129 pediatric patients undergoing myringotomy with tube placement for otitis media at a tertiary care pediatric hospital.. Ear samples were tested for pepsin A; cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor; and bacterial culture inoculation. Data were analyzed by descriptive statistics and regression analysis to identify risk factors for the presence of pepsin A and to correlate pepsin A levels with cytokine levels, infection status, and clinical outcomes.. Of the 129 patients, 199 ear samples were obtained; 82 samples (41%) and 64 patients (50%) were positive for pepsin A as measured by immunoassay. Pepsin A positivity correlated with age younger than 3.0 years (mean [SD], 2.3 [2.1] years in the positive group vs 3.3 [3.0] years in the negative group) and with all 3 cytokine levels (mean [SD] tumor necrosis factor, 29.5 [45.9] pg/mL in the positive group vs 13.2 [21.6] pg/mL in the negative group; IL-6, 6791.7 [9389.1] pg/mL in the positive group vs 2849.9 [4066.3] pg/mL in the negative group; and IL-8, 6828.2 [8122.3] pg/mL in the positive group vs 2925.1 [3364.5] pg/mL in the negative group [all P < .05]); however, logistic regression analysis showed that only IL-8 (odds ratio, 3.96; 95% CI, 1.3-12.0; P = .02) and age (odds ratio, 3.83; 95% CI, 1.2-12.7; P = .03) were significant independent variables. No statistically significant association was found with other parameters. Multiple linear regressions revealed that the levels of pepsin A were correlated with IL-8 levels (R2 = 0.248; P < .001) and the need for second or third tubes 6 to 12 months after the first (R2 = 0.102; P = .006). The presence of pepsin A in the middle ear was not associated with increased bacterial infection. Interleukin 8 was independent and significantly associated with both pepsin A levels and bacterial infection (R2 = 0.144 and 0.263, respectively; P = .001 for both).. Extraesophageal reflux as indicated by the presence of pepsin A is closely involved in the middle ear inflammatory process and may worsen the disease in some children; however, a proof of cause and effect between extraesophageal reflux and middle ear inflammation requires further investigation.

Topics: Child; Child, Preschool; Female; Gastroesophageal Reflux; Haemophilus influenzae; Humans; Infant; Interleukin-6; Interleukin-8; Male; Middle Ear Ventilation; Moraxella catarrhalis; Otitis Media with Effusion; Otitis Media, Suppurative; Pepsin A; Prospective Studies; Risk Factors; Streptococcus pneumoniae; Tumor Necrosis Factor-alpha

The pathophysiology of esophageal injury, repair, and inflammation in gastroesophageal reflux-disease (GERD) is complex. Whereas most studies have focused on the epithelial response to GERD injury, we are interested in the stromal response. We hypothesized that subepithelial esophageal myofibroblasts in GERD secrete proinflammatory cytokines in response to injurious agents encountered via epithelial barrier breaches or through dilated epithelial intercellular spaces. We determined the percentage of myofibroblasts [-smooth muscle actin (-SMA)+vimentin+CD31-] in the subepithelial GERD and normal esophageal stroma by immunomorphologic analysis. We performed -SMA coimmunostaining with IL-6 and p65. We established and characterized primary cultures of -SMA+vimentin+CD31-CD45- human esophageal myofibroblasts (HuEso MFs). We modeled GERD by treatment with pH 4.5-acidified media and Toll-like receptor 4 (TLR4) ligands, LPS and high-mobility group box 1 protein (HMGB1), and determined myofibroblast cytokine secretion in response to GERD injury. We demonstrate that spindle-shaped cell myofibroblasts are located near the basement membrane of stratified squamous epithelium in normal esophagus. We identify an increase in subepithelial myofibroblasts and activation of proinflammatory pathways in patients with GERD. Primary cultures of stromal cells obtained from normal esophagus retain myofibroblast morphology and express the acid receptor transient receptor potential channel vanilloid subfamily 1 (TRPV1) and TLR4. HuEso MFs stimulated with acid and TLR4 agonists LPS and HMGB1 increase IL-6 and IL-8 secretion via TRPV1 and NF-B activation. Our work implicates a role for human subepithelial stromal cells in the pathogenesis of GERD-related esophageal injury. Findings of this study can be extended to the investigation of epithelial-stromal interactions in inflammatory esophageal mucosal disorders.

Topics: Actins; Basement Membrane; Cell Culture Techniques; Esophagus; Gastroesophageal Reflux; HMGB1 Protein; Humans; Inflammation; Interleukin-6; Interleukin-8; Myofibroblasts; Platelet Endothelial Cell Adhesion Molecule-1; Stimulation, Chemical; Toll-Like Receptor 4; Vimentin

The state of homeostasis links in the children with intestinal colic is represented by the following parameters and clinical characteristics. The data of investigated children's contingent with intestinal colic prevailed by following comorbidities: SARS--12 (18.18% ± 4.78%), protein-energy malnutrition--9 (12.85% ± 3.82%), pneumonia--6 (8.57% ± 3.57%), atopic dermatitis--7 (10.00% ±.3.57%). All children have a next complaints: flatulence (100%), in the 62 children (88.57% ± 3.82%) were identificated frequent regurgitation, in the 48 (80.33%)--hyperbilirubinemia. ALT levels were elevated in 25 children (41%) and 31 (51.66%) children had increased levels of AST. IL8 level were elevated in the 40 children (71.42%). The level of antibodies to elastase was greatly increased in all 56 (100%) children.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Autoantibodies; Colic; Comorbidity; Dermatitis, Atopic; Female; Flatulence; Gastroesophageal Reflux; Humans; Hyperbilirubinemia; Infant; Infant, Newborn; Interleukin-8; Intestines; Male; Malnutrition; Pancreatic Elastase; Pneumonia, Bacterial; Severe Acute Respiratory Syndrome; Ukraine

Immune-mediated injury by the protease-activated receptor-2-interleukin-8 (PAR-2-IL8) pathway may underlie the development of gastroesophageal reflux disease (GERD). However, the localization of PAR-2 and the mechanism of PAR-2 activation remain unclear. This study aimed to address these questions on an esophageal stratified squamous epithelial model and in the human esophageal mucosa of GERD patients. Normal human esophageal epithelial cells were cultured with the air-liquid interface system to establish the model. SLIGKV-NH2 (PAR-2 synthetic agonist), trypsin (PAR-2 natural activator), and weak acid (pH 4, 5, and 6) were added to either the apical or basolateral compartment to evaluate their effects on transepithelial electrical resistance (TEER) and IL-8 production. PAR-2 localization was examined both in the cell model and biopsies from GERD patients by immunohistochemistry. Apical trypsin stimulation induced IL-8 accompanied by decreased TEER in vitro, whereas the effective concentration from the basolateral side was 10 times lower. SLIGKV-NH2 from basolateral but not apical stimulation induced IL-8 production. Apical weak acid stimulation did not influence TEER or IL-8 production. Immunohistochemistry showed intense reactivity of PAR-2 in the basal and suprabasal layers after stimulation with trypsin. A similar PAR-2 reactivity that was mainly located at the basal and suprabasal layers was detected in GERD patients. In conclusion, the activation of the PAR-2-IL-8 pathway probably occurred at the basal and suprabasal layers, while the esophageal epithelial barrier may influence the activation of PAR-2. Under proton pump inhibitor therapy, refluxed trypsin may remain active and be a potential agent in the pathogenesis of refractory GERD.

Topics: Electric Impedance; Epithelial Cells; Esophagus; Gastroesophageal Reflux; Humans; Interleukin-8; Oligopeptides; Receptor, PAR-2; Trypsin

The proteinase-activated receptor-2 (PAR-2) is activated by serine proteases and has been demonstrated to induce proinflammatory and neuroinflammatory effects. It is considered to alter transepithelial resistance and mediates visceral hypersensitivity. This study aimed to evaluate the expression of PAR-2 in human esophageal mucosa of patients with gastroesophageal reflux disease (GERD) in relation to mucosal alterations.. The study included 123 patients with GERD stratified to erosive reflux disease (n=50), non-erosive reflux disease (n=46), and reflux-negative patients as controls (n=27). Endoscopic and histopathological characterization was performed according to the Los Angeles classification and modified Ismail-Beigi criteria, respectively. PAR-2 expression was analyzed by quantitative reverse transcription (RT)-PCR and immunohistochemistry. The gene expression levels of interleukin (IL)-8 were determined by quantitative RT-PCR and correlated to PAR-2 expression in each patient. Performing in vitro studies, esophageal squamous cell lines (KYSE 150, KYSE 450) were incubated, adjusted to different pH (7.0, 6.0, and 5.0), and exposed to bile acids and PAR-2-activation peptide (SLIGKV-NH(2)).. PAR-2 gene expression was 7- to 10-fold upregulated (P<0.0001) in the mucosa of patients with GERD and correlated positively with IL-8 expression and with histomorphological alterations (dilated intercellular spaces, papillary elongation, basal cell hyperplasia (BCH); P<0.01). Immunohistochemistry showed an intense staining of PAR-2 throughout all epithelial layers in patients with GERD compared with controls (P=0.0005). In vitro studies revealed a 1.5- to 20-fold induction of PAR-2 gene expression in esophageal squamous cells by acidified medium (P<0.01), but not by additional bile acids. The activation of PAR-2 leads to expression and secretion of IL-8.. This study provides evidence of the functional importance of PAR-2-mediated pathways in the pathogenesis of GERD and GERD-associated mucosal alterations and inflammatory changes.

Topics: Adolescent; Adult; Aged; Cell Line; Endoscopy, Gastrointestinal; Esophagus; Female; Gastric Mucosa; Gastroesophageal Reflux; Humans; Immunohistochemistry; Interleukin-8; Male; Middle Aged; Receptor, PAR-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Up-Regulation

Gastroesophageal reflux disease (GERD) leads to endoscopic and histomorphological changes in the gastroesophageal (GE) mucosa.. To evaluate the expression of the cytokines interleukin-1beta (IL-1beta) and interleukin-8 (IL-8) in the GE mucosa in GERD patients and controls and to correlate the cytokine expression with the histomorphological parameters.. One hundred and fifteen patients, 48 with erosive reflux disease (ERD) and 41 with non-erosive reflux disease (NERD) with typical GERD-related symptoms, and 26 controls were included. Endoscopic and histological characterization of esophagitis was performed according to the Los Angeles and Ismeil-Beigi/Vieth criteria, respectively. Mucosal gene expression levels of IL-1beta and IL-8 were analyzed by real-time RT-PCR.. ERD and NERD patients revealed significant higher levels of IL-1beta and IL-8 transcript levels in the cardia and esophageal mucosa than controls. The esophageal mucosa revealed elevated IL-8 (2.5- and 8.7-fold) and IL-1beta (4.1- and 7.8-fold) transcript levels in NERD and ERD, respectively. Histological analysis demonstrated a stepwise increase of dilatation of intercellular spaces and the degree of basal cell hyperplasia from controls, NERD towards ERD. Gene expression levels of both cytokines correlated with histology.. ERD and NERD are associated with an induction of the proinflammatory cytokines IL-1beta and IL-8 that correlates with histomorphological changes in esophageal mucosa.

Topics: Adolescent; Adult; Aged; Female; Gastroesophageal Reflux; Gene Expression; Humans; Interleukin-1beta; Interleukin-8; Intestinal Mucosa; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction

Gastroesophageal reflux disease with extra-esophageal symptoms, especially those with respiratory distress was attracting more and more attention. The related mechanisms were still in controversy. The purpose of the work was to explore airway inflammation triggered by gastroesophageal reflux.. Sixteen Sprague-Dawley rats were used as study group and 9 as control. In the study group, a plastic extender with a trumpet-shaped distal end was inserted into the lower esophagus to dilate the cardia, the pylorus was ligated. One ml of 0.1 mol/L hydrochloric acid was injected into the stomach. While a simple laparotomy was performed for control animals. All animals from two groups were sacrificed 24 hours after operation. Then tracheotomy was carried and the bronchoalveolar lavage fluid was collected in all animals. Cells in the fluid were counted and levels of interleukin (IL)-5, -6, -8 in it were measured.. Compared with control group, the study group presented a neutrophil pattern of airway inflammation and an elevated concentration of IL-5, -6, -8 with no significant difference regarding eosinophil count.. The gastroesophageal reflux-triggered airway inflammation is characterized by a neutrophilic airway inflammation which differed from that caused by asthma, and enhanced levels of IL-5, -6 and -8, which are similar to that caused by asthma.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Gastroesophageal Reflux; Inflammation; Interleukin-5; Interleukin-6; Interleukin-8; Male; Rats; Rats, Sprague-Dawley

To determine the role of inflammatory cytokines and reactive oxygen species (ROS) in childhood reflux esophagitis.. A total of 59 subjects who had complaints suggesting GERD underwent esophagogastroduodenoscopy. Endoscopic and histopathologic diagnosis of reflux esophagitis was established by Savary-Miller and Vandenplas grading systems, respectively. Esophageal biopsy specimens were taken from the esophagus 20% proximal above the esophagogastric junction for conventional histopathological examination and the measurements of ROS and cytokine levels. ROS were measured by chemiluminescence, whereas IL-8 and MCP-1 levels were determined with quantitative immunometric ELISA on esophageal tissue. Esophageal tissue ROS, IL-8 and MCP-1 levels were compared among groups with and without endoscopic/histo-pathologic esophagitis.. Of 59 patients 28 (47.5%) had normal esophagus whereas 31 (52.5%) had endoscopic esophagitis. In histopathological evaluation, almost 73% of the cases had mild and 6.8% had moderate degree of esophagitis. When ROS and chemokine levels were compared among groups with and without endoscopic esophagitis, statistical difference could not be found between patients with and without esophagitis. Although the levels of ROS, IL-8 and MCP-1 were found to be higher in the group with histopathological reflux esophagitis, this difference was not statistically significant.. These results suggest that the grade of esophagitis is usually mild or moderate during childhood and factors apart from ROS, IL-8 and MCP-1 may be involved in the pathogenesis of reflux esophagitis in children.

Topics: Adolescent; Chemokine CCL2; Child; Child, Preschool; Endoscopy, Digestive System; Enzyme-Linked Immunosorbent Assay; Esophagus; Gastroesophageal Reflux; Humans; Infant; Interleukin-8; Luminescent Measurements; Mucous Membrane; Prospective Studies; Reactive Oxygen Species; Severity of Illness Index; Up-Regulation

Both gastroesophageal reflux and airway colonization with Pseudomonas aeruginosa (P aeruginosa) are common in lung transplantation (LTx) recipients. There is mounting evidence that, due to their interaction with the epithelium, both may be involved in chronic allograft dysfunction/bronchiolitis obliterans syndrome (BOS) after LTx. We investigated whether gastric aspiration and airway colonization with P aeruginosa after LTx are associated.. In this retrospective, cross-sectional, case-control study, 24 stable double (SS) LTx recipients were included. Markers of gastroesophageal reflux (pepsin, bile acids) and airway inflammation (neutrophilia and interleukin-8 (IL-8)) were evaluated in bronchoalveolar lavage (BAL) samples of post-operatively colonized (n = 12) and non-colonized matched-control LTx recipients (n = 12).. BAL bile acid levels, but not pepsin levels, as well as neutrophilia and IL-8 protein levels were significantly elevated in colonized compared with non-colonized patients. Furthermore, bile acid levels, but not pepsin levels, correlated positively with BAL neutrophilia and IL-8 protein levels.. Bile acid aspiration and airway colonization by P aeruginosa after LTx seem to be associated. This relationship between reflux and airway colonization and their role in the development of chronic allograft dysfunction/BOS after LTx should be further elucidated; nevertheless, induction of IL-8-mediated neutrophilic airway inflammation may be a putative mechanism.

Topics: Adult; Bile Acids and Salts; Biomarkers; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cross-Sectional Studies; Female; Gastroesophageal Reflux; Humans; Inflammation; Interleukin-8; Lung Transplantation; Male; Middle Aged; Neutrophils; Pepsin A; Pneumonia, Bacterial; Postoperative Complications; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Aspiration; Respiratory System; Retrospective Studies

Chronic inflammation of esophageal mucosa secondary to refluxed gastric juice increases gene expression of interleukin 8 (IL-8). Antireflux surgery can reduce this overexpression.. Prospective analysis of archival paraffin-embedded tissue.. Academic tertiary medical center.. One hundred eight patients with reflux symptoms were classified according to pH monitoring and endoscopic and histologic findings. Twenty patients did not have reflux or mucosal injury; 47 had reflux disease (16 esophagitis and 31 Barrett's esophagus), 20 had dysplasia, and 21 had adenocarcinoma. Microdissection was performed to exclude inflammatory cells and stromal tissue. After RNA isolation and reverse transcription, IL-8 messenger RNA expression was measured using quantitative real-time polymerase chain reaction. All patients with reflux disease had Nissen fundoplication with biopsies at matched levels within the esophagus preoperation and postoperation.. Expression of IL-8 was increased in patients with reflux compared with those without reflux. Patients with the highest IL-8 expression were those with Barrett's dysplasia and adenocarcinoma (P<.001). In patients with reflux, Nissen fundoplication led to significantly decreased IL-8 expression compared with preoperative levels in esophagitis (P = .01) and Barrett's esophagus (P = .03).. Interleukin 8 messenger RNA expression increases during the progression of reflux disease from normal squamous mucosa to esophageal adenocarcinoma. Elimination of reflux with Nissen fundoplication significantly reduces IL-8 expression in both squamous and Barrett's mucosa. These results demonstrate that effective antireflux surgery can modulate the gene expression of esophageal mucosa and may impact the natural history of reflux disease.

Topics: Adenocarcinoma; Barrett Esophagus; Case-Control Studies; Esophageal Neoplasms; Esophagectomy; Esophagitis, Peptic; Fundoplication; Gastroesophageal Reflux; Humans; Interleukin-8; RNA, Messenger

Gastroesophageal reflux (GER) may induce respiratory symptoms (RS) through inhalation of acid gastric contents. To characterize the airway inflammation associated with this condition, 20 children [7.4 (0.9) yr old] with "difficult to treat" RS and a positive 24-h oesophageal pH monitoring (pHm) were studied and bronchoalveolar lavage (BAL) performed. The control group included 10 children [7.3 (1.3) yr], non-atopics, with a respiratory clinical history similar to the cases but no reflux, as demonstrated by a negative 24-h oesophageal pHm. On BAL samples, in addition to inflammatory indexes, the lipid-laden macrophage (LLM) index was determined as index of gastric content inhalation. As compared to controls, GER children had higher neutrophil proportion (P=0.002), higher LLM index (P=0.004) and higher concentrations of interleukin (IL)-8 (P=0.005), myeloperoxidase (MPO) (P=0.001) and elastase (P=0.045) in BAL fluid. In GER children, but not in controls, neutrophil proportion significantly correlated with LLM index (r=0.65, P=0.002), with IL-8 (r=0.62, P=0.003) and MPO levels (r=0.54, P=0.014) but not with elastase concentrations. These results suggest an active pathogenetic role of IL-8 in the recruitment and activation of neutrophils in the airways of children with GER, respiratory symptoms and BAL findings suggestive of gastric content aspiration.

Topics: Asthma; Bronchitis; Bronchoalveolar Lavage Fluid; Child; Enzyme-Linked Immunosorbent Assay; Female; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Interleukin-8; Leukocytosis; Male; Neutrophil Activation; Neutrophils; Peroxidase; Respiratory Function Tests

Aspiration of gastroesophageal refluxate may contribute to lung transplant bronchiolitis obliterans syndrome (BOS). We investigated bile acids in bronchoalveolar lavage fluid (BALF) and studied its role in BOS.. Surveillance pulmonary function tests and BALF were evaluated in 120 lung recipients. BOS-(0p-3) was diagnosed after 6 months' survival. BOS was defined as "early" if diagnosed within 12 months after a transplant. BALF was assayed for differential cell count, bile acids, and interleukins 8 and 15. Bile acids were considered elevated if greater than normal serum levels ( or =8 micromol/L).. Elevated BALF bile acids were measured in 20 (17%) of 120 patients. BOS was diagnosed in 36 (34%) of 107 patients and judged "early" in 21 (57%) of 36. Median BALF bile acid values were 1.6 micromol/L (range, 0-32 micromol/L) in BOS patients and 0.3 micromol/L (range, 0-16 micromol/L) in non-BOS patients ( P = .002); 2.6 micromol/L (range, 0-32 micromol/L) in early BOS patients and 0.8 micromol/L (range, 0-4.6 micromol/L) in late BOS patients, ( P = .02). Bile acids correlated with BALF IL-8 and alveolar neutrophilia (r = 0.3, P = .0004, and r = 0.3, P = .004, respectively), but not with IL-15. Freedom from BOS was significantly shortened in patients with elevated BALF bile acids (Cox-Mantel test, P = .0001).. Aspiration of duodenogastroesophageal refluxate is prevalent after lung transplantation and is associated with the development of BOS. Elevated BALF bile acids may promote early BOS development via an inflammatory process, possibly mediated by IL-8 and alveolar neutrophilia.

Topics: Actuarial Analysis; Bile Acids and Salts; Biomarkers; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Bronchoscopy; Disease-Free Survival; Enzyme-Linked Immunosorbent Assay; Follow-Up Studies; Gastroesophageal Reflux; Humans; Inflammation; Interleukin-15; Interleukin-8; Leukocyte Count; Lung Transplantation; Neutrophils; Ontario; Prevalence; Respiratory Function Tests; Risk Factors; Spectrophotometry; Survival Analysis; Time Factors

The incidence of esophageal adenocarcinoma has increased significantly in the western world over the last 20 yr. Most cases arise in a background of chronic gastroesophageal reflux, and specialized intestinal metaplasia in Barrett's esophagus is frequently an antecedent phenotype or evident in association with adenocarcinoma. The molecular events that characterize the pathway from inflammation to metaplasia to dysplasia and adenocarcinoma are poorly understood.. To examine the expression of the proinflammatory cytokines IL-8 and IL-1beta along the esophagitis, metaplasia, dysplasia, and adenocarcinoma pathway, and to correlate this with histological changes and expression of the transcription factor NF-kappaB.. Fresh biopsy specimens were collected from patients with reflux esophagitis (n=15), Barrett's esophagus (n=35), Barrett's adjacent to adenocarcinoma (n=8), and esophageal adenocarcinoma (n=35). IL-8 and IL-1beta expression were measured using enzyme-linked immunosorbent assay. NF-kappaB expression was measured by electrophoretic mobility shift assay.. Elevated expression of NF-kappaB was found in 2 (13%) out of 15 patients with reflux esophagitis, 21 (60%) out of 35 patients with Barrett's esophagus, and 28 (80%) out of 35 patients with esophageal adenocarcinoma. All 5 patients with Barrett's esophagus and high-grade dysplasia showed elevated expression of NF-kappaB. IL-8 and IL-1beta were significantly increased in esophagitis, Barrett's, and adenocarcinoma compared with squamous epithelium, and in adenocarcinoma compared with all other groups. There was a stepwise increase in the expression of IL-8, IL-1beta, and NF-kappaB from normal through Barrett's epithelium to adenocarcinoma in eight cases of esophageal adenocarcinoma. The levels of both IL-8 and IL-1beta in adenocarcinoma patients correlated with stage of disease. Patients with adenocarcinoma who were NF-kappaB positive had significantly higher levels of both IL-8 (p=0.04) and IL-1beta (p=0.03) compared to adenocarcinoma patients who were NF-kappaB negative.. The proinflammatory cytokines IL-8 and IL-1beta are elevated in esophagitis and Barrett's epithelium, and markedly elevated in adenocarcinoma. NF-kappaB activation is infrequent in esophagitis, but is increased in Barrett's epithelium and adenocarcinoma. The association of NF-kappaB activation with cytokine upregulation was only evident in patients with adenocarcinoma. These patterns may play an important role in Barrett's inflammation and tumourigenesis, and inhibition of the NF-kappaB/proinflammatory cytokine pathway may be an important target for future chemoprevention strategies.

Topics: Adenocarcinoma; Barrett Esophagus; Biomarkers; Biopsy; Electrophoresis; Endoscopy, Digestive System; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Esophagitis; Female; Gastroesophageal Reflux; Humans; Interleukin-1; Interleukin-8; Intestinal Mucosa; Male; Metaplasia; Middle Aged; NF-kappa B; Precancerous Conditions; Prospective Studies

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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Esophagoscopy; Esophagus; Female; Gastroesophageal Reflux; Humans; Immunohistochemistry; Interleukin-8; Male; Middle Aged; Mucous Membrane; NF-kappa B; RNA, Messenger

At the gastric cardia, the molecular mechanisms of inflammation and metaplasia are incompletely understood. Thus, the aim of this study was to determine the expression of TFF1, TFF2 and TFF3 at this site and correlate these data with Helicobacter pylori infection or gastro-esophageal reflux disease (GERD). In 27 patients without intestinal metaplasia at the cardia, endoscopic biopsies were obtained for histology and RT-PCR. TFF1 and TFF2 were expressed in all cardia samples. TFF3 expression was significantly more frequent at the cardia (n = 15/24) than in the corpus (n = 2/26). TFF3 expression at the cardia was mainly observed in GERD patients, and there was a clear tendency towards higher interleukin-8 (IL-8) transcription levels; whereas TFF3 expression was not correlated with the H. pylori status or to tumor necrosis factor-alpha (TNF-alpha) expression. The expression of TFF3 at the cardia may represent an adaptation to GERD and precede the development of Barrett's esophagus.

Topics: Barrett Esophagus; Cardia; Esophagogastric Junction; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Humans; Interleukin-8; Mucins; Muscle Proteins; Peptides; Proteins; Trefoil Factor-1; Trefoil Factor-2; Trefoil Factor-3; Tumor Necrosis Factor-alpha; Tumor Suppressor Proteins

It has been reported that inflammatory cell infiltration can be detected in patients with endoscopically negative gastroesophageal reflux disease (GERD) as well as those with erosive reflux esophagitis. In this study, we examined the expression of mRNA for interleukin (IL)-8, a potent chemokine for neutrophils, in the esophageal mucosa of patients with GERD and compared the results with their endoscopic findings and symptoms.. Biopsy samples were obtained from 80 patients. Endoscopic diagnosis was performed according to the Los Angeles classification. Patients with typical symptoms such as heartburn despite normal endoscopic findings were classified as the non-erosive GERD group. Total cellular RNA was extracted from the biopsy samples and IL-8 mRNA was quantified by real-time polymerase chain reaction (PCR). Localization of IL-8 protein in the esophageal mucosa was done by immunostaining.. Expression of IL-8 mRNA was correlated with the endoscopic grade of esophagitis or with inflammatory cell infiltration, but not with the symptoms of the patients. Expression of IL-8 mRNA was also detected in all patients with non-erosive GERD. The level of IL-8 expression in non-erosive GERD was low compared with that in erosive GERD, but was higher than that in normal controls. IL-8 immunostaining was found in the basal layers of the esophageal mucosa. Administration of lansoprazole, a proton-pump inhibitor, decreased both IL-8 mRNA and protein levels in the esophageal mucosa.. These results suggest that IL-8 in the esophageal mucosa may be involved in the pathogenesis of esophageal inflammation, including non-erosive GERD.

Topics: Base Sequence; Biopsy, Needle; Endoscopy, Gastrointestinal; Esophagitis, Peptic; Female; Gastroesophageal Reflux; Humans; Immunohistochemistry; Inflammation Mediators; Interleukin-8; Male; Molecular Sequence Data; Mucous Membrane; Polymerase Chain Reaction; Probability; Prognosis; Prospective Studies; RNA, Messenger; Sampling Studies; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric

Topics: Esophagoscopy; Esophagus; Gastroesophageal Reflux; Helicobacter Infections; Humans; Immunohistochemistry; Interleukin-8; Mucous Membrane; NF-kappa B; RNA, Messenger

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.. 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.. 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.. 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.

Topics: Adult; Aged; Alcohol Drinking; Base Sequence; DNA Primers; Endoscopy, Digestive System; Female; Gastroesophageal Reflux; Gene Expression Regulation; Helicobacter Infections; Helicobacter pylori; Hernia, Hiatal; Humans; Interleukin-8; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA, Messenger; Smoking