Increased Expression of Cytokines and Adhesion Molecules in Rat Chronic Esophagitis

Abstract

Background/Aims: Cytokines and adhesion molecules regulate many inflammatory processes in several gastrointestinal diseases. The dynamics of cytokines and adhesion molecules in reflux esophagitis are unknown in detail. We examined the expression and dynamics of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), MIP-2, GRO/cytokine-induced neutrophil chemoattractant-2α (CINC-2α), intercellular adhesion molecule-1 (ICAM-1), leukocyte function-associated antigen 1 (LFA-1; CD11a/CD18), and Mac-1 (CD11b/CD18) in rat chronic reflux esophagitis. Methods: Chronic acid reflux esophagitis was induced in Wistar rats by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus with a small piece of an 18-Fr Nélaton catheter. Rats were killed 3 or 21 days after operation. The levels of mRNA expression of cytokines and ICAM-1 were determined by real-time quantitative RT-PCR. Localization of adhesion molecules and cytokines was investigated by immunohistochemical staining, and numbers of LFA-1- or Mac-1-positive cells were quantified. Results: IL-1β, TNF-α, MCP-1, MIP-1α, MIP-2, CINC-2α, and ICAM-1 mRNA expression was significantly increased in esophageal lesions compared with normal esophagus. There were few these cytokines- or adhesion molecule-positive cells in normal esophagus. In regions of esophagitis, numerous inflammatory leukocytes in lamina propria and the submucosal layer exhibited positive reactions for these cytokines and endothelial cells were intensely stained for ICAM-1. Numbers of LFA-1- and Mac-1-positive cells were significantly increased in rat chronic esophagitis. Treatment with rabeprazole almost completely inhibited development of chronic acid reflux esophagitis and significantly decreased expression of cytokines and ICAM-1 mRNA in esophageal tissue compared with control. Conclusion: Cytokines and adhesion molecules play important roles in the pathogenesis of chronic reflux esophagitis in this rat model.

Inflammatory mediators in gastroesophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis

“…Hamaguchi et al (46) detected elevated TNF mRNA levels in a rat esophagitis model, a finding in contrast to data derived from a cat esophagitis model (9), as well as from human biopsies (103). IL-10 and IL-4 are considered anti-inflammatory or immunoregulatory cytokines that exert an important function in the control of inflammation.…”

“…IL-1␤ is increased in the esophageal mucosa during reflux induced inflammation, in animal models as well as in humans. It is produced upon contact of the esophageal mucosa with acid (11,13,36,46,103). IL-1␤ may be present in severe GERD cases only, and its expression is restricted to the lower third of the esophagus (103).…”

“…Immunohistochemical detection of cytokines is difficult, but ample data on the ability of immune cells to secrete cytokines are available from other organs. In GERD immunohistochemical staining shows expression of IL-1␤, IL-8, TNF, and IL-10 (36,46,55). In addition, neutrophils, monocytes, and macrophages are a major source of ROS and PAF in inflammation.…”

Interleukin-1Beta and Interleukin-8 Expression Correlate with the Histomorphological Changes in Esophageal Mucosa of Patients with Erosive and Non-Erosive Reflux Disease

“…Recent interest has focused on the role of inflammatory mediators in this disease [14,15,16,17]. The proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-8 (IL-8) appear to have a crucial role in inflammation in various diseases of upper gastrointestinal tract [17, 18]. IL-8 is a potent neutrophil chemotactic factor which is produced by various cell types including monocytes, fibroblasts, endothelial, and epithelial cells [14, 15].…”

“…IL-8 is a potent neutrophil chemotactic factor which is produced by various cell types including monocytes, fibroblasts, endothelial, and epithelial cells [14, 15]. IL-1 is produced principally by monocytes and may be important in perpetuating inflammation and fibrosis [16,17,18]. We chose to study IL-1 and IL-8 because these cytokines are secreted in a multitude of inflammatory diseases and are involved in the process of leukocyte attraction and transmigration.…”