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Immune and Inflammatory Responses in GERD and Lansoprazole.

Isomoto H, Nishi Y, Kanazawa Y, Shikuwa S, Mizuta Y, Inoue K, Kohno S - J Clin Biochem Nutr (2007)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Based on immunohistochemical analysis with anti-IL-8 antisera, IL-8 expression was found in the epithelium of esophageal biopsy specimens. Reprinted with permission [22].
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Figure 2: Based on immunohistochemical analysis with anti-IL-8 antisera, IL-8 expression was found in the epithelium of esophageal biopsy specimens. Reprinted with permission [22].

Mentions: Chemokines are a group of cytokines with potent chemotactic activity towards different populations of leukocytes; they are involved in the pathogenesis of a variety of inflammatory conditions. IL-8 exhibits a potent chemotactic activity for neutrophils and plays a critical role in the induction of acute and chronic inflammatory reactions [20, 21]. For example, in patients with Helicobacter pylori (H. pylori)-related gastritis, enhanced production of IL-8 in gastric mucosa has been reported [22]. The selective infiltration into the esophagus of the polynuclear leukocyte subset suggests that this chemokine plays a role in the immune and inflammatory processes of GERD, and this is the case. Fitzgerald et al. [15] found that, compared to subjects with noninflamed or Barrett’s esophagus, GERD patients had significantly higher expression levels of IL-8 messenger ribonucleic acid (mRNA), as assessed by competitive reverse transcriptase polymerase chain reaction (RT-PCR). Our studies have also found that Japanese RE patients had increased relative IL-8 mRNA expression levels, as assessed using real-time PCR technology [17]. In addition, IL-8 protein levels measured by enzyme-linked immunosorbent assay (ELISA) were increased to a greater degree in the esophageal biopsy samples obtained from RE patients compared to normal controls [16]. The mucosal IL-8 concentrations were found to parallel the endoscopic severity of RE (Fig. 1) [16]. Based on immunohistochemical analysis with anti-IL-8 antisera, IL-8 expression was found in the epithelium of esophageal biopsy specimens (Fig. 2) [22]. In particular, GERD patients had intense immunoreactivity against anti-IL-8 antibody. Not only epithelial cells but also infiltrating leukocytes showed immunoreactivity for IL-8 antigen. In contrast, there was little or no expression of IL-8 in normal control subjects who were free of any histopathological abnormality. Recently, we demonstrated that the relative IL-8 mRNA expression levels were significantly higher in the esophageal mucosa of NERD patients than controls [17, 19, 23]. It is of clinical importance that IL-8 production is enhanced in such incipient GERD patients who do not have mucosal breaks. The study also found that NERD patients who were classified in grade M based on the modified Los Angeles (LA) system [24] had significantly higher IL-8 mRNA expression levels than those classified in grade N; this highlights the immunologic and endoscopic heterogeneity among NERD patients [23]. Collectively, IL-8, which is produced locally by esophageal epithelium and inflammatory cells, is involved in the pathogenesis of GERD, including NERD, and plays a role in the development and progression of RE.


Immune and Inflammatory Responses in GERD and Lansoprazole.

Isomoto H, Nishi Y, Kanazawa Y, Shikuwa S, Mizuta Y, Inoue K, Kohno S - J Clin Biochem Nutr (2007)

Based on immunohistochemical analysis with anti-IL-8 antisera, IL-8 expression was found in the epithelium of esophageal biopsy specimens. Reprinted with permission [22].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2170946&req=5

Figure 2: Based on immunohistochemical analysis with anti-IL-8 antisera, IL-8 expression was found in the epithelium of esophageal biopsy specimens. Reprinted with permission [22].
Mentions: Chemokines are a group of cytokines with potent chemotactic activity towards different populations of leukocytes; they are involved in the pathogenesis of a variety of inflammatory conditions. IL-8 exhibits a potent chemotactic activity for neutrophils and plays a critical role in the induction of acute and chronic inflammatory reactions [20, 21]. For example, in patients with Helicobacter pylori (H. pylori)-related gastritis, enhanced production of IL-8 in gastric mucosa has been reported [22]. The selective infiltration into the esophagus of the polynuclear leukocyte subset suggests that this chemokine plays a role in the immune and inflammatory processes of GERD, and this is the case. Fitzgerald et al. [15] found that, compared to subjects with noninflamed or Barrett’s esophagus, GERD patients had significantly higher expression levels of IL-8 messenger ribonucleic acid (mRNA), as assessed by competitive reverse transcriptase polymerase chain reaction (RT-PCR). Our studies have also found that Japanese RE patients had increased relative IL-8 mRNA expression levels, as assessed using real-time PCR technology [17]. In addition, IL-8 protein levels measured by enzyme-linked immunosorbent assay (ELISA) were increased to a greater degree in the esophageal biopsy samples obtained from RE patients compared to normal controls [16]. The mucosal IL-8 concentrations were found to parallel the endoscopic severity of RE (Fig. 1) [16]. Based on immunohistochemical analysis with anti-IL-8 antisera, IL-8 expression was found in the epithelium of esophageal biopsy specimens (Fig. 2) [22]. In particular, GERD patients had intense immunoreactivity against anti-IL-8 antibody. Not only epithelial cells but also infiltrating leukocytes showed immunoreactivity for IL-8 antigen. In contrast, there was little or no expression of IL-8 in normal control subjects who were free of any histopathological abnormality. Recently, we demonstrated that the relative IL-8 mRNA expression levels were significantly higher in the esophageal mucosa of NERD patients than controls [17, 19, 23]. It is of clinical importance that IL-8 production is enhanced in such incipient GERD patients who do not have mucosal breaks. The study also found that NERD patients who were classified in grade M based on the modified Los Angeles (LA) system [24] had significantly higher IL-8 mRNA expression levels than those classified in grade N; this highlights the immunologic and endoscopic heterogeneity among NERD patients [23]. Collectively, IL-8, which is produced locally by esophageal epithelium and inflammatory cells, is involved in the pathogenesis of GERD, including NERD, and plays a role in the development and progression of RE.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus