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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

The CXCR-1 mRNA transcripts were detected as 257 bp band using the reverse transcriptase polymerase chain reaction. Each lane represents the following: 1; asymptomatic normal control, 2; endoscopy-negative GERD patient, 3–5; reflux esophagitis patients, 6; non-template negative control and 7; positive control.
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Figure 4: The CXCR-1 mRNA transcripts were detected as 257 bp band using the reverse transcriptase polymerase chain reaction. Each lane represents the following: 1; asymptomatic normal control, 2; endoscopy-negative GERD patient, 3–5; reflux esophagitis patients, 6; non-template negative control and 7; positive control.

Mentions: Evidence is accumulating that chemokines exert an overlapping but distinct action on specific types of leukocytes by interacting with their specific G-protein-coupled receptors that have 7 transmembrane domains [26]. To date, CXC chemokine receptor1 (CXCR-1) and -2 have been found to be two distinct receptors for IL-8 [27]. It is possible that increased IL-8 levels may facilitate trafficking of neutrophils into the mucosa affected by GERD through IL-8’s interaction with these receptors. Based on this hypothesis, we studied CXCR-1 and -2 mRNA expression using RT-PCR [28]. CXCR-1 (Fig. 4) as well as CXCR-2 mRNA was evidently expressed in esophageal mucosa of GERD patients. On the real-time PCR basis, in NERD patients, the relative CXCR-1 mRNA levels, expressed as the ratio of CXCR-1/tubulin alpha 3 (housekeeping gene) in arbitrary units using real-time PCR, were significantly higher than in controls [28]. On the other hand, the relative expression levels of CXCR-2 mRNA were comparable between GERD patients and controls. No significant correlation was noted between the mRNA expression levels of CXCR-1 and CXCR-2. As shown previously, intraepithelial neutrophils, a histopathological indicator of RE [29], were immunoreactive for CXCR-1 in the esophageal mucosa of GERD patients [17]. The enhanced expression of this specific IL-8 receptor could make the affected esophageal mucosa more responsive to locally overexpressed IL-8; thus, enhanced expression of IL-8 and CXCR-1 could mutually encourage the trafficking of neutrophils into esophageal mucosa [27, 30–32]. IL-8 is regulated in an autocrine manner [33, 34]; therefore, the interplay between IL-8 and CXCR-1 may contribute to the amplification and protraction of inflammatory responses in GERD. In this regard, on immunohistochemical analysis, epithelial cells of GERD patients were found to express abundant IL-8 antigen, and, at the same time, the epithelium was the potential cellular source of CXCR-1 protein [17]. IL-8 exerts mitogenic actions directly or by binding to its receptors on epithelial cells [35]. In fact, IL-8 mRNA and protein levels are found to be associated with basal cell hyperplasia and papillary elongation [16, 17], both of which are histopathological hallmarks of RE [29]; these findings support the notion that IL-8, possibly along with other cytokines and growth factors, could contribute to esophageal epithelial cell proliferation even in the early stage of incipient GERD and could eventually lead to carcinogenesis. Unlike CXCR-1, CXCR-2 is not specific for IL-8 and can bind to other chemokines, such as growth-related oncogene α; however, CXCR-2 has a 2- to 5-fold higher affinity for IL-8 than CXCR-1 [36]. Further research is needed to elucidate the diverse receptor-mediated signaling pathway that is part of the pathophysiological mechanisms of GERD.


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)

The CXCR-1 mRNA transcripts were detected as 257 bp band using the reverse transcriptase polymerase chain reaction. Each lane represents the following: 1; asymptomatic normal control, 2; endoscopy-negative GERD patient, 3–5; reflux esophagitis patients, 6; non-template negative control and 7; positive control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: The CXCR-1 mRNA transcripts were detected as 257 bp band using the reverse transcriptase polymerase chain reaction. Each lane represents the following: 1; asymptomatic normal control, 2; endoscopy-negative GERD patient, 3–5; reflux esophagitis patients, 6; non-template negative control and 7; positive control.
Mentions: Evidence is accumulating that chemokines exert an overlapping but distinct action on specific types of leukocytes by interacting with their specific G-protein-coupled receptors that have 7 transmembrane domains [26]. To date, CXC chemokine receptor1 (CXCR-1) and -2 have been found to be two distinct receptors for IL-8 [27]. It is possible that increased IL-8 levels may facilitate trafficking of neutrophils into the mucosa affected by GERD through IL-8’s interaction with these receptors. Based on this hypothesis, we studied CXCR-1 and -2 mRNA expression using RT-PCR [28]. CXCR-1 (Fig. 4) as well as CXCR-2 mRNA was evidently expressed in esophageal mucosa of GERD patients. On the real-time PCR basis, in NERD patients, the relative CXCR-1 mRNA levels, expressed as the ratio of CXCR-1/tubulin alpha 3 (housekeeping gene) in arbitrary units using real-time PCR, were significantly higher than in controls [28]. On the other hand, the relative expression levels of CXCR-2 mRNA were comparable between GERD patients and controls. No significant correlation was noted between the mRNA expression levels of CXCR-1 and CXCR-2. As shown previously, intraepithelial neutrophils, a histopathological indicator of RE [29], were immunoreactive for CXCR-1 in the esophageal mucosa of GERD patients [17]. The enhanced expression of this specific IL-8 receptor could make the affected esophageal mucosa more responsive to locally overexpressed IL-8; thus, enhanced expression of IL-8 and CXCR-1 could mutually encourage the trafficking of neutrophils into esophageal mucosa [27, 30–32]. IL-8 is regulated in an autocrine manner [33, 34]; therefore, the interplay between IL-8 and CXCR-1 may contribute to the amplification and protraction of inflammatory responses in GERD. In this regard, on immunohistochemical analysis, epithelial cells of GERD patients were found to express abundant IL-8 antigen, and, at the same time, the epithelium was the potential cellular source of CXCR-1 protein [17]. IL-8 exerts mitogenic actions directly or by binding to its receptors on epithelial cells [35]. In fact, IL-8 mRNA and protein levels are found to be associated with basal cell hyperplasia and papillary elongation [16, 17], both of which are histopathological hallmarks of RE [29]; these findings support the notion that IL-8, possibly along with other cytokines and growth factors, could contribute to esophageal epithelial cell proliferation even in the early stage of incipient GERD and could eventually lead to carcinogenesis. Unlike CXCR-1, CXCR-2 is not specific for IL-8 and can bind to other chemokines, such as growth-related oncogene α; however, CXCR-2 has a 2- to 5-fold higher affinity for IL-8 than CXCR-1 [36]. Further research is needed to elucidate the diverse receptor-mediated signaling pathway that is part of the pathophysiological mechanisms of GERD.

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