endothelin-1 and Helicobacter-Infections

To investigate the effect of Helicobacter pylori eradication on endothelin-1 (ET-1) and nitric oxide (NO) in duodenal ulcer (DU) patients.. Sixty-six H pylori-infected active DU patients were consecutively enrolled to receive one-week triple therapy (rabeprazole, amoxicillin and metronidazole) and then one-month rabeprazole therapy. They were asked back to determine ulcer and H pylori status using endoscopy one month later. Thirty-seven healthy controls (H pylori +/-: 17/20) were enrolled for comparison. Blood samples were collected in each visit to measure plasma ET-1 and nitrate/nitrite levels using an enzyme immunoassay kit.. Sixty DU patients finished trial per protocol. The ulcer healing and H pylori-eradication rates were 86.7% and 83.3%, respectively. Plasma ET-1 level in DU patients was higher than that of H pylori-negative and positive controls (3.59+/-0.96 vs 0.89+/-0.54 vs 0.3+/-0.2 pg/mL, P<0.01), while nitrate/nitrite levels among them were also significantly different (8.55+/-0.71 vs 5.27+/-0.68 vs 6.39+/-0.92 mumol/L, P<0.05). H pylori eradication diminished ET-1 levels (3.64+/-0.55 vs 2.64+/-0.55 pg/mL, P<0.01) but elevated nitrate/nitrite level (8.16+/-0.84 vs 11.41+/-1.42 mumol/L, P<0.05).. Both plasma ET-1 and nitrate/nitrite levels increase in active DU patients. After an effective H pylori eradication, DU healing is associated with diminished blood ET-1 level and elevated nitrate/nitrite level.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Aged, 80 and over; Amoxicillin; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Ulcer Agents; Benzimidazoles; Biomarkers; Drug Therapy, Combination; Duodenal Ulcer; Endothelin-1; Female; Follow-Up Studies; Helicobacter Infections; Helicobacter pylori; Humans; Male; Metronidazole; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Omeprazole; Rabeprazole

We investigated the relationship between microcirculatory disturbance and the host response to Helicobacter pylori infections in gastric ulcer scars to determine the role of endothelin-1 (ET) in ulcer recurrence. The subjects were divided into three groups. The GuS group consisted of patients who had red scarring (S1 stage) at the gastric angle with H. pylori, the gast+ group who had gastritis with H. pylori, and the gast- group who had gastritis without H. pylori. During endoscopic examination, biopsies were taken from the gastric angle. Mucosal ET, nitric oxide (NO), interleukin-8 (IL-8), and RANTES were measured. ET, inducible NO synthase (iNOS), and endothelial constitutive NOS (ecNOS) were immunostained. Mucosal ET and oxides of nitrogen (NOx) were significantly higher in the GuS group than in the other groups. IL-8 was elevated in the GuS and gast+ groups, and RANTES was elevated in the gast+ group (p < 0.01). There was prominent inflammatory cell infiltration in the GuS group. ET-positive cells were found in vascular smooth muscle, gastric epithelium, and gastric smooth muscle. iNOS-positive cells were found in vascular smooth muscle, gastric epithelium, gastric smooth muscle, and inflammatory cells. In conclusion, local inflammation and microcirculatory disturbance persist at the center of the ulcer scar (S1). Decreased cytokine levels and increased ET and NO (mainly synthesized by iNOS) levels suggested that microcirculatory disturbance is a more important factor than immune response in ulcer recurrence.

Topics: Cytokines; Endothelin-1; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Microcirculation; Nitric Oxide; Recurrence; Stomach Ulcer

The study included 60 patients with chronic Halicobacter gastritis (30 with chronic non-atrophic and 30 with atrophic Halicobacter gastritis (CNAHG and CAHG)). The control group was comprised of 15 practically healthy subjects. The aim of the work was to elucidate the role of Helicobacter infection, disturbances of regeneration, endothelin-1 and melatonin-secreting neuroendocrine cells of gastric antrum in progression of chronic Helicobacter gastritis (CHG). It was shown that CHG is due to H. pylori persistence and that patients with CNAHG undergo grade III microbial contamination while in CAHG patients atrophic changes are accompanied by metaplasia of gastric mucosa (GM) and inflammation of different severity. Patients with CNAHG has an increased number of melatonin-positive gastric cells and enhanced apoptotic activity of GM epitheliocytes. Patients with CAHG experience a reduction of melatonin-positive cells correlated with enhanced apoptotic activity of GM epitheliocytes. The number of endothelin-1 positive cells in patients with CNAHG and CAHG was similar to that in controls. Adequate eradication promoted normalization of the number of gastric endothelin-1 and melatonin-secreting neuroendocrine cells in patients with CHG. The apoptotic index reached the control value within 1 month after eradication in CNAHG patients but remained relatively high in CAHG patients.

Topics: Adult; Chronic Disease; Disease Progression; Endothelin-1; Gastritis; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Middle Aged; Pyloric Antrum; Severity of Illness Index

The study included 100 patients with duodenal ulcer (DU), 30 with chronic non-atrophic gastritis (CNAG), 30 with chronic atrophic gastritis (CAG) and 12 practically healthy subjects. All patients with DU and CNAG had morphologically confirmed H. pylori infection. The patients with DU were divided into 2 groups each including age-matched subjects with endoscopically, morphologically, immunohistochemically identical characteristics. Those of group 1 underwent eradication of H. pylori by a traditional 7-day procedure including the use of omeprazole (20 mg BID), claritromycin (500 mg BID) and amoxicillin (1000 mg BID). In group 2 this scheme was supplemented by melatonin (3 mg before bedtime). Patients of group 1 continued to use omeprazole and those in group 2 omeprazole + melatonin till the end of the second month. Healthy subjects and patients with CAG served as controls. All patients underwent FGDS on weeks 2 and 4, immunohistochemical study was conducted to detect endothelin-1 and melatonin-positive cells, apoptotic activity of mucosal epitheliocytes from gastric antrum was determined before and 6 weeks after the onset of therapy. It was shown that introduction of melatonin in the scheme of eradication therapy increases efficacy of H. pylori elimination and accelerates DU cicatrization. Two-month therapy with omeprazole + melatonin more effectively normalizes immunohistochemical parameters (endothelin-1 and melatonin-positive cells) and epitheliocyte apoptotic activity, than omeprazole alone.

Topics: Adult; Antioxidants; Apoptosis; Drug Therapy, Combination; Duodenal Ulcer; Endothelin-1; Epithelial Cells; Female; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Male; Melatonin; Middle Aged; Young Adult

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Duodenal Ulcer; Endothelin-1; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Melatonin; Middle Aged; Nitric Oxide Synthase; Young Adult

Endothelins (ETs) participate directly and indirectly in angiogenesis via ET receptors. During early fetal angiogenesis, vascular endothelial growth factor (VEGF) and its receptors kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase-1 (Flt-1) are required for the development of the systemic vasculature. In late angiogenesis, stromal-cell-derived factor (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) act in an organ-specific manner to promote the formation and development of large blood vessels supplying the gastrointestinal tract. We studied the roles of these ligand receptors in angiogenesis during healing of gastric ulcers. We studied the following five groups, each consisting of ten cases of endoscopically confirmed gastric ulcer: active stage (GA), healing stage (GH) and scar stage (GS) of gastric ulcers located in the angulus; Helicobacter pylori (Hp)-positive gastritis (gast+); and Hp-negative gastritis (gast-). All cases in the ulcer groups were Hp-positive. The study materials consisted of frozen biopsy specimens of lesions arising in the angulus. ET-1 was measured by enzyme immunoassay. The other factors were assayed by reverse-transcription-PCR. The distributions of ET-1, ETA receptor (ETAR), SDF-1 and CXCR4 in the gastric mucosa were evaluated by enzyme immunoassay. ET-1 and ETAR reached peak levels during the GH (ET: P<0.05, ETAR: P<0.01). VEGF mRNA increased slightly during the GA, but did not differ significantly among the groups. KDR and Flt-1 levels were high during the GA, the level being significantly higher than those during the GH and GS (P<0.05). SDF-1 levels significantly decreased during the GH and GS compared with levels during the GA, and CXCR4 significantly increased during the GH and GS (P<0.01). On immunostaining, ET-1-positive cells and ETAR-positive cells were found in the endothelium, vascular smooth muscle and gastric epithelium, and CXCR4-positive cells were found in the endothelium and gastric epithelium during the GH and GS. Our results suggest that VEGF receptors are mainly expressed early in ulcer development and participate in the initial stage of angiogenesis. SDF-1 receptors and ETAR are primarily expressed during the GH and GS and are involved in vascular maturation and gastric mucosal regeneration during late angiogenesis.

Topics: Chemokine CXCL12; Chemokines, CXC; Endothelial Growth Factors; Endothelin-1; Extracellular Matrix Proteins; Gastric Mucosa; Growth Substances; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Lymphokines; Neovascularization, Physiologic; Receptor, Endothelin A; Receptors, CXCR4; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; Stomach Ulcer; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors

The animal model of H. pylori lipopolysaccharide (LPS)-induced gastritis was used to study the role of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in the mucosal release of tumor necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1) in response to H. pylori infection. Rats, pretreated with specific inhibitors of p38 and ERK pathways, SB203580 and PD98059, were submitted to intragastric application of H. pylori LPS and maintained on the daily regimen of the inhibitors for 4 days. In the absence of inhibitors, the LPS elicited a pattern of mucosal inflammatory responses resembling that of acute gastritis, and reflected in a massive increase in the mucosal level of ET-1 and TNF-alpha. Administration of SB203580 led to a 63.4% reduction in the extent of inflammatory involvement, the level of ET-1 fell by a 42% and TNF-alpha declined by a 52.3%, whereas PD98059 elicited a 21.2% reduction in the extent of inflammatory involvement and a 22.7% decrease in TNF-alpha, but had no effect on the LPS-induced increase in ET-1. A combination of both inhibitors, while exerting additive effect on TNF-alpha, produced no additional reduction in ET-1 and the extent of inflammatory involvement achieved with SB203580 alone. The findings suggest that the p38 MAPK signaling pathway plays a key role in the mediation of gastric mucosal inflammatory reaction to H. pylori infection.

Topics: Animals; Endothelin-1; Flavonoids; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Imidazoles; Lipopolysaccharides; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Pyridines; Rats; Rats, Sprague-Dawley; Signal Transduction; Tumor Necrosis Factor-alpha