Original Articles
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World J Gastrointest Pathophysiol. Dec 15, 2010; 1(5): 154-165
Published online Dec 15, 2010. doi: 10.4291/wjgp.v1.i5.154
Histamine 3 receptor activation mediates inhibition of acid secretion during Helicobacter-induced gastritis
Yana Zavros, Nisreen Mesiwala, Meghna Waghray, Andrea Todisco, Arthur Shulkes, Juanita L Merchant
Yana Zavros, Nisreen Mesiwala, Meghna Waghray, Andrea Todisco, Juanita L Merchant, Departments of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109-2200, United States
Arthur Shulkes, Department of Surgery, Austin and Repatriation Medical Center, University of Melbourne, Melbourne, Victoria 3084, Australia
Juanita L Merchant, Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-2200, United States
Yana Zavros, Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, United States
Author contributions: Zavros Y was responsible for study design, data interpretation and statistical analysis for Figures 1-9, manuscript preparation and critical review, and obtained funding; Mesiwala N was involved in study design, data interpretation and statistical analysis for Figures 1-4, 6 and 9, manuscript preparation and critical review; Waghray M assisted with H. felis infection and tissue analysis; Todisco A prepared canine parietal and D cell cultures used in Figures 6-9; Shulkes A participated in study design, data interpretation and provided funding and reagents for sheep studies; and Merchant JL participated in study design, data interpretation, manuscript review and funding.
Correspondence to: Juanita L Merchant, MD, PhD, Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, 109 Zina Pitcher Place, BSRB, Room 2051, Ann Arbor, MI 48109-2200, United States. merchanj@umich.edu
Telephone: +1-734-9366365 Fax: +1-734-7634686
Received: May 25, 2010
Revised: November 24, 2010
Accepted: December 1, 2010
Published online: December 15, 2010
Abstract

AIM: To test the hypothesis that histamine 3 receptor (H3R) activation during Helicobacter infection inhibits gastric acid secretion in vivo and in vitro.

METHODS: Helicobacter felis (H. felis) infected and uninfected C57Bl/6 mice were infused with either PBS or the H3 receptor antagonist thioperamide (THIO) for 12 wk. After treatment, mice were analyzed for morphological changes and gastric acid content. Total RNA was prepared from the stomachs of each group and analyzed for changes in somatostatin and gastrin mRNA abundance by real time-polymerase chain reaction (RT-PCR). Location of H3 receptors in the stomach was analyzed by co-localization using antibodies specific for the H3 receptor and parietal cell marker H+, K+-ATPase β subunit.

RESULTS: Inflammation and parietal cell atrophy was observed after 12 wk of H. felis infection. Interestingly, treatment with the H3R antagonist thioperamide (THIO) prior to and during infection prevented H. felis-induced inflammation and atrophy. Compared to the uninfected controls, infected mice also had significantly decreased gastric acid. After eradication of H. felis with THIO treatment, gastric acidity was restored. Compared to the control mice, somatostatin mRNA abundance was decreased while gastrin gene expression was elevated during infection. Despite elevated gastric acid levels, after eradication of H. felis with THIO, somatostatin mRNA was elevated whereas gastrin mRNA was suppressed. Immunofluorescence revealed the presence of H3 receptors on the parietal cells, somatostatin-secreting D-cells as well as the inflammatory cells.

CONCLUSION: This study shows that during H. felis infection, gastric acidity is suppressed as a consequence of an inhibitory effect on the parietal cell by H3R activation. The stimulation of gastric mucosal H3Rs increases gastrin expression and release by inhibiting release of somatostatin.

Keywords: Gastrin; Somatostatin; Histamine; Parietal cell; Helicobacter felis; Nα-methylhistamine; Rα-methylhistamine; Thioperamide