Gastric H+, K+-adenosine triphosphatase β subunit is required for normal function, development, and membrane structure of mouse parietal cells

Scarff, Katrina Louise; Judd, Louise M.; Toh, Ban‐Hock; Gleeson, Paul A.; Driel, Ian R. van

doi:10.1016/s0016-5085(99)70453-1

Cited by 133 publications

(110 citation statements)

References 42 publications

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“…These authors also reported much lower levels of bacterial survival, approximately 2.5% in gastrin-deficient mice compared to 0.1% in control mice. This low level of survival may have been due to the fact that the gastrindeficient mouse strain had a stomach pH of 4.2, which is much lower than the stomach pH of the H ϩ ,K ϩ -ATPase ␤-subunitdeficient mouse strain used here and previously (13,31).…”

Section: Fig 4 Treatment Of Mice With Acid-suppressing Agents (A) mentioning

confidence: 74%

Influence of Gastric Acid on Susceptibility to Infection with Ingested Bacterial Pathogens

et al. 2008

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Despite the widely held belief that gastric acid serves as a barrier to bacterial pathogens, there are almost no experimental data to support this hypothesis. We have developed a mouse model to quantify the effectiveness of gastric acid in mediating resistance to infection with ingested bacteria. Mice that were constitutively hypochlorhydric due to a mutation in a gastric H ؉ /K ؉ -ATPase (proton pump) gene were infected with Yersinia enterocolitica, Salmonella enterica serovar Typhimurium, Citrobacter rodentium, or Clostridium perfringens cells or spores. Significantly greater numbers of Yersinia, Salmonella, and Citrobacter cells (P < 0.006) and Clostridium spores (P ‫؍‬ 0.02) survived in hypochlorhydric mice, resulting in reduced median infectious doses. Experiments involving intraperitoneal infection or infection of mice treated with antacids indicated that the increased sensitivity of hypochlorhydric mice to infection was entirely due to the absence of stomach acid. Apart from establishing the role of gastric acid in nonspecific immunity to ingested bacterial pathogens, our model provides an excellent system with which to investigate the effects of hypochlorhydria on susceptibility to infection and to evaluate the in vivo susceptibility to gastric acid of orally administered therapies, such as vaccines and probiotics.

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Section: Fig 4 Treatment Of Mice With Acid-suppressing Agents (A) mentioning

confidence: 74%

Influence of Gastric Acid on Susceptibility to Infection with Ingested Bacterial Pathogens

et al. 2008

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“…Increased proliferation and cell turnover in this compartment were also described in patients with atrophy (Biasco et al, 1989;Miwa et al, 1997) and in animals treated with the proton pumpinhibitor omeprazole (Kakei et al, 1993(Kakei et al, , 1995. These animals, like the H,K-ATPase knockout mice in previous studies (Scarff et al, 1999;Spicer et al, 2000), showed both achlorhydria and suppressed differentiation of gastric chief cells. Therefore, it might be speculated that gastric acid represents a key factor for gastric morphogenesis.…”

Section: Dimmler Et Almentioning

confidence: 77%

Transcription of Sonic Hedgehog, a Potential Factor for Gastric Morphogenesis and Gastric Mucosa Maintenance, Is Up-regulated in Acidic Conditions

Dimmler

Brabletz

Hlubek

et al. 2003

Laboratory Investigation

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SUMMARY:Gastric body mucosa atrophy predisposes one to gastric cancer. Disturbances in the gastric differentiation process might play a role in the evolution of gastric atrophy. Sonic hedgehog (Shh) has recently been implicated as a crucial factor in gastric organogenesis and gland differentiation. In this study we investigated the expression of key factors in the Shh pathway, namely Shh and its receptor Patched (Ptc), in normal and pathologic stomach mucosa. Furthermore, the potential role of pH for Shh dysregulation was analyzed. Ten gastric biopsy specimens each from normal gastric mucosa, chronic nonatrophic gastritis, atrophic gastritis, and gastric cancer were included. Expression of Shh and Ptc was analyzed by immunohistochemistry. In normal body mucosa and in nonatrophic body gastritis, Shh was strongly expressed in parietal cells. Ptc was also expressed in gastric chief cells. Shh expression was almost completely lost in atrophic gastritis and in gastric cancer and absent in intestinal metaplasia. Ptc was markedly reduced in atrophy and only weakly positive in intestinal metaplasia and gastric cancer. In in vitro experiments, gastric cancer cell line 23132 was found positive for Shh. In long-term culture as well as in culture conditions with low pH, transcription of Shh in 23132 was significantly increased in quantitative reverse transcription PCR analyses. We concluded that the decreased expression of the Shh pathway in atrophic gastritis and gastric cancer might reflect altered differentiation processes within the gastric unit and contributes to the development of gastric atrophy. The increase of gastric pH might play a role in the development of gastric mucosa atrophy via reduction of Shh transcription. (Lab Invest 2003, 83:1829 -1837.

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“…The clone was partially characterized by restriction mapping, Southern blot analysis, polymerase chain reaction, and DNA sequencing. Exons 4,7,16,19, and 20 were amplified by polymerase chain reaction, and DNA sequence analysis showed that they matched the published mouse cDNA sequence (15). A polymerase chain reaction strategy was used to obtain fragments for insertion into the MJK ϩ KO (16) targeting vector.…”

Section: Methodsmentioning

confidence: 99%

“…The peptide hormone gastrin is known to play an important role in the regulation of acid secretion (21) and is induced in several mouse models of achlorhydria (7,16) or hypochlorhydria (22). Northern blot analysis showed that gastrin mRNA was increased ϳ4-fold in Atp4a Ϫ/Ϫ stomachs compared with Atp4a ϩ/ϩ or Atp4a ϩ/Ϫ stomachs (Fig.…”

Section: Generation Of Atp4amentioning

confidence: 96%

Stomachs of Mice Lacking the Gastric H,K-ATPase α-Subunit Have Achlorhydria, Abnormal Parietal Cells, and Ciliated Metaplasia

Spicer¹,

Miller²,

Andringa³

et al. 2000

Journal of Biological Chemistry

163

135

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The H,K-ATPase of the gastric parietal cell is the most critical component of the ion transport system mediating acid secretion in the stomach. To study the requirement of this enzyme in the development, maintenance, and function of the gastric mucosa, we used gene targeting to prepare mice lacking the ␣-subunit. Homozygous mutant (Atp4a ؊/؊ ) mice appeared healthy and exhibited normal systemic electrolyte and acid-base status but were achlorhydric and hypergastrinemic. Immunocytochemical, histological, and ultrastructural analyses of Atp4a ؊/؊ stomachs revealed the presence of chief cells, demonstrating that the lack of acid secretion does not interfere with their differentiation. Parietal cells were also present in normal numbers, and despite the absence of ␣-subunit mRNA and protein, the ␤-subunit was expressed. However, Atp4a ؊/؊ parietal cells had dilated canaliculi and lacked typical canalicular microvilli and tubulovesicles, and subsets of these cells contained abnormal mitochondria and/or massive glycogen stores. Stomachs of adult Atp4a؊/؊ mice exhibited metaplasia, which included the presence of ciliated cells. We conclude that ablation of the H,K-ATPase ␣-subunit causes achlorhydria and hypergastrinemia, severe perturbations in the secretory membranes of the parietal cell, and metaplasia of the gastric mucosa; however, the absence of the pump appears not to perturb parietal cell viability or chief cell differentiation.

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Gastric H+, K+-adenosine triphosphatase β subunit is required for normal function, development, and membrane structure of mouse parietal cells

Cited by 133 publications

References 42 publications

Influence of Gastric Acid on Susceptibility to Infection with Ingested Bacterial Pathogens

Influence of Gastric Acid on Susceptibility to Infection with Ingested Bacterial Pathogens

Transcription of Sonic Hedgehog, a Potential Factor for Gastric Morphogenesis and Gastric Mucosa Maintenance, Is Up-regulated in Acidic Conditions

Stomachs of Mice Lacking the Gastric H,K-ATPase α-Subunit Have Achlorhydria, Abnormal Parietal Cells, and Ciliated Metaplasia

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