Duodenal Carbonic Anhydrase: Mucosal Protection, Luminal Chemosensing, and Gastric Acid Disposal

Kaunitz, Jonathan D.; Akiba, Yasutada

doi:10.2302/kjm.55.96

Cited by 22 publications

(15 citation statements)

References 88 publications

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“…Jacob et al recognized that this pathway was not essential for a full forskolin-stimulated secretory response as long as Na ϩ HCO 3 Ϫ cotransporter was fully active, but was not able to provide HCO 3 Ϫ for secretion if Na ϩ HCO 3 Ϫ cotransporter was pharmacologically inhibited (10). The group of Kaunitz and Akiba first recognized the role of CAs in duodenal ''acid sensing'' (24). In a series of papers, they used CA inhibitors with differential membrane permeability, luminal acid or CO 2 application, and measured enterocyte pH i , DBS, as well as pH and pCO 2 changes in the portal venous blood and recognized the importance of CAs in the HCO 3 Ϫ secretory response to high pCO 2 (25).…”

Section: Discussionmentioning

confidence: 99%

Duodenal acidity “sensing” but not epithelial HCO ₃ ⁻ supply is critically dependent on carbonic anhydrase II expression

Sjöblom

Singh

Zheng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Carbonic anhydrase (CA) is strongly expressed in the duodenum and has been implicated in a variety of physiological functions including enterocyte HCO 3 ؊ supply for secretion and the ''sensing'' of luminal acid and CO 2. Here, we report the physiological role of the intracellular CAII isoform involvement in acid-, PGE 2, and forskolin-induced murine duodenal bicarbonate secretion (DBS) in vivo. CAII-deficient and WT littermates were studied in vivo during isoflurane anesthesia. An approximate 10-mm segment of the proximal duodenum with intact blood supply was perfused under different experimental conditions and DBS was titrated by pH immediately. Two-photon confocal microscopy using the pH-sensitive dye SNARF-1F was used to assess duodenocyte pH i in vivo. After correction of systemic acidosis by infusion of isotonic Na 2CO3, basal DBS was not significantly different in CAII-deficient mice and WT littermates. The duodenal bicarbonate secretory response to acid was almost abolished in CAII-deficient mice, but normal to forskolin-or 16,16-dimethyl PGE 2 stimulation. The complete inhibition of tissue CAs by luminal methazolamide and i.v. acetazolamide completely blocked the response to acid, but did not significantly alter the response to forskolin. While duodenocytes acidified upon luminal perfusion with acid, no significant pH i change occurred in CAII-deficient duodenum in vivo. The results suggest that CA II is important for duodenocyte acidification by low luminal pH and for eliciting the acid-mediated HCO 3 ؊ secretory response, but is not important in the generation of the secreted HCO 3 ؊ ions.bicarbonate secretion ͉ duodenal mucosal protection ͉ duodenal ulcers ͉ gastrointestinal phenotype ͉ gastric acid T he proximal duodenum serves as a key segment in neutralizing the high amounts of hydrochloric acid expelled from the stomach (1). As a physiological defense to these acidic challenges, the proximal duodenum secretes HCO 3 Ϫ in higher rates than more distal parts of the small intestine in all species tested, including humans, and even a short contact with luminal acid causes a long lasting increase in duodenal bicarbonate secretion (DBS) (1). A deficiency in basal as well as acid-stimulated DBS is observed in patients with duodenal ulcer disease (2). Thus, DBS is accepted as an important duodenal mucosal defense mechanism (1, 3).CO 2 has been suggested to be a key transmitting factor in sensing the acidic luminal content (4-6), diffusing through the continuous layer of viscoelastic mucus gel on top of the epithelial surface and further through the apical cell-membrane. The generation of CO 2 from luminal acid has been suggested to depend on the action of extracellular carbonic anhydrases (5, 6). Because CA inhibitors suppressed duodenal HCO 3 Ϫ secretion, CO 2 entry and hydration in the enterocyte was thought to be a major supply pathway for basal and stimulated duodenal HCO 3 Ϫ secretion (7, 8), although this issue has remained controversial (9, 10).CAs are heavily expressed in duodenal epithelial cells...

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Section: Discussionmentioning

confidence: 99%

Duodenal acidity “sensing” but not epithelial HCO ₃ ⁻ supply is critically dependent on carbonic anhydrase II expression

Sjöblom

Singh

Zheng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…These mechanisms coordinately regulate mucus and HCO 3 – secretion, pH i and cellular buffering, and submucosal neuronal activation and blood flow responses. Since duodenal luminal pH rapidly changes between 2 and 7 as a result of the constant mixture of secreted HCO 3 – with jets of antrally-propelled gastric acid, the duodenal mucosa must rapidly adjust its defense mechanisms according to luminal pH [5]. …”

Section: Duodenal Acid/co2 Sensingmentioning

confidence: 99%

Duodenal Chemosensing and Mucosal Defenses

Akiba

Kaunitz²

2011

Digestion

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The duodenal mucosa is exposed to endogenous and exogenous chemicals, including acid, CO₂, bile acids and nutrients. Mucosal chemical sensors are necessary to exert physiological responses such as secretion, digestion, absorption, and motility. We propose a mucosal chemosensing system by which luminal chemicals are sensed via mucosal acid sensors and G-protein-coupled receptors. Luminal acid/CO₂ sensing consists of ecto- and cytosolic carbonic anhydrases, epithelial ion transporters, and acid sensors expressed on the afferent nerves in the duodenum. Furthermore, a luminal L-glutamate signal is mediated via mucosal L-glutamate receptors, including metabotropic glutamate receptors and taste receptor 1 family heterodimers, with activation of afferent nerves and cyclooxygenase, whereas luminal Ca²⁺ is differently sensed via the calcium-sensing receptor in the duodenum. Recent studies also show the involvement of enteroendocrine G-protein-coupled receptors in bile acid and fatty acid sensing in the duodenum. These luminal chemosensors help activate mucosal defense mechanisms in or- der to maintain the mucosal integrity and physiological responses. Stimulation of luminal chemosensing in the duodenal mucosa may prevent mucosal injury, affect nutrient metabolism, and modulate sensory nerve activity.

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“…8,10 The metalloenzyme CA catalyzes the interconversion of CO 2 and HCO 3 À , which is important for urease-mediated acid resistance in the gastric environment. 9 This journal is © The Royal Society of Chemistry 2014 with time and followed similar excretion kinetics with that of 13 C-enriched labelled urea. It is therefore noteworthy that the excretion kinetics of d DOB 18 O& followed a similar pattern regardless of the isotopic labelled substrate.…”

Section: Resultsmentioning

confidence: 55%

“…d DOB 13 C&, is usually $2&, is strongly associated with the presence of H. pylori infection in human stomach. 7 However, several reports 8,9 suggest that H. pylori encodes two different forms of the metalloenzyme carbonic anhydrase (a-CA and b-CA), which plays an important role in the interconversion of carbon dioxide and bicarbonate (CO 2 + H 2 O 4 H + + HCO 3 ), as well as for maintaining the urease activity in the human gastrointestinal tract. 10-12 Some authors [13][14][15] have also demonstrated that the oxygen-16 ( 16 O) isotope in 12 In this article, we report for the rst time, the potential links between the 18 O-isotope of breath CO 2 and H. pylori infections by exploiting the time-dependent excretion kinetics of the 18 O/ 16 O isotope ratios of CO 2 in breath samples from individuals with and without H. pylori infections.…”

Section: Introductionmentioning

confidence: 99%

Oxygen-18 stable isotope of exhaled breath CO₂as a non-invasive marker of Helicobacter pylori infection

Maity

Som

Ghosh

et al. 2014

J. Anal. At. Spectrom.

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We report for the first time the time-dependent excretion kinetics of 18 O/ 16 O isotope ratios of CO 2 in exhaled breath samples using an optical cavity-enhanced integrated cavity output spectroscopy (ICOS) method for the detection of Helicobacter pylori (H. pylori) infection in human stomach. We observed large differences in the oxygen-18 isotopic fractionations of breath CO 2 between H. pylori positive and negative individuals in response to orally administered, both unlabelled and labelled 13 C-enriched urea, suggesting a potential link between H. pylori infections and the 18 O-isotopic exchange in exhaled breath. An optimal diagnostic cut-off point of 18 O/ 16 O isotope ratios of breath CO 2 for the presence of H. pylori infection was determined to be 1.92& using the receiver operating characteristic curve (ROC) analysis, which exhibited both diagnostic sensitivity and specificity of 100% with an accuracy of 100%. Moreover, the methodology of monitoring 18 O in breath CO 2 manifested both positive and negative predictive values of 100%, demonstrating excellent diagnostic accuracy and suggesting that breath C 18 O 16 O could be used as a potential marker for the identification of H. pylori infections. Our findings also suggest that monitoring the 18 O/ 16 O isotope ratios of breath CO 2 is a valid and sufficiently robust novel non-invasive approach for the accurate and specific detection of H. pylori infection in real-time, which may open new perspectives in the molecular diagnosis of H. pylori infection for largescale screening purposes, early detection and follow-up of patients.

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Duodenal Carbonic Anhydrase: Mucosal Protection, Luminal Chemosensing, and Gastric Acid Disposal

Cited by 22 publications

References 88 publications

Duodenal acidity “sensing” but not epithelial HCO ₃ ⁻ supply is critically dependent on carbonic anhydrase II expression

Duodenal acidity “sensing” but not epithelial HCO ₃ ⁻ supply is critically dependent on carbonic anhydrase II expression

Duodenal Chemosensing and Mucosal Defenses

Oxygen-18 stable isotope of exhaled breath CO₂as a non-invasive marker of Helicobacter pylori infection

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Duodenal Carbonic Anhydrase: Mucosal Protection, Luminal Chemosensing, and Gastric Acid Disposal

Cited by 22 publications

References 88 publications

Duodenal acidity “sensing” but not epithelial HCO 3 − supply is critically dependent on carbonic anhydrase II expression

Duodenal acidity “sensing” but not epithelial HCO 3 − supply is critically dependent on carbonic anhydrase II expression

Duodenal Chemosensing and Mucosal Defenses

Oxygen-18 stable isotope of exhaled breath CO2as a non-invasive marker of Helicobacter pylori infection

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Duodenal acidity “sensing” but not epithelial HCO ₃ ⁻ supply is critically dependent on carbonic anhydrase II expression

Duodenal acidity “sensing” but not epithelial HCO ₃ ⁻ supply is critically dependent on carbonic anhydrase II expression

Oxygen-18 stable isotope of exhaled breath CO₂as a non-invasive marker of Helicobacter pylori infection