Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor

Thiagarajah, Jay R.; Broadbent, Talmage; Hsieh, Emily; Verkman, A. S.

doi:10.1053/j.gastro.2003.11.005

Cited by 143 publications

(142 citation statements)

References 28 publications

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“…CFTR inh Ϫ172 efficiently blocks CFTR in airway epithelial cells but is less efficient in colonic cells unless the tissue has been permeabilized (11). In our experiments, 20 M CFTR inh Ϫ172 bilaterally produced an I sc decay of Ϫ18 Ϯ 2 A in CFTRϩ͞Ϫ tissue.…”

Section: Resultsmentioning

confidence: 49%

Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

Bruscia¹,

Price²,

Cheng³

et al. 2006

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

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Several studies have demonstrated that bone marrow (BM)-derived cells give rise to rare epithelial cells in the gastrointestinal (GI) and respiratory tracts after BM transplantation into myeloablated recipients. We investigate whether, after transplantation of cystic fibrosis transmembrane conductance regulator (CFTR)-positive BM-derived cells, BM-derived GI and airway epithelial cells can provide CFTR activity in the GI tract and nasal epithelium of recipient cystic fibrosis mice. CFTR؊͞؊ mice were transplanted with wild-type BM after receiving different doses of irradiation, and CFTR activity was assessed in vivo in individual mice over time by using rectal and nasal potential difference analyses and in vitro by Ussing chamber analysis. The data suggest that rare BM-derived epithelial cells in the GI and nasal epithelium detected in CFTR؊͞؊ transplanted mice provide a modest level of CFTR-dependent chloride secretion. Detection of CFTR mRNA and protein in tissues of transplanted CFTR؊͞؊ mice supports these data.bone marrow stem cells ͉ chloride channel ͉ epithelial cells

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Section: Resultsmentioning

confidence: 49%

Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

Bruscia¹,

Price²,

Cheng³

et al. 2006

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

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“…This pretreatment is confirmed to inhibit acid-induced HCO 3 Ϫ secretion due to CFTR inhibition in rat duodenum (4). Furthermore, CFTRinh-172 has been recognized as a potent and selective CFTR inhibitor in the gastrointestinal tract of rodents (26,36), although its efficacy is dependent on tissue type (less potent in airway epithelia) and species (less potent in pig and ferret than in human and mouse) (25). CFTR inh-172 inhibition can mimic CFTR dysfunction in human tracheal epithelia (29).…”

Section: Measurement Of Luminal Ph and [Co2]mentioning

confidence: 67%

CFTR inhibition augments NHE3 activity during luminal high CO₂exposure in rat duodenal mucosa

Mizumori

Choi²,

Guth³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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We hypothesized that the function of duodenocyte apical membrane acid-base transporters are essential for H ϩ absorption from the lumen. We thus examined the effect of inhibition of Na ϩ /H ϩ exchanger-3 (NHE3), cystic fibrosis transmembrane regulator (CFTR), or apical anion exchangers on transmucosal CO 2 diffusion and HCO 3 Ϫ secretion in rat duodenum. Duodena were perfused with a pH 6.4 high CO 2 solution or pH 2.2 low CO2 solution with the NHE3 inhibitor, S3226, the anion transport inhibitor, DIDS, or pretreatment with the potent CFTR inhibitor, CFTRinh-172, with simultaneous measurements of luminal and portal venous (PV) pH and carbon dioxide concentration ([CO2] Ϫ loss by NHE3 inhibition and reduced intracellular acidification during CFTR inhibition is consistent with activation or unmasking of NHE3 activity by CFTR inhibition, increasing cell surface H ϩ available to neutralize luminal HCO 3 Ϫ with consequent CO2 absorption. NHE3, by secreting H ϩ into the luminal microclimate, facilitates net transmucosal HCO 3 Ϫ absorption with a mechanism similar to proximal tubular HCO 3 Ϫ absorption.CO 2 absorption; bicarbonate secretion; portal venous PCO2 EPITHELIAL HCO 3 Ϫ SECRETION is considered to be the primary defense against duodenal injury from gastric acid. One of the unexplained mysteries of duodenal HCO 3 Ϫ secretion is why it is needed, given that secretion into the lumen from pancreas and liver is more than adequate to fully neutralize the bulk luminal content (13). Epithelial HCO 3 Ϫ secretion has thus been hypothesized to neutralize a distinct "preepithelial layer" adjacent to the apical plasma membrane of the mucosa (10, 24). Moreover, the upper intestine absorbs HCO 3 Ϫ by an electroneutral Na ϩ -dependent mechanism, hypothesized to be Na ϩ /H ϩ exchange (37). Since the epithelial Na ϩ /H ϩ exchanger (NHE) 3, which helps facilitate intestinal neutral NaCl absorption, is highly expressed in duodenum (31), we wondered whether duodenal NHE3 additionally functions as an H ϩ secretor, as it does in the proximal tubule (33, 38), facilitating HCO 3 Ϫ absorption. The duodenum must also absorb ϳ450 mmol of gastric H ϩ /24 h to decrease luminal hydrogen concentration ([H ϩ ]) by 6 log orders over its 15-cm length (12). HCl in the duodenal lumen is neutralized by HCO 3 Ϫ secreted by the pancreas and duodenal epithelium. This generates extremely high luminal CO 2 pressures (PCO 2 Ͼ 400 Torr), which are dissipated by the proximal jejunum (32). Gastric mucosal CO 2 and H ϩ permeability is low, since pyloric obstruction leads to severe metabolic alkalosis due to the inability of the normal stomach to absorb substantial quantities of H ϩ or CO 2 (16). Thus the duodenum is the major site for intestinal H ϩ and CO 2 absorption.We have demonstrated sequential transmucosal CO 2 and H ϩ movement from duodenal lumen into the portal vein (PV), facilitated by epithelial cytosolic and membrane-bound carbonic anhydrases (CAs) in the rat (27). Cellular acidification by luminal CO 2 /H ϩ rapidly induces protective responses su...

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“…In intact intestine the active secretion of chloride into the lumen drives sodium and water secretion, resulting in secretory diarrhea. [30][31][32] The cholera toxin model is useful for testing of antisecretory compounds that affect any of these processes involved in fluid secretion. Enteroid swelling in response to other secretagogues, such as rotaviral calcium agonists, should provide useful information on enterocyte secretory mechanisms.…”

Section: Enteroid Swelling Measurementsmentioning

confidence: 99%

Microfluidics platform for measurement of volume changes in immobilized intestinal enteroids

et al. 2014

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Intestinal enteroids are ex vivo primary cultured single-layer epithelial cell spheroids of average diameter ∼150 μm with luminal surface facing inward. Measurement of enteroid swelling in response to secretagogues has been applied to genetic testing in cystic fibrosis and evaluation of drug candidates for cystic fibrosis and secretory diarrheas. The current measurement method involves manual addition of drugs and solutions to enteroids embedded in a Matrigel matrix and estimation of volume changes from confocal images of fluorescently stained enteroids. We developed a microfluidics platform for efficient trapping and immobilization of enteroids for quantitative measurement of volume changes. Multiple enteroids are trapped in a “pinball machine-like” array of polydimethylsiloxane posts for measurement of volume changes in unlabeled enteroids by imaging of an extracellular, high-molecular weight fluorescent dye. Measurement accuracy was validated using slowly expanding air bubbles. The method was applied to measure swelling of mouse jejunal enteroids in response to an osmotic challenge and cholera toxin-induced chloride secretion. The microfluidics platform allows for parallel measurement of volume changes on multiple enteroids during continuous superfusion, without an immobilizing matrix, and for quantitative volume determination without chemical labeling or assumptions about enteroid shape changes during swelling.

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Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor

Cited by 143 publications

References 28 publications

Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

CFTR inhibition augments NHE3 activity during luminal high CO₂exposure in rat duodenal mucosa

Microfluidics platform for measurement of volume changes in immobilized intestinal enteroids

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Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor

Cited by 143 publications

References 28 publications

Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

CFTR inhibition augments NHE3 activity during luminal high CO2exposure in rat duodenal mucosa

Microfluidics platform for measurement of volume changes in immobilized intestinal enteroids

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CFTR inhibition augments NHE3 activity during luminal high CO₂exposure in rat duodenal mucosa