Esomeprazole Increases Airway Surface Liquid pH in Primary Cystic Fibrosis Epithelial Cells

Delpiano, Livia; Thomas, Joseph J.; Yates, Annabel R.; Rice, S.J.; Gray, Michael A.; Saint‐Criq, Vinciane

doi:10.3389/fphar.2018.01462

Cited by 19 publications

(30 citation statements)

References 66 publications

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“…Moreover, as CF cells can not compensate for acidic challenges, control of acidic gastro-esophageal reflux is crucial. Importantly, our results suggest that pendrin activation might offer a novel strategy, by triggering ASL alkalization 38 , possibly in combination with ATP12A inhibitors 39,40 , which should be further investigated.…”

Section: Discussionmentioning

confidence: 87%

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Simonin

Bille

Crambert

et al. 2019

Sci Rep

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Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Morbidity is mainly due to early airway infection. We hypothesized that S. aureus clearance during the first hours of infection was impaired in CF human Airway Surface Liquid (ASL) because of a lowered pH. The ASL pH of human bronchial epithelial cell lines and primary respiratory cells from healthy controls (WT) and patients with CF was measured with a pH microelectrode. The antimicrobial capacity of airway cells was studied after S. aureus apical infection by counting surviving bacteria. ASL was significantly more acidic in CF than in WT respiratory cells. This was consistent with a defect in bicarbonate secretion involving CFTR and SLC26A4 (pendrin) and a persistent proton secretion by ATP12A. ASL demonstrated a defect in S. aureus clearance which was improved by pH normalization. Pendrin inhibition in WT airways recapitulated the CF airway defect and increased S. aureus proliferation. ATP12A inhibition by ouabain decreased bacterial proliferation. Antimicrobial peptides LL-37 and hBD1 demonstrated a pH-dependent activity. Normalizing ASL pH might improve innate airway defense in newborns with CF during onset of S. aureus infection. Pendrin activation and ATP12A inhibition could represent novel therapeutic strategies to normalize pH in CF airways.

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Section: Discussionmentioning

confidence: 87%

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Simonin

Bille

Crambert

et al. 2019

Sci Rep

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“…Upscaling this method to a 96 well plate format using polarized system (HTS 96 well plates) 38 would provide even higher throughput as a drug discovery assay. Moreover, we have shown how this technique can be used to study the acute effect of agonists on ASL pH and we have already published that this method can be used to study the long-term effect of an apical proton pump inhibitor on CF hAECs ASL 39 . As pH has been shown to regulate infection, inflammation, mucus viscosity and ion transport, identifying molecular targets that can increase pH will be valuable in the research fields of chronic lung diseases and this technique will potentially facilitate the development of drug screening in personalized medicine approaches.…”

Section: Discussionmentioning

confidence: 99%

Real-Time, Semi-Automated Fluorescent Measurement of the Airway Surface Liquid pH of Primary Human Airway Epithelial Cells

Saint‐Criq¹,

Haq²,

Gardner³

et al. 2019

JoVE

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In recent years, the importance of mucosal surface pH in the airways has been highlighted by its ability to regulate airway surface liquid (ASL) hydration, mucus viscosity and activity of antimicrobial peptides, key parameters involved in innate defense of the lungs. This is of primary relevance in the field of chronic respiratory diseases such as cystic fibrosis (CF) where these parameters are dysregulated. While different groups have studied ASL pH both in vivo and in vitro, their methods report a relatively wide range of ASL pH values and even contradictory findings regarding any pH differences between non-CF and CF cells. Furthermore, their protocols do not always provide enough details in order to ensure reproducibility, most are low throughput and require expensive equipment or specialized knowledge to implement, making them difficult to establish in most labs. Here we describe a semi-automated fluorescent plate reader assay that enables the real-time measurement of ASL pH under thin film conditions that more closely resemble the in vivo situation. This technique allows for stable measurements for many hours from multiple airway cultures simultaneously and, importantly, dynamic changes in ASL pH in response to agonists and inhibitors can be monitored. To achieve this, the ASL of fully differentiated primary human airway epithelial cells (hAECs) are stained overnight with a pH-sensitive dye in order to allow for the reabsorption of the excess fluid to ensure thin film conditions. After fluorescence is monitored in the presence or absence of agonists, pH calibration is performed in situ to correct for volume and dye concentration. The method described provides the required controls to make stable and reproducible ASL pH measurements, which ultimately could be used as a drug discovery platform for personalized medicine, as well as adapted to other epithelial tissues and experimental conditions, such as inflammatory and/or host-pathogen models.

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“…The pharmacology of HKA2 is complicated and has not been fully investigated (for review see 30 ). However, some data exist in the literature suggesting that HKA2 could be inhibited by the “proton-pump inhibitors” (PPIs) of the omeprazole family 56 – 59 . These compounds are well-known to inhibit the H,K-ATPase type 1, which is structurally and functionally closely related to HKA2.…”

Section: Discussionmentioning

confidence: 99%

Increased colonic K+ excretion through inhibition of the H,K-ATPase type 2 helps reduce plasma K+ level in a murine model of nephronic reduction

Walter

Rafael

Genna

et al. 2021

Sci Rep

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Hyperkalemia is frequently observed in patients at the end-stage of chronic kidney disease (CKD), and has possible harmful consequences on cardiac function. Many strategies are currently used to manage hyperkalemia, one consisting of increasing fecal K+ excretion through the administration of cation-exchange resins. In this study, we explored another more specific method of increasing intestinal K+ secretion by inhibiting the H,K-ATPase type 2 (HKA2), which is the main colonic K+ reabsorptive pathway. We hypothetised that the absence of this pump could impede the increase of plasma K+ levels following nephronic reduction (N5/6) by favoring fecal K+ secretion. In N5/6 WT and HKA2KO mice under normal K+ intake, the plasma K+ level remained within the normal range, however, a load of K+ induced strong hyperkalemia in N5/6 WT mice (9.1 ± 0.5 mM), which was significantly less pronounced in N5/6 HKA2KO mice (7.9 ± 0.4 mM, p < 0.01). This was correlated to a higher capacity of HKA2KO mice to excrete K+ in their feces. The absence of HKA2 also increased fecal Na+ excretion by inhibiting its colonic ENaC-dependent absorption. We also showed that angiotensin-converting-enzyme inhibitor like enalapril, used to treat hypertension during CKD, induced a less severe hyperkalemia in N5/6 HKA2KO than in N5/6 WT mice. This study therefore provides the proof of concept that the targeted inhibition of HKA2 could be a specific therapeutic maneuver to reduce plasma K+ levels in CKD patients.

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Esomeprazole Increases Airway Surface Liquid pH in Primary Cystic Fibrosis Epithelial Cells

Cited by 19 publications

References 66 publications

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Real-Time, Semi-Automated Fluorescent Measurement of the Airway Surface Liquid pH of Primary Human Airway Epithelial Cells

Increased colonic K+ excretion through inhibition of the H,K-ATPase type 2 helps reduce plasma K+ level in a murine model of nephronic reduction

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