Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis

Song, Yuanlin; Salinas, Danieli; Nielson, Dennis W.; Verkman, A. S.

doi:10.1152/ajpcell.00379.2005

Cited by 165 publications

(188 citation statements)

References 42 publications

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“…Studying a porcine model of cystic fibrosis (CF) (37,38), we found that loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channels reduced HCO 3 − secretion and decreased ASL pH (39,40), results consistent with earlier findings in human airway epithelia (41)(42)(43)(44). Importantly, the abnormally acidic pH partially inhibited bacterial killing by ASL (40).…”

supporting

confidence: 87%

“…In cultured human and porcine airway epithelia, in vitro studies of airways, and in vivo studies in newborn piglets and neonatal humans, CF ASL is abnormally acidic (40,(42)(43)(44), consistent with the loss of CFTR-dependent HCO 3 − transport (39,41). However, in older children and adults with CF, the effect of genotype in ASL pH is more variable (44,58,74).…”

Section: Discussionmentioning

confidence: 86%

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pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

Alaiwa¹,

Reznikov²,

Gansemer³

et al. 2014

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

181

162

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The pulmonary airways are continuously exposed to bacteria. As a first line of defense against infection, the airway surface liquid (ASL) contains a complex mixture of antimicrobial factors that kill inhaled and aspirated bacteria. The composition of ASL is critical for antimicrobial effectiveness. For example, in cystic fibrosis an abnormally acidic ASL inhibits antimicrobial activity. Here, we tested the effect of pH on the activity of an ASL defensin, human β-defensin-3 (hBD-3), and the cathelicidin-related peptide, LL-37. We found that reducing pH from 8.0 to 6.8 reduced the ability of both peptides to kill Staphylococcus aureus. An acidic pH also attenuated LL-37 killing of Pseudomonas aeruginosa. In addition, we discovered synergism between hBD-3 and LL-37 in killing S. aureus. LL-37 and lysozyme were also synergistic. Importantly, an acidic pH reduced the synergistic effects of combinations of ASL antibacterials. These results indicate that an acidic pH reduces the activity of individual ASL antimicrobials, impairs synergism between them, and thus may disrupt an important airway host defense mechanism.

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supporting

confidence: 87%

Section: Discussionmentioning

confidence: 86%

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

Alaiwa¹,

Reznikov²,

Gansemer³

et al. 2014

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

181

162

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“…These defects decrease the rate of liquid secretion by submucosal glands and reduce the pH of the secreted liquid (30,31,35). We found that blocking Cl − secretion and eliminating HCO 3 − secretion in non-CF airways reproduced some of the abnormalities of CF airways.…”

Section: Muc5b Forms Mucus Strands and Muc5ac Forms Mucus Threads Andmentioning

confidence: 64%

Gel-forming mucins form distinct morphologic structures in airways

Ostedgaard

Moninger

McMenimen

et al. 2017

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

149

178

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Gel-forming mucins, the primary macromolecular components of airway mucus, facilitate airway clearance by mucociliary transport. In cystic fibrosis (CF) altered mucus properties impair mucociliary transport. Airways primarily secrete two closely related gel-forming mucins, MUC5B and MUC5AC. However, their morphologic structures and associations in airways that contain abundant submucosal glands and goblet cells are uncertain. Moreover, there is limited knowledge about mucins in airways not affected by inflammation, infection, or remodeling or in CF airways. Therefore, we examined airways freshly excised from newborn non-CF pigs and CF pigs before secondary manifestations develop. We found that porcine submucosal glands produce MUC5B, whereas goblet cells produce predominantly MUC5AC plus some MUC5B. We found that MUC5B emerged from submucosal gland ducts in the form of strands composed of multiple MUC5B filaments. In contrast, MUC5AC emerged from goblet cells as wispy threads and sometimes formed mucin sheets. In addition, MUC5AC often partially coated the MUC5B strands. Compared with non-CF, MUC5B more often filled CF submucosal gland ducts. MUC5AC sheets also accumulated in CF airways overlying MUC5B strands. These results reveal distinct morphology and interactions for MUC5B and MUC5AC and suggest that the two mucins make distinct contributions to mucociliary transport. Thus, they provide a framework for understanding abnormalities in disease.mucus | cystic fibrosis | lung | asthma | COPD

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“…ASL pH was measured using the pH-sensitive fluorophore BCECF conjugated to 10 kDa dextran (Invitrogen) as described elsewhere (40), which was added 4 to 6 h before measurement (20 ml of 0.5 mg/ml in PBS). Cell inserts were incubated in HCO 3…”

Section: Asl Depth and Ph Measurementsmentioning

confidence: 99%

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Haggie

Phuan²,

Tan³

et al. 2016

FASEB j.

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Pendrin (SLC26A4) is a Cl 2 /anion exchanger expressed in the epithelium of inflamed airways where it is thought to facilitate Cl 2 absorption and HCO 3 2 secretion. Studies using pendrin knockout mice and airway epithelial cells from hearing-impaired subjects with pendrin loss of function suggest involvement of pendrin in inflammatory lung diseases, including cystic fibrosis (CF), perhaps by regulation of airway surface liquid (ASL) volume. Here we identified small-molecule pendrin inhibitors and demonstrated their efficacy in increasing ASL volume. A cell-based, functional high-throughput screen of ∼36,000 synthetic small molecules produced 3 chemical classes of inhibitors of human pendrin. After structure-activity studies, tetrahydropyrazolopyridine and pyrazolothiophenesulfonamide compounds reversibly inhibited pendrin-facilitated Cl 2 exchange with SCN 2 , I 2 , NO 3 2 , and HCO 3 2 with drug concentration causing 50% inhibition down to ∼2.5 mM. In well-differentiated primary cultures of human airway epithelial cells from non-CF and CF subjects, treatment with IL-13, which causes inflammation with strong pendrin up-regulation, strongly increased Cl 2 /HCO 3 2 exchange and the increase was blocked by pendrin inhibition. Pendrin inhibition significantly increased ASL depth (by ∼8 mm) in IL-13-treated non-CF and CF cells but not in untreated cells. These studies implicate the involvement of pendrin-facilitated Cl 2 / HCO 3 2 in the regulation of ASL volume and suggest the utility of pendrin inhibitors in inflammatory lung diseases, including CF

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Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis

Cited by 165 publications

References 42 publications

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

Gel-forming mucins form distinct morphologic structures in airways

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

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