Effect of Aerosolized Uridine-5 ′ -Triphosphate on Airway Clearance with Cough in Patients with Primary Ciliary Dyskinesia

Noone, Peadar G.; Bennett, William D.; Regnis, Jeff A.; Zeman, Kirby L.; Carson, Johnny L.; King, Malcolm; Boucher, Richard C.; Knowles, Michael R.

doi:10.1164/ajrccm.160.1.9806146

Cited by 90 publications

(52 citation statements)

References 26 publications

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“…Our findings that other purinergic or ␤-adrenergic agonists also failed to increase CBF in small airways is consistent with this hypothesis. By contrast, increases in airway mucoclearance in response to purinergic agonists or UTP in patients with primary ciliary dyskinesia have been reported (33). However, in view of the inherent ciliary dysfunction, it is likely that these increases in mucus transport result from changes of other components of the mucociliary interface rather than being the result of a direct effect on the cilia.…”

Section: Discussionmentioning

confidence: 94%

Ciliary Beat Frequency Is Maintained at a Maximal Rate in the Small Airways of Mouse Lung Slices

Delmotte

Sanderson

2006

Am J Respir Cell Mol Biol

103

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Ciliary beat frequency (CBF) is a key factor in the defense of the airways, and ATP can stimulate CBF by increasing intracellular calcium concentration ([Ca 2؉ ] i ). However, the regulatory effects of ATP have been mainly studied in cultured or isolated epithelial cells from the large cartilaginous airways. The aim of this study was to evaluate the regulation of CBF in small airways of lung slices that are representative of in vivo tissue. Mice lungs were inflated with agarose and cut into thin slices with a vibratome. CBF in the small bronchioles was observed with differential interference contrast microscopy and quantified using high-speed digital imaging (at 240 images s ؊1 ). We found that the in situ organization of the ciliated cells was well preserved and that their CBF was high. We verified the fidelity of our recording system by analyzing rapid changes in CBF in response to temperature. However, we found that ATP had no effect on CBF, despite the fact that the [Ca 2؉ ] i , measured with confocal fluorescence imaging, was increased. Ionomycin and purinergic or ␤-adrenergic agonists also failed to increase CBF. Similar results were obtained in outgrowths of cells cultured from lung slices. By contrast, ATP increased the slower CBF of outgrowths of ciliated cells cultured from tracheal rings. Therefore, we conclude that CBF in intrapulmonary airways of mice is maintained at a maximum rate and cannot be further increased by agonist stimulation. These conditions would ensure that mucociliary clearance is constantly active to provide continuous airway protection. Keywords: ATP; Ca 2؉; high-speed digital microscopy; small airways Mucociliary clearance is an important defense mechanism that clears foreign particles and chemicals from the airways to maintain healthy lungs. A key parameter determining the rate of mucus clearance is ciliary beat frequency (CBF). The density (cilia per cell and number of ciliated cells) and length of cilia are greater in the trachea than in small airways, and this correlates with an increase in mucus transport and CBF toward the oropharynx (1-5). This suggests that CBF is regulated throughout the airways to provide local control of mucociliary clearance. Unfortunately, this hypothesis is difficult to test in the smaller airways because of the inaccessibility of cilia. Consequently, most studies addressing the regulation of CBF have used cultured epithelial cells from the trachea or the large airways (cartilaginous bronchi) or trachea rings, and have found that CBF increases in response to a variety of stimuli, such as nucleotides (ATP, cAMP, UTP, cGMP) (6-12), mechanical deformation (13), NO (14,15), and ␤-agonists (16-18). Frequently, this increase in CBF has been associated with increases in intracellular calcium concentration ([Ca 2ϩ ] i ) (6,9,(12)(13)(14)(15)19). By contrast, the In this article, we describe a unique method to study CBF in the smaller airways. Thin lung slices that retain the in vivo organization of the lung are prepared from mice and provide access...

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Section: Discussionmentioning

confidence: 94%

Ciliary Beat Frequency Is Maintained at a Maximal Rate in the Small Airways of Mouse Lung Slices

Delmotte

Sanderson

2006

Am J Respir Cell Mol Biol

103

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“…Physiologic data have shown that "effective" coughs may result in lung clearance almost equal to normal mucociliary clearance over short time periods, even in subjects with PCD who lack clearance at baseline (24). Chronic airway infection and inflammation lead to bronchiectasis in almost all patients by early adulthood, and pulmonary function testing typically shows progressive, airflow-obstructive defects.…”

Section: Original Researchmentioning

confidence: 99%

Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents

et al. 2016

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Rationale: Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations.Objectives: To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents.

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“…The higher Ca 2ϩ i mobilization may be particularly useful to CF patients, who depend solely on CaCC to compensate for the absent cAMP-mediated Cl Ϫ secretion in CF (3). Thus, the approximate doubling of Ca and ciliary beat to transiently restore mucus clearance (28).…”

Section: Er Ca 2ϩ Stores In Cf Airway Epitheliamentioning

confidence: 99%

Cystic Fibrosis Airway Epithelial Ca2+ Signaling

Ribeiro

Paradiso

Carew

et al. 2005

Journal of Biological Chemistry

103

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In cystic fibrosis (CF) airways, abnormal epithelial ion transport likely initiates mucus stasis, resulting in persistent airway infections and chronic inflammation. Mucus clearance is regulated, in part, by activation of apical membrane receptors coupled to intracellular calcium (Ca storage capacity of apically confined endoplasmic reticulum (ER) Ca 2؉ stores. To address whether the ER upregulation resulted from ER retention of misfolded ⌬F508 CFTR or was an acquired response to chronic luminal airway infection/inflammation, three approaches were used. First, ER density was studied in normal and CF sweat duct human epithelia expressing high levels of ⌬F508 CFTR, and it was found to be the same in normal and CF epithelia. Second, apical ER density was morphometrically analyzed in airway epithelia from normal subjects, ⌬F508 homozygous CF patients, and a disease control, primary ciliary dyskinesia; it was found to be greater in both CF and primary ciliary dyskinesia. Third, apical ER density and P2Y 2 -R activation-mobilized Ca

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Effect of Aerosolized Uridine-5 ′ -Triphosphate on Airway Clearance with Cough in Patients with Primary Ciliary Dyskinesia

Cited by 90 publications

References 26 publications

Ciliary Beat Frequency Is Maintained at a Maximal Rate in the Small Airways of Mouse Lung Slices

Ciliary Beat Frequency Is Maintained at a Maximal Rate in the Small Airways of Mouse Lung Slices

Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents

Cystic Fibrosis Airway Epithelial Ca2+ Signaling

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