The effects of sildenafil on ciliary beat frequency in patients with pulmonary non-tuberculous mycobacteria disease: phase I/II trial

RationalePulmonary non-tuberculous mycobacterial (PNTM) disease has increased over the past several decades, especially in older women. Abnormal mucociliary clearance and abnormal nasal nitric oxide (nNO) have been associated with PNTM disease in other patient cohorts. Mucociliary clearance can be affected by NO-cyclic guanosine monophosphate signalling and, therefore, modulation of the pathway may be possible with phosphodiesterase inhibitors such as sildenafil as a novel therapeutic approach.ObjectiveTo define ex vivo characteristics of PNTM disease affected by sildenafil.MethodsSubjects with PNTM infections were recruited into an open-label dose-escalation trial of sildenafil. Laboratory measurements and mucociliary measurements—ciliary beat frequency, nNO and 24-hour sputum production—were collected throughout the study period. Patients received sildenafil daily during the study period, with escalation from 20 to 40 mg three times per day.Measurements and main resultsIncreased ciliary beat frequency occurred after a single dose of 40 mg sildenafil and after extended dosing of 40 mg sildenafil. The increase ciliary beat frequency was not seen with 20 mg sildenafil dosing. There were no changes in sputum production, nNO production, Quality of Life-Bronchiectasis-NTM module (QOL-B-NTM) questionnaire or the St George’s Respiratory Questionnaire during the study period.ConclusionSildenafil, 40 mg, increased ciliary beat frequency acutely as well as with extended administration.

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Regulation of Ciliary Beat Frequency by the Nitric Oxide–Cyclic Guanosine Monophosphate Signaling Pathway in Rat Airway Epithelial Cells

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/ajrcmb.23.2.4022 ◽

2000 ◽

Vol 23 (2) ◽

pp. 175-181 ◽

Cited By ~ 77

Author(s):

Dechun Li ◽

Gotaro Shirakami ◽

Xinhua Zhan ◽

Roger A. Johns

Keyword(s):

Nitric Oxide ◽

Epithelial Cells ◽

Signaling Pathway ◽

Beat Frequency ◽

Ciliary Beat Frequency ◽

Cyclic Guanosine Monophosphate ◽

Airway Epithelial Cells ◽

Guanosine Monophosphate ◽

Airway Epithelial ◽

Ciliary Beat

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Differential effect of anesthetics on mucociliary clearance in vivo in mice

Scientific Reports ◽

10.1038/s41598-021-84605-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kyle S. Feldman ◽

Eunwon Kim ◽

Michael J. Czachowski ◽

Yijen Wu ◽

Cecilia W. Lo ◽

...

Keyword(s):

Mucociliary Clearance ◽

Defense Mechanism ◽

Ex Vivo ◽

Beat Frequency ◽

Ciliary Beat Frequency ◽

Wild Type ◽

Sulfur Colloid ◽

Ct System

AbstractRespiratory mucociliary clearance (MCC) is a key defense mechanism that functions to entrap and transport inhaled pollutants, particulates, and pathogens away from the lungs. Previous work has identified a number of anesthetics to have cilia depressive effects in vitro. Wild-type C57BL/6 J mice received intra-tracheal installation of 99mTc-Sulfur colloid, and were imaged using a dual-modality SPECT/CT system at 0 and 6 h to measure baseline MCC (n = 8). Mice were challenged for one hour with inhalational 1.5% isoflurane, or intraperitoneal ketamine (100 mg/kg)/xylazine (20 mg/kg), ketamine (0.5 mg/kg)/dexmedetomidine (50 mg/kg), fentanyl (0.2 mg/kg)/1.5% isoflurane, propofol (120 mg/Kg), or fentanyl/midazolam/dexmedetomidine (0.025 mg/kg/2.5 mg/kg/0.25 mg/kg) prior to MCC assessment. The baseline MCC was 6.4%, and was significantly reduced to 3.7% (p = 0.04) and 3.0% (p = 0.01) by ketamine/xylazine and ketamine/dexmedetomidine challenge respectively. Importantly, combinations of drugs containing fentanyl, and propofol in isolation did not significantly depress MCC. Although no change in cilia length or percent ciliation was expected, we tried to correlate ex-vivo tracheal cilia ciliary beat frequency and cilia-generated flow velocities with MCC and found no correlation. Our results indicate that anesthetics containing ketamine (ketamine/xylazine and ketamine/dexmedetomidine) significantly depress MCC, while combinations containing fentanyl (fentanyl/isoflurane, fentanyl/midazolam/dexmedetomidine) and propofol do not. Our method for assessing MCC is reproducible and has utility for studying the effects of other drug combinations.

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Correlations among Mucociliary Transport, Ciliary Function, and Ciliary Structure

American Journal of Rhinology ◽

10.2500/105065898782102945 ◽

1998 ◽

Vol 12 (1) ◽

pp. 53-58 ◽

Cited By ~ 20

Author(s):

Mark Jorissen

Keyword(s):

Defense Mechanisms ◽

Ex Vivo ◽

Beat Frequency ◽

Ciliary Beat Frequency ◽

Preliminary Evidence ◽

Relevant Parameter ◽

Mucociliary Transport ◽

Ciliary Dyskinesia ◽

Ciliary Beat

Mucociliary transport is one of the most important defense mechanisms of the airway. Mucociliary transport time or rate, as measured using the saccharin test or the radioisotope technique, respectively, is clinically the most relevant parameter, although subject to large intra- and interindividual variability. There is no correlation between mucociliary transport in vivo and ciliary beat frequency ex vivo. Preliminary evidence demonstrates that mucociliary transport correlates with ciliary structure and orientation as investigated with transmission and scanning electron microscopy. A correlation is presented between ciliary beat frequency and secondary ciliary abnormalities. This correlation can best be described according to the logistic sigmoid model (r = 0.69). Based on these functional data, an ultrastructural distinction is proposed among normal (less than 5%), light (5 to 15%), moderate (15 to 25%), and severe (more than 25%) secondary ciliary dyskinesia.

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