scholarly journals Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy

2016 ◽  
Vol 310 (10) ◽  
pp. L928-L939 ◽  
Author(s):  
Susan E. Birket ◽  
Kengyeh K. Chu ◽  
Grace H. Houser ◽  
Linbo Liu ◽  
Courtney M. Fernandez ◽  
...  
Keyword(s):  
Ion Transport ◽  
Functional Imaging ◽  
Clinical Benefit ◽  
Effective Viscosity ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Clinical Results ◽  
Mucociliary Transport ◽  
Sweat Chloride

Recently approved therapies that modulate CFTR function have shown significant clinical benefit, but recent investigations regarding their molecular mechanism when used in combination have not been consistent with clinical results. We employed micro-optical coherence tomography as a novel means to assess the mechanism of action of CFTR modulators, focusing on the effects on mucociliary clearance. Primary human airway monolayers from patients with a G551D mutation responded to ivacaftor treatment with increased ion transport, airway surface liquid depth, ciliary beat frequency, and mucociliary transport rate, in addition to decreased effective viscosity of the mucus layer, a unique mechanism established by our findings. These endpoints are consistent with the benefit observed in G551D patients treated with ivacaftor, and identify a novel mechanism involving mucus viscosity. In monolayers derived from F508del patients, the situation is more complicated, compounded by disparate effects on CFTR expression and function. However, by combining ion transport measurements with functional imaging, we establish a crucial link between in vitro data and clinical benefit, a finding not explained by ion transport studies alone. We establish that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen. We further show that improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponds to changes in sweat chloride. Functional imaging reveals insights into clinical efficacy and CFTR biology that significantly impact our understanding of novel therapies.

Mucociliary interaction in vitro: effects of physiological and inflammatory stimuli

1990 ◽  
Vol 68 (4) ◽  
pp. 1421-1426 ◽  
Author(s):  
Z. V. Seybold ◽  
A. T. Mariassy ◽  
D. Stroh ◽  
C. S. Kim ◽  
H. Gazeroglu ◽  
...  
Keyword(s):  
Liquid Velocity ◽  
Beat Frequency ◽  
Platelet Activating Factor ◽  
Ciliary Beat Frequency ◽  
Ciliary Activity ◽  
Base Line ◽  
Mucociliary Transport ◽  
Epithelial Surface ◽  
Surface Liquid

Mucociliary transport in the airways is governed by the interaction between ciliary activity and the depth and rheological properties of the liquids (mucus) covering the epithelial surface. A change in one of these parameters may not predict the direction and magnitude of a concomitant change in mucociliary transport. We therefore determined the effects of physiological (neurotransmitters) and pathological (inflammatory mediators) stimuli on ciliary beat frequency (CBF), surface liquid velocity (SLV), surface liquid depth (SLD), and viscoelasticity of mucus in pieces of sheep trachea (n = 5 for each treatment) mounted in a chamber such that the submucosal side was bathed with Krebs-Henseleit perfusate (KH) and the luminal side was exposed to conditioned air. SLV, SLD, and CBF were measured with a microscope provided with an electronic micrometer and strobe light. Apparent viscosity and shear elastic modulus were measured with a microcapillary method using mucus collected at the downstream end of the preparation. Control CBF, SLV, and SLD were 11.6 +/- 0.4 (SE) Hz, 91 +/- 8 micron/s, and 33 +/- 5 microns, respectively, at base line and did not change during KH perfusion for 100 min. Perfusion with both acetylcholine and epinephrine (10(-5) to 10(-3) M) produced concentration-dependent increases in mean CBF (maximum increases at 10(-3) M of 16 and 9%, P less than 0.05), whereas only acetylcholine increased mean SLV (+56% at 10(-3) M, P less than 0.05). Perfusion with platelet-activating factor (10(-7) to 10(-5) M) decreased both mean CBF and SLV in a dose-dependent fashion (-6 and -63% at 10(-5) M, P less than 0.05), whereas antigen perfusion (1:60 dilution) increased mean CBF (+10%, P less than 0.05) but decreased SLV (-47%, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Differential effect of anesthetics on mucociliary clearance in vivo in mice

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.

Liquid secretion inhibitors reduce mucociliary transport in glandular airways

2002 ◽  
Vol 283 (2) ◽  
pp. L329-L335 ◽  
Author(s):  
Stephen T. Ballard ◽  
Laura Trout ◽  
Anil Mehta ◽  
Sarah K. Inglis
Keyword(s):  
Beat Frequency ◽  
Anion Channel ◽  
Ciliary Beat Frequency ◽  
Mucociliary Transport ◽  
Transmembrane Conductance Regulator ◽  
Inhibitory Effects ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Liquid Absorption ◽  
Cf Transmembrane Conductance Regulator

Because of its possible importance in cystic fibrosis (CF) pulmonary pathogenesis, the effect of anion and liquid secretion inhibitors on airway mucociliary transport was examined. When excised porcine tracheas were treated with ACh to induce gland liquid secretion, the rate of mucociliary transport was increased nearly threefold from 2.5 ± 0.5 to 6.8 ± 0.8 mm/min. Pretreatment with both bumetanide and dimethylamiloride (DMA), to respectively inhibit Cl− and HCO[Formula: see text]secretion, significantly reduced mucociliary transport in the presence of ACh by 92%. Pretreatment with the anion channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid similarly reduced mucociliary transport in ACh-treated airways by 97%. These agents did not, however, reduce ciliary beat frequency. Luminal application of benzamil to block liquid absorption significantly attenuated the inhibitory effects of bumetanide and DMA on mucociliary transport. We conclude that anion and liquid secretion is essential for normal mucociliary transport in glandular airways. Because the CF transmembrane conductance regulator protein likely mediates Cl−, HCO[Formula: see text], and liquid secretion in normal glands, we speculate that impairment of gland liquid secretion significantly contributes to defective mucociliary transport in CF.

Correlations among Mucociliary Transport, Ciliary Function, and Ciliary Structure

1998 ◽  
Vol 12 (1) ◽  
pp. 53-58 ◽  
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.

Luffa Operculata Affects Mucociliary Function of the Isolated Frog Palate

2005 ◽  
Vol 19 (4) ◽  
pp. 353-357 ◽  
Author(s):  
Mônica Aidar Menon-Miyake ◽  
Regiani Carvalho de Oliveira ◽  
Geraldo Lorenzi-Filho ◽  
Paulo Hilário Nascimento Saldiva ◽  
Ossamu Butugan
Keyword(s):  
Alternative Medicine ◽  
Nasal Mucosa ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
The United States ◽  
Mucociliary Transport ◽  
Transport Velocity ◽  
Mucociliary Function ◽  
Frog Palate ◽  
Ciliary Beat

Background Luffa operculata is a medicinal plant used in homeopathic and alternative medicine. In the United States, it is sold in a purified spray form, whereas a homemade L. operculata dry fruit infusion (DFI) is commonly used in Latin America. The L. operculata DFI is applied intranasally, inducing profuse mucous secretion and relieving nasal symptoms. Nevertheless, this medication may cause irritation of the nasal mucosa, as well as epistaxis or anosmia. Given the growing popularity of alternative medicine, a decision was made to evaluate the effects of this substance on mucous membranes. Methods The effects of L. operculata DFI on mucociliary transport velocity, ciliary beat frequency, and transepithelial potential difference (PD) were evaluated in an isolated frog palate preparation. We tested 46 palates immediately before immersion and again at 5 and 20 minutes after immersion. Four groups (n = 10) were tested in frog Ringer: control; L. operculata DFI, 60 mg/L; 600 mg/L; and 1200 mg/L. An additional group was tested using L. operculata DFI prepared with water (600 mg/L of H2O, n = 6). Epithelial samples were harvested for ultrastructural study. Results In treated palates, mucociliary transport velocity and ciliary beat frequency decreased significantly (p < 0.001 and p < 0.008, respectively). There was a dose-dependent decrease in PD modulus (p < .007). Our PD findings indicated ion-fluid transport abnormalities, which were confirmed by transmission electron microscopy that showed enlargement of interepithelial spaces. Conclusion In this ex vivo model, the L. operculata DFI infusion promoted significant changes in the mucociliary function of the epithelium, suggesting that it is potentially noxious to human nasal mucosa.

Nasal Mucociliary Transport: New Evidence for a Key Role of Ciliary Beat Frequency

2002 ◽  
Vol 112 (3) ◽  
pp. 570-573 ◽  
Author(s):  
Wilbert M. Boek ◽  
Kees Graamans ◽  
Hanny Natzijl ◽  
Peter P. van Rijk ◽  
Egbert H. Huizing
Keyword(s):  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Mucociliary Transport ◽  
New Evidence ◽  
Ciliary Beat

The effects of in vitro cotitine on nasal ciliary beat frequency

1995 ◽  
Vol 20 (5) ◽  
pp. 465-469 ◽  
Author(s):  
A. M. AGIUS ◽  
M. WAKE ◽  
A. L. PAHOR ◽  
A. SMALLMAN
Keyword(s):  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Ciliary Beat

Effects of ethanol on in vitro ciliary motility

1988 ◽  
Vol 65 (4) ◽  
pp. 1617-1620 ◽  
Author(s):  
D. R. Maurer ◽  
J. Liebman
Keyword(s):  
Beat Frequency ◽  
Slow Motion ◽  
Ciliary Beat Frequency ◽  
Blood Levels ◽  
Ciliary Beating ◽  
Ciliary Motility ◽  
Social Drinking ◽  
High Concentrations ◽  
Ciliary Beat

Consumption of ethanol can impair lung function and slow total lung clearance. High concentrations of ethanol have been shown to slow or arrest ciliary beating. This study examined the effects of concentrations of alcohol comparable to blood levels achieved from social drinking on ciliary beat frequency. We obtained ciliated cells by brushing the trachea of unanesthetized sheep during fiber-optic bronchoscopy. The cells were suspended in a perfusion chamber and physiological conditions were maintained in vitro. Ciliary beat frequency and synchrony were determined by slow-motion analysis of video images obtained by interference contrast microscopy. Metachronal ciliary coordination was observed in all preparations. The ciliary beat frequency was stimulated at ethanol concentrations from 0.01 up to but not including 0.1%, unchanged at 0.5 and 1%, and slowed at 2%. While confirming inhibition of ciliary motility at very high ethanol levels, we observed no acute impairment of ciliary function at ethanol concentrations comparable to those achieved from social drinking. Indeed, we found an unexpected stimulation of ciliary beating at low levels of ethanol. How this alteration in ciliary beating would affect pulmonary clearance remains unknown at this time.

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