The Mechanism of Mucus Clearance in Cough

Basser, Peter J.; McMahon, Thomas A.; Griffith, P.

doi:10.1115/1.3168381

Cited by 56 publications

(57 citation statements)

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“…Phasic Motion (Shear Stress) Culture Conditions; Normal Versus CF Bronchial Epithelial PCL Volume Regulation-Breathing imparts shear on pulmonary surfaces by airflow-induced shear stress, cyclic compressive (transmural) shear, and stretch (13). However, calculation of total shear-stress on pulmonary surfaces has been difficult, and comprehensive model systems are unavailable.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the observations that (i) tidal volume expansion and airflow impart shear to airway surfaces (13), (ii) shear releases nucleotides from many cell types into the extracellular environment (14,15), and (iii) extracellular nucleotides interact with P2Y 2 and P2X purinoceptors to regulate airway ion transport (16,17), we hypothesized that the failure to recapitulate in vitro the phasic motion associated with tidal breathing has hindered the identification of the pathways for PCL volume autoregulation. Accordingly, we developed a novel culture system that mimics the best characterized shear stress in the lung, i.e.…”

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confidence: 99%

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Normal and Cystic Fibrosis Airway Surface Liquid Homeostasis

Tarran

Button

Picher

et al. 2005

Journal of Biological Chemistry

301

178

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Mammalian airways normally regulate the volume of a thin liquid layer, the periciliary liquid (PCL), to facilitate the mucus clearance component of lung defense. Studies under standard (static) culture conditions revealed that normal airway epithelia possess an adenosine-regulated pathway that blends Na ؉ absorption and Cl ؊ secretion to optimize PCL volume. In cystic fibrosis (CF), the absence of CF transmembrane conductance regulator results in a failure of adenosine regulation of PCL volume, which is predicted to initiate mucus stasis and infection. However, under conditions that mimic the phasic motion of the lung in vivo, ATP release into PCL was increased, CF ion transport was rebalanced, and PCL volume was restored to levels adequate for lung defense. This ATP signaling system was vulnerable, however, to insults that trigger CF bacterial infections, such as viral (respiratory syncitial virus) infections, which up-regulated extracellular ATPase activity and abolished motion-dependent ATP regulation of CF PCL height. These studies demonstrate (i) how the normal coordination of opposing ion transport pathways to maintain PCL volume is disrupted in CF, (ii) the hitherto unknown role of phasic motion in regulating key aspects of normal and CF innate airways defense, and (iii) that maneuvers directed at increasing motion-induced nucleotide release may be therapeutic in CF patients.The lung must continually defend itself against bacteria that deposit on airway surfaces during normal tidal breathing. It appears that mechanical clearance of bacteria mediated by mucus transport is the principal innate defense mechanism of mammalian airways (1-4). Recent data have shown that a critical component of this defense system is the thin (ϳ7) m liquid layer lining airway surfaces, the periciliary liquid (PCL), 2 that provides a low viscosity solution for ciliary beating and acts a lubricant layer for mucus transport (5, 6). In cystic fibrosis (CF) lung disease, it appears that the primary pathophysiologic defect is the depletion of PCL volume, resulting in a failure of mucus clearance of bacteria and persistent airways infection (7,8).However, questions have been raised as to the relevance of PCL depletion to CF pathogenesis in vivo (9). For example, whereas in vitro data from standard (static) culture systems describe rapid depletion of PCL height and a complete failure of mucus transport (7), young CF patients exhibit reduced but measurable rates of mucus clearance in vivo (10). This inconsistency suggests that mechanisms for PCL height regulation operating in vivo are absent from standard static culture systems. In addition, clinical observations suggest that CF lung disease exacerbates intermittently and is heterogeneous. Often, viral infections trigger these disease exacerbations (11, 12), but no links between viral infection and PCL regulation have been reported.To investigate these questions, we used a well differentiated airway epithelial culture system that exhibits PCL volume regulation and mucus transport (7). Ba...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Normal and Cystic Fibrosis Airway Surface Liquid Homeostasis

Tarran

Button

Picher

et al. 2005

Journal of Biological Chemistry

301

178

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“…Consistent with this thesis are previous studies which have reported that ATP is released from human airway epithelia subjected to physical forces. This includes forces generated by mechanical deformation (Kallok et al, 1983;Grygorczyk et al, 1997;Homolya et al, 2000;Knight et al, 2002), fluid shear stress (Grierson et al, 1995;Guyot et al, 2002;Lazarowski et al, 2004;Tarran et al, 2005), compression/stretch (Basser et al, 1989;Button et al, 2007), osmotic shock (Mitchell et al, 1998;Okada et al, 2006), or by simply changing of the media of cultured cells .…”

Section: Stress-stimulated Atp Releasementioning

confidence: 99%

Role of mechanical stress in regulating airway surface hydration and mucus clearance rates

Button

Boucher

2008

Respiratory Physiology & Neurobiology

137

141

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Effective clearance of mucus is a critical innate airway defense mechanism, and under appropriate conditions, can be stimulated to enhance clearance of inhaled pathogens. It has become increasingly clear that extracellular nucleotides (ATP and UTP) and nucleosides (adenosine) are important regulators of mucus clearance in the airways as a result of their ability to stimulate fluid secretion, mucus hydration, and cilia beat frequency (CBF). One ubiquitous mechanism to stimulate ATP release is through external mechanical stress. This article addresses the role of physiologicallyrelevant mechanical forces in the lung and their effects on regulating mucociliary clearance (MCC). The effects of mechanical forces on the stimulating ATP release, fluid secretion, CBF, and MCC are discussed. Also discussed is evidence suggesting that airway hydration and stimulation of MCC by stress-mediated ATP release may play a role in several therapeutic strategies directed at improving mucus clearance in patients with obstructive lung diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).

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“…4 The mucus is a nonNewtonian fluid 5 that exhibits viscoelastic and shear thinning characteristics, and possesses a yield stress. 6,7 In the terminal bronchioles, beyond generation 17, there is essentially a single fluid layer whose viscous properties are similar to those of water.…”

Section: Introductionmentioning

confidence: 99%

The effect of viscoelasticity on the stability of a pulmonary airway liquid layer

2010

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The lungs consist of a network of bifurcating airways that are lined with a thin liquid film. This film is a bilayer consisting of a mucus layer on top of a periciliary fluid layer. Mucus is a non-Newtonian fluid possessing viscoelastic characteristics. Surface tension induces flows within the layer, which may cause the lung's airways to close due to liquid plug formation if the liquid film is sufficiently thick. The stability of the liquid layer is also influenced by the viscoelastic nature of the liquid, which is modeled using the Oldroyd-B constitutive equation or as a Jeffreys fluid. To examine the role of mucus alone, a single layer of a viscoelastic fluid is considered. A system of nonlinear evolution equations is derived using lubrication theory for the film thickness and the film flow rate. A uniform film is initially perturbed and a normal mode analysis is carried out that shows that the growth rate g for a viscoelastic layer is larger than for a Newtonian fluid with the same viscosity. Closure occurs if the minimum core radius, R min ͑t͒, reaches zero within one breath. Solutions of the nonlinear evolution equations reveal that R min normally decreases to zero faster with increasing relaxation time parameter, the Weissenberg number We. For small values of the dimensionless film thickness parameter , the closure time, t c , increases slightly with We, while for moderate values of , ranging from 14% to 18% of the tube radius, t c decreases rapidly with We provided the solvent viscosity is sufficiently small. Viscoelasticity was found to have little effect for Ͼ0.18, indicating the strong influence of surface tension. The film thickness parameter and the Weissenberg number We also have a significant effect on the maximum shear stress on tube wall, max͑ w ͒, and thus, potentially, an impact on cell damage. Max͑ w ͒ increases with for fixed We, and it decreases with increasing We for small We provided the solvent viscosity parameter is sufficiently small. For large Ϸ 0.2, there is no significant difference between the Newtonian flow case and the large We cases.

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The Mechanism of Mucus Clearance in Cough

Cited by 56 publications

References 0 publications

Normal and Cystic Fibrosis Airway Surface Liquid Homeostasis

Normal and Cystic Fibrosis Airway Surface Liquid Homeostasis

Role of mechanical stress in regulating airway surface hydration and mucus clearance rates

The effect of viscoelasticity on the stability of a pulmonary airway liquid layer

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