New insights into the mechanisms controlling the bronchial mucus balance

Cyril Karamaoun, Benjamin Sobac, Benjamin Mauroy, Alain Van Muylem, Benoît Haut, Cyril Karamaoun, Benjamin Sobac, Benjamin Mauroy, Alain Van Muylem, Benoît Haut

Abstract

In this work, we aim to analyze and compare the mechanisms controlling the volume of mucus in the bronchial region of the lungs of a healthy human adult, at rest and in usual atmospheric conditions. This analysis is based on a balance equation for the mucus in an airway, completed by a computational tool aiming at characterizing the evaporation, during respiration, of the water contained in the bronchial mucus. An idealized representation of the lungs, based on Weibel's morphometric model, is used. The results indicate that the mechanisms controlling the volume of mucus in an airway depend on the localization of the airway in the bronchial region of the lungs. In the proximal generations, the volume of mucus in an airway is mainly controlled by the evaporation of the water it contains and the replenishment, with water, of the mucus layer by epithelial cells or the submucosal glands. Nevertheless, cilia beating in this part of the bronchial region remains of fundamental importance to transport the mucus and hence to eliminate dust and pathogens trapped in it. On the other hand, in the distal generations of the bronchial region, the volume of mucus in an airway is mainly controlled by the mucociliary transport and by the absorption of liquid by the epithelium. This absorption is a consequence of the mucus displacement by the cilia along generations with an interface between the epithelium and the airway surface layer of decreasing area. The numerical results obtained are in good agreement with previously published experimental data, thus validating our approach. We also briefly discuss how our results can improve the understanding and, possibly, the treatment of pulmonary diseases.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Three levels of details of…
Fig 1. Three levels of details of the human bronchial region.
a) Picture of a lung cast showing the human bronchial region. b) Schematic transverse view of an airway, with the different layers surrounding the lumen of the airway. c) The epithelial cilia penetrate in the ASL and generate the displacement of the mucus layer.
Fig 2. Scheme of an airway in…
Fig 2. Scheme of an airway in generation i and a bifurcation.
Several parameters related to the balance of the mucus in the airway are represented on this figure. The picture is not to scale.
Fig 3. Results obtained with the computational…
Fig 3. Results obtained with the computational tool.
Left: calculated value of Ei/Si as a function of the generation index. Right: calculated average temperature of the air on a flow cross-section as a function of the distance from the top of the trachea, at the end of the inspiration (circles) and the expiration (squares). These results have been obtained with the computational tool, using tin = 2 s, f = 0.25 s−1, Qin = 250 ml s−1, Tin = 30°C and RHin = 0.80.
Fig 4. Magnitude of the various mechanisms…
Fig 4. Magnitude of the various mechanisms controlling the bronchial mucus balance.
The results were obtained with the data given in Table 1. Left figures: Tin = 30°C and RHin = 0.80, right figures: Tin = 34°C and RHin = 0.95. Top figures: δμ1 = 10 μm, vμ1 = 5 mm min−1, δμ16 = 2 μm and vμ16 = 0.5 mm min−1. Bottom figures: δμ1 = 30 μm, vμ1 = 5 mm min−1, δμ16 = 3 μm and vμ16 = 0.5 mm min−1. Squares-continuous lines: ΔMi, diamonds-dashed lines: Ei, circles-dotted lines: Bi.
Fig 5. Schematic diagram of an airway,…
Fig 5. Schematic diagram of an airway, during inspiration.
Several notations used in the model are presented on this figure. The picture is not to scale.

References

    1. Weibel ER. Morphometry of the human lung. Academic Press; 1963.
    1. Weibel ER, Sapoval B, Filoche M. Design of peripheral airways for efficient gas exchange. Respir Physiol Neurobiol. 2005;148(1-2):3–21. doi:
    1. West JB. Respiratory Physiology: The Essentials. 9th ed Philadelphia: Lippincott Williams and Wilkins; 2011.
    1. Button B, Cai LH, Ehre C, Kesimer M, Hill DB, Sheehan JK, et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science. 2012;337(6097):937–941. doi:
    1. King M. Physiology of mucus clearance. Paediatr Respir Rev. 2006;7 Suppl 1:S212–214. doi:
    1. Boucher RC. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med. 2007;58:157–170. doi:
    1. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–2653. doi:
    1. Regnis JA, Robinson M, Bailey DL, Cook P, Hooper P, Chan HK, et al. Mucociliary clearance in patients with cystic fibrosis and in normal subjects. Am J Respir Crit Care Med. 1994;150(1):66–71.
    1. Fahy JV, Dickey BF. Airway mucus function and dysfunction. N Engl J Med. 2010;363(23):2233–2247. doi:
    1. Lai SK, Wang YY, Wirtz D, Hanes J. Micro- and macrorheology of mucus. Adv Drug Deliv Rev. 2009;61(2):86–100. doi:
    1. Norton MM, Robinson RJ, Weinstein SJ. Model of ciliary clearance and the role of mucus rheology. Phys Rev E. 2011;83(1):011921 doi:
    1. Smith DJ, Gaffney EA, Blake JR. Modelling mucociliary clearance. Respir Physiol Neurobiol. 2008;163(1-3):178–188. doi:
    1. Herschlag G, Garcia GJM, Button B, Tarran R, Lindley B, Reinhardt B, et al. A mechanochemical model for auto-regulation of lung airway surface layer volume. J Theor Biol. 2013;325:42–51. doi:
    1. Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest. 2002;109(5):571–577. doi:
    1. Mauroy B, Fausser C, Pelca D, Merckx J, Flaud P. Toward the modeling of mucus draining from the human lung: role of the geometry of the airway tree. Phys Biol. 2011;8(5):056006 doi:
    1. Mauroy B, Flaud P, Pelca D, Fausser C, Merckx J, Mitchell BR. Toward the modeling of mucus draining from human lung: role of airways deformation on air-mucus interaction. Front Physiol. 2015;6:214 doi:
    1. Mcfadden ER. Heat and Water Exchange in Human Airways. Am Rev Respir Dis. 1992;146:S8–S10. doi:
    1. Asmundsson T, Kilburn KH. Mucociliary clearance rates at various levels in dog lungs. Am Rev Respir Dis. 1970;102(3):388–397. doi:
    1. Kilburn KH. A hypothesis for pulmonary clearance and its implications. Am Rev Respir Dis. 1968;98(3):449–463. doi:
    1. Widdicombe JH. Regulation of the depth and composition of airway surface liquid. J Anat. 2002;201(4):313–318. doi:
    1. Warren NJ, Crampin EJ, Tawhai MH. The role of airway epithelium in replenishment of evaporated airway surface liquid from the human conducting airways. Ann Biomed Eng. 2010;38(12):3535–3549. doi:
    1. Cho HJ, Joo NS, Wine JJ. Defective fluid secretion from submucosal glands of nasal turbinates from CFTR-/- and CFTRΔF508/ΔF508 pigs. PLOS ONE. 2011;6(8):1–11. doi:
    1. Joo NS, Irokawa T, Robbins RC, Wine JJ. Hyposecretion, not hyperabsorption, is the basic defect of cystic fibrosis airway glands. J Biol Chem. 2006;281(11):7392–7398. doi:
    1. Joo NS, Cho HJ, Khansaheb M, Wine JJ. Hyposecretion of fluid from tracheal submucosal glands of CFTR-deficient pigs. J Clin Invest. 2010;120(9):3161–3166. doi:
    1. Elad D, Wolf M, Keck T. Air-conditioning in the human nasal cavity. Respir Physiol Neurobiol. 2008;163(1-3):121–127. doi:
    1. ERM Jr, Denison DM, Waller JF, Assoufi B, Peacock A, Sopwith T. Direct recordings of the temperatures in the tracheobronchial tree in normal man. J Clin Invest. 1982;69(3):700–705. doi:
    1. McFadden ER, Pichurko BM, Bowman HF, Ingenito E, Burns S, Dowling N, et al. Thermal mapping of the airways in humans. J Appl Physiol. 1985;58(2):564–570. doi:
    1. Scherer PW, Hanna LM. Heat and water transport in the human respiratory system In: Shitzer A, Eberhart RC, editors. Heat Transfer in Medicine and Biology. Springer; US; 1985. p. 287–306.
    1. Boucher RC, Stutts MJ, Bromberg PA, Gatzy JT. Regional differences in airway surface liquid composition. J Appl Physiol Respir Environ Exerc Physiol. 1981;50(3):613–620. doi:
    1. Williams R, Rankin N, Smith T, Galler D, Seakins P. Relationship between the humidity and temperature of inspired gas and the function of the airway mucosa. Crit Care Med. 1996;24(11):1920–1929. doi:
    1. Karamaoun C, Van Muylem A, Haut B. Modeling of the nitric oxide transport in the human lungs. Front Physiol. 2016;7:255 doi:
    1. Kim DW, Chung SK, Na Y. Numerical study on the air conditioning characteristics of the human nasal cavity. Comput Biol Med. 2017;86:18–30. doi:
    1. Leal J, Smyth HDC, Ghosh D. Physicochemical properties of mucus and their impact on transmucosal drug delivery. Int J Pharm. 2017;532(1):555–572. doi:
    1. Mercer RR, Russell ML, Crapo JD. Mucous lining layers in human and rat airways. Am Rev Respi Disease. 1992;145.
    1. Sanders N, Rudolph C, Braeckmans K, De Smedt SC, Demeester J. Extracellular barriers in respiratory gene therapy. Adv Drug Deliv Rev. 2009;61(2):115–127. doi:
    1. Yager D, Cloutier T, Feldman H, Bastacky J, Drazen JM, Kamm RD. Airway surface liquid thickness as a function of lung volume in small airways of the guinea pig. J Appl Physiol. 1994;77(5):2333–2340. doi:
    1. Foster WM, Langenback E, Bergofsky EH. Measurement of tracheal and bronchial mucus velocities in man: relation to lung clearance. J Appl Physiol Respir Environ Exerc Physiol. 1980;48(6):965–971. doi:
    1. Kilgour E, Rankin N, Ryan S, Pack R. Mucociliary function deteriorates in the clinical range of inspired air temperature and humidity. Intensive Care Med. 2004;30(7):1491–1494. doi:
    1. Mussatto DJ, Garrard CS, Lourenco RV. The effect of inhaled histamine on human tracheal mucus velocity and bronchial mucociliary clearance. Am Rev Respi Disease. 1988;138(4):775–779. doi:
    1. Yeates DB, Aspin N, Levison H, Jones MT, Bryan AC. Mucociliary tracheal transport rates in man. J Appl Physiol. 1975;39(3):487–495. doi:
    1. Asgharian B, Hofmann W, Miller FJ. Mucociliary clearance of insoluble particles from the tracheobronchial airways of the human lung. J Aerosol Sci. 2001;32(6):817–832. doi:
    1. Iravani J, Melville GN. Mucociliary function in the respiratory tract as influenced by physicochemical factors. Pharmacol Ther B. 1976;2(3):471–492.
    1. Daviskas E, Gonda I, Anderson SD. Mathematical modeling of heat and water transport in human respiratory tract. J Appl Physiol. 1990;69(1):362–372. doi:
    1. Hanna LM, Scherer PW. A theoretical model of localized heat and water vapor transport in the human respiratory tract. J Biomech Eng. 1986;108(1):19–27. doi:
    1. Ingenito EP, Solway J, McFadden ER, Pichurko BM, Cravalho EG, Drazen JM. Finite difference analysis of respiratory heat transfer. J Appl Physiol. 1986;61(6):2252–2259. doi:
    1. Tawhai MH, Hunter PJ. Modeling water vapor and heat transfer in the normal and the intubated airways. Ann Biomed Eng. 2004;32(4):609–622. doi:
    1. Tsai CL, Saidel GM, McFadden ER, Fouke JM. Radial heat and water transport across the airway wall. J Appl Physiol. 1990;69(1):222–231. doi:
    1. Boucher RC. Regulation of airway surface liquid volume by human airway epithelia. Pflugers Arch. 2003;445(4):495–498. doi:
    1. Tawhai MH, Hunter P, Tschirren J, Reinhardt J, McLennan G, Hoffman EA. CT-based geometry analysis and finite element models of the human and ovine bronchial tree. J Appl Physiol. 2004;97(6):2310–2321. doi:
    1. Warnock L, Gates A. Chest physiotherapy compared to no chest physiotherapy for cystic fibrosis. Cochrane Database Syst Rev. 2015;(12):CD001401.
    1. Robinson M, Regnis JA, Bailey DL, King M, Bautovich GJ, Bye PT. Effect of hypertonic saline, amiloride, and cough on mucociliary clearance in patients with cystic fibrosis. Am J Respir Crit Care Med. 1996;153(5):1503–1509.
    1. Elkins M, Dentice R. Timing of hypertonic saline inhalation for cystic fibrosis. Cochrane Database Syst Rev. 2012;(2):CD008816 doi:
    1. Miller S, Hall DO, Clayton CB, Nelson R. Chest physiotherapy in cystic fibrosis: a comparative study of autogenic drainage and the active cycle of breathing techniques with postural drainage. Thorax. 1995;50(2):165–169. doi:
    1. Harkness LM, Ashton AW, Burgess JK. Asthma is not only an airway disease, but also a vascular disease. Pharmacol Ther. 2015;148:17–33. doi:
    1. O’Byrne PM, Ryan G, Morris M, McCormack D, Jones NL, Morse JLC, et al. Asthma induced by cold air and its relation to nonspecific bronchial responsiveness to methacholine. American Review of Respiratory Disease. 1982;125(3):281–285. doi:
    1. Mäkinen TM, Juvonen R, Jokelainen J, Harju TH, Peitso A, Bloigu A, et al. Cold temperature and low humidity are associated with increased occurrence of respiratory tract infections. Respir Med. 2009;103(3):456–62. doi:
    1. Sobac B, Talbot P, Haut B, Rednikov A, Colinet P. A comprehensive analysis of the evaporation of a liquid spherical drop. J Colloid Interface Sci. 2015;438:306–317. doi:
    1. van Ertbruggen C, Hirsch C, Paiva M. Anatomically based three-dimensional model of airways to simulate flow and particle transport using computational fluid dynamics. J Appl Physiol. 2005;98(3):970–980. doi:

Source: PubMed

3
订阅