Cellular and Non-cellular Barriers to Particle Transport Across the Lungs

  • Nicole Schneider-DaumEmail author
  • Marius Hittinger
  • Xabier Murgia
  • Claus-Michael Lehr
Part of the NanoScience and Technology book series (NANO)


Compared to the human body’s other outer epithelia, like e.g. the skin and the GI tract, the lungs have the largest surface area. Moreover, the so called “air-blood-barrier” is extremely thin, but also very tight to fulfill its physiological function. This chapter discusses the lung as a biological barrier in the context of inhaled particles. This important function is provided by some specific cellular as well as non-cellular elements. How the lung copes with particles “after landing” is not only relevant regarding the risks of accidentally inhaled nanomaterials, but also for designing safe and efficient nanopharmaceuticals to be inhaled on purpose.


Mucus Surfactant Epithelial transport Aerosol medicine 


  1. 1.
    Rackley, C.R., Stripp, B.R.: Building and maintaining the epithelium of the lung. J. Clin. Investig. 122, 2724–2730 (2012)CrossRefGoogle Scholar
  2. 2.
    Besnard, V., Whitsett, J.A.: Chapter 73—Tissue engineering for the respiratory epithelium: cell-based therapies for treatment of lung disease A2—Lanza, Robert. In: Langer, R., Vacanti, J. (eds.) Principles of Tissue Engineering, 4th edn., pp. 1543–1560. Academic Press, Boston (2014)CrossRefGoogle Scholar
  3. 3.
    Crapo, J.D., Barry, B.E., Gehr, P., et al.: Cell number and cell characteristics of the normal human lung. Am. Rev. Respir. Dis. 126, 332–337 (1982)Google Scholar
  4. 4.
    Weibel, E.R.: Lung morphometry: the link between structure and function. Cell Tissue Res. 367, 413–426 (2017)CrossRefGoogle Scholar
  5. 5.
    Klein, S.G., Hennen, J., Serchi, T., et al.: Potential of coculture in vitro models to study inflammatory and sensitizing effects of particles on the lung. Toxicol. In Vitro 25 (2011)Google Scholar
  6. 6.
    Hastedt, J.E., Bäckman, P., Clark, A.R., et al.: Scope and relevance of a pulmonary biopharmaceutical classification system. In: AAPS/FDA/USP Workshop March 16–17th, 2015 in Baltimore, MD. AAPS Open 2:1 (2016)Google Scholar
  7. 7.
    Bourquin, J., Milosevic, A., Hauser, D., et al.: Biodistribution, clearance, and long-term fate of clinically relevant nanomaterials. Adv. Mater. (Deerfield Beach, Fla.) (2018)Google Scholar
  8. 8.
    Patton, J.S., Byron, P.R.: Inhaling medicines: delivering drugs to the body through the lungs. Nat. Rev. Drug Discov. 6, 67–74 (2007)CrossRefGoogle Scholar
  9. 9.
    Herd, H., Daum, N., Jones, A.T., et al.: Nanoparticle geometry and surface orientation influence mode of cellular uptake. ACS Nano 7, 1961–1973 (2013)CrossRefGoogle Scholar
  10. 10.
    Hillaireau, H., Couvreur, P.: Nanocarriers’ entry into the cell: relevance to drug delivery. Cell. Mol. Life Sci. CMLS 66, 2873–2896 (2009)CrossRefGoogle Scholar
  11. 11.
    Puisney, C., Baeza-Squiban, A., Boland, S.: Mechanisms of uptake and translocation of nanomaterials in the lung. Adv. Exp. Med. Biol. 1048, 21–36 (2018)CrossRefGoogle Scholar
  12. 12.
    Rivera-Gil, P., Jimenez De Aberasturi, D., Wulf, V., et al.: The challenge to relate the physicochemical properties of colloidal nanoparticles to their cytotoxicity. Acc. Chem. Res. 46, 743–749 (2013)CrossRefGoogle Scholar
  13. 13.
    Vercauteren, D., Vandenbroucke, R.E., Jones, A.T., et al.: The use of inhibitors to study endocytic pathways of gene carriers: optimization and pitfalls. Mol. Ther. J. Am. Soc. Gene Ther. 18, 561–569 (2010)CrossRefGoogle Scholar
  14. 14.
    Doshi, N., Mitragotri, S.: Needle-shaped polymeric particles induce transient disruption of cell membranes. J. R. Soc. Interface 7(Suppl 4), S403–410 (2010)Google Scholar
  15. 15.
    Elder, A., Gelein, R., Silva, V., et al.: Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ. Health Perspect. 114, 1172–1178 (2006)CrossRefGoogle Scholar
  16. 16.
    Nickel, S., Clerkin, C.G., Selo, M.A., et al.: Transport mechanisms at the pulmonary mucosa: implications for drug delivery. Expert Opin. Drug Deliv. 13, 667–690 (2016)CrossRefGoogle Scholar
  17. 17.
    Dreaden, E.C., Raji, I.O., Austin, L.A., et al.: P-glycoprotein-dependent trafficking of nanoparticle-drug conjugates. Small 10, 1719–1723 (2014)CrossRefGoogle Scholar
  18. 18.
    Soundararajan, R., Sasaki, K., Godfrey, L., et al.: Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate. Int. J. Pharm. 514, 121–132 (2016)CrossRefGoogle Scholar
  19. 19.
    Gupta, D., Singh, A., Khan, A.U.: Nanoparticles as efflux pump and biofilm inhibitor to rejuvenate bactericidal effect of conventional antibiotics. Nanoscale Res. Lett. 12, 454 (2017)CrossRefADSGoogle Scholar
  20. 20.
    Kasper, J.Y., Feiden, L., Hermanns, M.I., et al.: Pulmonary surfactant augments cytotoxicity of silica nanoparticles: studies on an in vitro air-blood barrier model. Beilstein J. Nanotechnol. 6, 517–528 (2015)CrossRefGoogle Scholar
  21. 21.
    Rothen-Rutishauser, B.M., Kiama, S.G., Gehr, P.: A three-dimensional cellular model of the human respiratory tract to study the interaction with particles. Am. J. Respir. Cell Mol. Biol. 32, 281–289 (2005)CrossRefGoogle Scholar
  22. 22.
    Hittinger, M., Mell, N.A., Huwer, H., et al.: Autologous co-culture of primary human alveolar macrophages and epithelial cells for investigating aerosol medicines. Part II: Evaluation of IL-10-loaded microparticles for the treatment of lung inflammation. ATLA Altern. Lab. Anim. 44, 349–360 (2016)Google Scholar
  23. 23.
    Ong, H.X., Benaouda, F., Traini, D., et al.: In vitro and ex vivo methods predict the enhanced lung residence time of liposomal ciprofloxacin formulations for nebulisation. Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 86, 83–89 (2014)Google Scholar
  24. 24.
    Salomon, J.J., Muchitsch, V.E., Gausterer, J.C., et al.: The cell line NCl-H441 is a useful in vitro model for transport studies of human distal lung epithelial barrier. Mol. Pharm. 11, 995–1006 (2014)CrossRefGoogle Scholar
  25. 25.
    De Souza Carvalho, C., Daum, N., Lehr, C.M.: Carrier interactions with the biological barriers of the lung: advanced in vitro models and challenges for pulmonary drug delivery. Adv. Drug Deliv. Rev. 75, 129–140 (2014)CrossRefGoogle Scholar
  26. 26.
    Muller, L., Riediker, M., Wick, P., et al.: Oxidative stress and inflammation response after nanoparticle exposure: differences between human lung cell monocultures and an advanced three-dimensional model of the human epithelial airways. J. R. Soc. Interface 7(Suppl 1), S27–40 (2010)Google Scholar
  27. 27.
    Hittinger, M., Juntke, J., Kletting, S., et al.: Preclinical safety and efficacy models for pulmonary drug delivery of antimicrobials with focus on in vitro models. Adv. Drug Deliv. Rev. 85, 44–56 (2015)CrossRefGoogle Scholar
  28. 28.
    Zhu, Y., Chidekel, A., Shaffer, T.H.: Cultured human airway epithelial cells (Calu-3): a model of human respiratory function, structure, and inflammatory responses. Crit. Care Res. Pract. 2010, 1–8 (2010)CrossRefGoogle Scholar
  29. 29.
    Knowles, M.R., Boucher, R.C.: Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Investig. 109, 571–577 (2002)CrossRefGoogle Scholar
  30. 30.
    Wanner, A., Salathé, M., O’riordan, T.G.: Mucociliary clearance in the airways. Am. J. Respir. Crit. Care Med. 154, 1868–1902 (1996)CrossRefGoogle Scholar
  31. 31.
    Leff, A.R., Schumacker, P.T.: Respiratory physiology: basics and applications (1993)Google Scholar
  32. 32.
    Lieleg, O., Ribbeck, K.: Biological hydrogels as selective diffusion barriers. Trends Cell Biol. 21, 543–551 (2011)CrossRefGoogle Scholar
  33. 33.
    Murgia, X., Loretz, B., Hartwig, O., et al.: The role of mucus on drug transport and its potential to affect therapeutic outcomes. Adv. Drug Deliv. Rev. 124, 82–97 (2018)CrossRefGoogle Scholar
  34. 34.
    Schuster, B.S., Suk, J.S., Woodworth, G.F., et al.: Nanoparticle diffusion in respiratory mucus from humans without lung disease. Biomaterials 34, 3439–3446 (2013)CrossRefGoogle Scholar
  35. 35.
    Lillehoj, E.P., Kim, K.C.: Airway mucus: its components and function. Arch. Pharmacal. Res. 25, 770 (2002)CrossRefGoogle Scholar
  36. 36.
    Lai, S.K., Wang, Y.-Y., Hida, K., et al.: Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses. Proc. Natl. Acad. Sci. U.S.A. 107, 598–603 (2010)CrossRefADSGoogle Scholar
  37. 37.
    Taylor, C., Allen, A., Dettmar, P.W., et al.: The gel matrix of gastric mucus is maintained by a complex interplay of transient and nontransient associations. Biomacromolecules 4, 922–927 (2003)CrossRefGoogle Scholar
  38. 38.
    Lillehoj, E.P., Kato, K., Lu, W., et al.: Cellular and molecular biology of airway mucins. Int. Rev. Cell Mol. Biol. 303, 139–202 (2013)CrossRefGoogle Scholar
  39. 39.
    Wickström, C., Davies, J.R., Eriksen, G.V., et al.: MUC5B is a major gel-forming, oligomeric mucin from human salivary gland, respiratory tract and endocervix: identification of glycoforms and C-terminal cleavage. Biochem. J. 334(Pt 3), 685–693 (1998)Google Scholar
  40. 40.
    Bansil, R., Turner, B.S.: Mucin structure, aggregation, physiological functions and biomedical applications. Curr. Opin. Colloid Interface Sci. 11, 164–170 (2006)CrossRefGoogle Scholar
  41. 41.
    Perez-Vilar, J., Hill, R.L.: The structure and assembly of secreted mucins. J. Biol. Chem. 274, 31751–31754 (1999)CrossRefGoogle Scholar
  42. 42.
    Thornton, D.J., Sheehan, J.K.: From mucins to mucus. Proc. Am. Thorac. Soc. 1, 54–61 (2004)CrossRefGoogle Scholar
  43. 43.
    Turner, B.S., Bhaskar, K.R., Hadzopoulou-Cladaras, M., et al.: Cysteine-rich regions of pig gastric mucin contain von Willebrand factor and cystine knot domains at the carboxyl terminal1. The sequences described in this paper have been submitted to the GenBank Nucleotide Sequence Database, and have been assigned the Ge. Biochim. Biophys. Acta (BBA) Gene Struct. Expr. 1447, 77–92 (1999)Google Scholar
  44. 44.
    Boegh, M., Nielsen, H.M.R.: Mucus as a barrier to drug delivery—understanding and mimicking the barrier properties. Basic Clin. Pharmacol. Toxicol. 116, 179–186 (2015)CrossRefGoogle Scholar
  45. 45.
    Murgia, X., De Souza Carvalho, C., Lehr, C.-M.: Overcoming the pulmonary barrier: new insights to improve the efficiency of inhaled therapeutics. Eur. J. Nanomed. 6, 157–169 (2014)CrossRefGoogle Scholar
  46. 46.
    Murgia, X., Yasar, H., Carvalho-Wodarz, C., et al.: Modelling the bronchial barrier in pulmonary drug delivery: a human bronchial epithelial cell line supplemented with human tracheal mucus. Eur. J. Pharm. Biopharm. 118, 79–88 (2017)CrossRefGoogle Scholar
  47. 47.
    Rubin, B.K., Ramirez, O., Zayas, J.G., et al.: Collection and analysis of respiratory mucus from subjects without lung disease. Am. Rev. Respir. Dis. 141, 1040–1043 (1990)CrossRefGoogle Scholar
  48. 48.
    Balsamo, R., Lanata, L., Egan, C.G.: Mucoactive drugs. Eur. Respir. Rev. 19, 127–133 (2010)Google Scholar
  49. 49.
    Elborn, J.S.: Cystic fibrosis. The Lancet 388, 2519–2531 (2017)CrossRefGoogle Scholar
  50. 50.
    Ramos, F.L., Krahnke, J.S., Kim, V.: Clinical issues of mucus accumulation in COPD. Int. J. COPD 139–150 (2014)Google Scholar
  51. 51.
    Kreda, S.M., Davis, C.W., Rose, M.C.: CFTR, mucins, and mucus obstruction in cystic fibrosis. Cold Spring Harbor Perspect. Med. 2, a009589 (2012)CrossRefGoogle Scholar
  52. 52.
    Yuan, S., Hollinger, M., Lachowicz-Scroggins, M.E., et al.: Oxidation increases mucin polymer cross-links to stiffen airway mucus gels. Sci. Transl. Med. 7:276ra227–276ra227 (2015)Google Scholar
  53. 53.
    Perks, B., Shute, J.K.: DNA and actin bind and inhibit interleukin-8 function in cystic fibrosis sputa. Am. J. Respir. Crit. Care Med. 162, 1767–1772 (2000)CrossRefGoogle Scholar
  54. 54.
    Kirch, J., Schneider, A., Abou, B., et al.: Optical tweezers reveal relationship between microstructure and nanoparticle penetration of pulmonary mucus. Proc. Natl. Acad. Sci. U.S.A. 109, 18355–18360 (2012)CrossRefADSGoogle Scholar
  55. 55.
    Sanders, N.N., De Smedt, S.C., Van Rompaey, E., et al.: Cystic fibrosis sputum. Am. J. Respir. Crit. Care Med. 162, 1905–1911 (2000)Google Scholar
  56. 56.
    Schuster, B.S., Ensign, L.M., Allan, D.B., et al.: Particle tracking in drug and gene delivery research: state-of-the-art applications and methods. Adv. Drug Deliv. Rev. 91, 70–91 (2015)CrossRefGoogle Scholar
  57. 57.
    Kirch, J., Guenther, M., Doshi, N., et al.: Mucociliary clearance of micro- and nanoparticles is independent of size, shape and charge—an ex vivo and in silico approach. J. Control. Release 159, 128–134 (2012)CrossRefGoogle Scholar
  58. 58.
    Murgia, X., Pawelzyk, P., Schaefer, U.F., et al.: Size-limited penetration of nanoparticles into porcine respiratory mucus after aerosol deposition. Biomacromolecules 17, 1536–1542 (2016)CrossRefGoogle Scholar
  59. 59.
    Nordgård, C.T., Nonstad, U., Olderøy, M.Ø., et al.: Alterations in mucus barrier function and matrix structure induced by guluronate oligomers. Biomacromol 15, 2294–2300 (2014)CrossRefGoogle Scholar
  60. 60.
    Suk, J.S., Xu, Q., Kim, N., et al.: PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 99, 28–51 (2016)CrossRefGoogle Scholar
  61. 61.
    Bhattacharjee, S., Mahon, E., Harrison, S.M., et al.: Nanoparticle passage through porcine jejunal mucus: microfluidics and rheology. Nanomed. Nanotechnol. Biol. Med. 13, 863–873 (2017)CrossRefGoogle Scholar
  62. 62.
    Beisner, J., Dong, M., Taetz, S., et al.: Nanoparticle mediated delivery of 2′-O-methyl-RNA leads to efficient telomerase inhibition and telomere shortening in human lung cancer cells. Lung Cancer 68, 346–354 (2017)CrossRefGoogle Scholar
  63. 63.
    Kuzmov, A., Minko, T.: Nanotechnology approaches for inhalation treatment of lung diseases. J. Control. Release 219, 500–518 (2015)CrossRefGoogle Scholar
  64. 64.
    Mahiny, A.J., Dewerth, A., Mays, L.E., et al.: In vivo genome editing using nuclease-encoding mRNA corrects SP-B deficiency. Nat. Biotech. 33, 584–586 (2015)CrossRefGoogle Scholar
  65. 65.
    Duneclift, S., Wells, U., Widdicombe, J.: Estimation of thickness of airway? Surface liquid in ferret trachea in vitro estimation of thickness of airway surface liquid in ferret trachea in vitro. 761–767 (2012)Google Scholar
  66. 66.
    Widdicombe, J.H.: Regulation of the depth and composition of airway surface liquid. J. Anat. 201 (2002)Google Scholar
  67. 67.
    Yoneda, K.: Mucous blanket of rat bronchus. Am. Rev. Respir. Dis. 114, 837–842 (1976)Google Scholar
  68. 68.
    Abuchowski, A., Mccoy, J.R., Palczuk, N.C., et al.: Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J. Biol. Chem. 252, 3582–3586 (1977)Google Scholar
  69. 69.
    Huckaby, J.T., Lai, S.K.: PEGylation for enhancing nanoparticle diffusion in mucus. Adv. Drug Deliv. Rev. (2017)Google Scholar
  70. 70.
    Schneider, C.S., Xu, Q., Boylan, N.J., et al.: Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation. Sci. Adv. 3 (2017)Google Scholar
  71. 71.
    Shan, W., Zhu, X., Tao, W., et al.: Enhanced oral delivery of protein drugs using zwitterion-functionalized nanoparticles to overcome both the diffusion and absorption barriers. ACS Appl. Mater. Interfaces 8, 25444–25453 (2016)CrossRefGoogle Scholar
  72. 72.
    Vukosavljevic, B., Murgia, X., Schwarzkopf, K., et al.: Tracing molecular and structural changes upon mucolysis with N-acetyl cysteine in human airway mucus. Int. J. Pharm. 553, 373–376 (2017)CrossRefGoogle Scholar
  73. 73.
    Rubin, B.K.: Secretion properties, clearance, and therapy in airway disease. Transl. Respir. Med. 2, 6 (2014)CrossRefGoogle Scholar
  74. 74.
    Suk, J.S., Boylan, N.J., Trehan, K., et al.: N-acetylcysteine enhances cystic fibrosis sputum penetration and airway gene transfer by highly compacted DNA nanoparticles. Mol. Ther. 19, 1981–1989 (2011)CrossRefGoogle Scholar
  75. 75.
    Deacon, J., Abdelghany, S.M., Quinn, D.J., et al.: Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: formulation, characterisation and functionalisation with dornase alfa (DNase). J. Control. Release 198, 55–61 (2015)CrossRefGoogle Scholar
  76. 76.
    Dünnhaupt, S., Kammona, O., Waldner, C., et al.: Nano-carrier systems: strategies to overcome the mucus gel barrier. Eur. J. Pharm. Biopharm. 96, 447–453 (2015)CrossRefGoogle Scholar
  77. 77.
    Mathiowitz, E., Chickering III, D.E., Lehr, C.-M.: Bioadhesive drug delivery systems: fundamentals, novel approaches, and development. 696 (1999)Google Scholar
  78. 78.
    Bravo-Osuna, I., Vauthier, C., Farabollini, A., et al.: Mucoadhesion mechanism of chitosan and thiolated chitosan-poly(isobutyl cyanoacrylate) core-shell nanoparticles. Biomaterials 28, 2233–2243 (2007)CrossRefGoogle Scholar
  79. 79.
    Schipper, N.G.M., Vårum, K.M., Stenberg, P., et al.: Chitosans as absorption enhancers of poorly absorbable drugs. Eur. J. Pharm. Sci. 8, 335–343 (1999)CrossRefADSGoogle Scholar
  80. 80.
    Iqbal, J., Shahnaz, G., Dünnhaupt, S., et al.: Preactivated thiomers as mucoadhesive polymers for drug delivery. Biomaterials 33, 1528–1535 (2012)CrossRefGoogle Scholar
  81. 81.
    Cui, F., Qian, F., Yin, C.: Preparation and characterization of mucoadhesive polymer-coated nanoparticles. Int. J. Pharm. 316, 154–161 (2006)CrossRefGoogle Scholar
  82. 82.
    Cooper, J.L., Quinton, P.M., Ballard, S.T.: Mucociliary transport in porcine trachea: differential effects of inhibiting chloride and bicarbonate secretion. Am. J. Physiol. Lung Cell. Mol. Physiol. 304, L184–L190 (2013)CrossRefGoogle Scholar
  83. 83.
    Foster, W.M., Langenback, E., Bergofsky, E.H.: Measurement of tracheal and bronchial mucus velocities in man: relation to lung clearance. J. Appl. Physiol. 48, 965–971 (1980)Google Scholar
  84. 84.
    Friedman, M., Dougherty, R., Nelson, S.R., et al.: Acute effects of an aerosol hair spray on tracheal mucociliary transport. Am. Rev. Respir. Dis. 116, 281–286 (1977)Google Scholar
  85. 85.
    Henning, A., Schneider, M., Bur, M., et al.: Embryonic chicken trachea as a new in vitro model for the investigation of mucociliary particle clearance in the airways. AAPS PharmSciTech 9, 521–527 (2008)CrossRefGoogle Scholar
  86. 86.
    Hoegger, M.J., Awadalla, M., Namati, E., et al.: Assessing mucociliary transport of single particles in vivo shows variable speed and preference for the ventral trachea in newborn pigs. Proc. Natl. Acad. Sci. U.S.A. 111, 2355–2360 (2014)CrossRefADSGoogle Scholar
  87. 87.
    Veldhuizen, R., Nag, K., Orgeig, S., et al.: The role of lipids in pulmonary surfactant. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 1408, 90–108 (1998)Google Scholar
  88. 88.
    Avery, M.E., Said, S.: Surface phenomena in lungs in health and disease. Medicine 44, 503–526 (1965)CrossRefGoogle Scholar
  89. 89.
    Papaioannou, A.I., Papiris, S., Papadaki, G., et al.: Surfactant proteins in smoking-related lung disease. Bentham Sci. 1574–1581 (2016)Google Scholar
  90. 90.
    Bernhard, W.: Lung surfactant: function and composition in the context of development and respiratory physiology. Ann. Anat. 208, 146–150 (2016)CrossRefGoogle Scholar
  91. 91.
    Serrano, A.G., Pérez-Gil, J.: Protein-lipid interactions and surface activity in the pulmonary surfactant system. Chem. Phys. Lipid. 141, 105–118 (2006)CrossRefGoogle Scholar
  92. 92.
    Baoukina, S., Tieleman, D.P.: Computer simulations of lung surfactant. Biochim. Biophys. Acta Biomembr. 1858, 2431–2440 (2016)CrossRefGoogle Scholar
  93. 93.
    Pérez-Gil, J.: Structure of pulmonary surfactant membranes and films: the role of proteins and lipid-protein interactions. Biochim. Biophys. Acta Biomembr. 1778, 1676–1695 (2008)CrossRefGoogle Scholar
  94. 94.
    Nathan, N., Taytard, J., Duquesnoy, P., et al.: Surfactant protein A: a key player in lung homeostasis. Int. J. Biochem. Cell Biol. 81, 151–155 (2016)CrossRefGoogle Scholar
  95. 95.
    Lopez-Rodriguez, E., Gay-Jordi, G., Mucci, A., et al.: Lung surfactant metabolism: early in life, early in disease and target in cell therapy. Cell Tissue Res. 367, 721–735 (2017)CrossRefGoogle Scholar
  96. 96.
    Brandsma, J., Postle, A.D.: Analysis of the regulation of surfactant phosphatidylcholine metabolism using stable isotopes. Ann. Anat. Anatomischer Anz. 211, 176–183 (2017)CrossRefGoogle Scholar
  97. 97.
    Khan, A., Agarwal, R.: Pulmonary alveolar proteinosis. Respir. Care 56, 1016–1028 (2011)CrossRefGoogle Scholar
  98. 98.
    Räsch, S.S.: The nanoparticle corona in the deep lung: pulmonary surfactant adsorption and its role in nano-bio interactions (2016)Google Scholar
  99. 99.
    Amigoni, A., Pettenazzo, A., Stritoni, V., et al.: Surfactants in acute respiratory distress syndrome in infants and children: past, present and future. Clin. Drug Investig. 37, 1–8 (2017)CrossRefGoogle Scholar
  100. 100.
    Griese, M.: Pulmonary alveolar proteinosis: a comprehensive clinical perspective. Pediatrics 140, e20170610 (2017)CrossRefGoogle Scholar
  101. 101.
    Carey, B., Trapnell, B.C.: The molecular basis of pulmonary alveolar proteinosis. Clin. Immunol. 135, 223–235 (2011)CrossRefGoogle Scholar
  102. 102.
    Ijaz, M.K., Zargar, B., Wright, K.E., et al.: Generic aspects of the airborne spread of human pathogens indoors and emerging air decontamination technologies. Am. J. Infect. Control 44, S109–S120 (2016)CrossRefGoogle Scholar
  103. 103.
    Hidalgo, A., Cruz, A., Pérez-Gil, J.: Pulmonary surfactant and nanocarriers: toxicity versus combined nanomedical applications. Biochim. Biophys. Acta Biomembr. 1859, 1740–1748 (2017)CrossRefGoogle Scholar
  104. 104.
    Raesch, S.S., Tenzer, S., Storck, W., et al.: Proteomic and lipidomic analysis of nanoparticle corona upon contact with lung surfactant reveals differences in protein, but not lipid composition. ACS Nano 9, 11872–11885 (2015)CrossRefGoogle Scholar
  105. 105.
    Kapralov, A.A., Feng, W.H., Amoscato, A.A., et al.: Adsorption of surfactant lipids by single-walled carbon nanotubes in mouse lung upon pharyngeal aspiration. ACS Nano 6, 4147–4156 (2012)CrossRefGoogle Scholar
  106. 106.
    Ruge, C.A., Schaefer, U.F., Herrmann, J., et al.: The interplay of lung surfactant proteins and lipids assimilates the macrophage clearance of nanoparticles. PLoS ONE 7, e40775 (2012)CrossRefADSGoogle Scholar
  107. 107.
    Vennemann, A., Alessandrini, F., Wiemann, M.: Differential effects of surface-functionalized zirconium oxide nanoparticles on alveolar macrophages, rat lung, and a mouse allergy model. Nanomaterials 7, 280 (2017)CrossRefGoogle Scholar
  108. 108.
    Moliva, J.I., Rajaram, M.V.S., Sidiki, S., et al.: Molecular composition of the alveolar lining fluid in the aging lung. Age (Dordrecht, Netherlands) 36, 9633 (2014)CrossRefGoogle Scholar
  109. 109.
    Ujma, S., Horsnell, W.G.C., Katz, A.A., et al.: Non-pulmonary immune functions of surfactant proteins A and D. J. Innate Immun. 9, 3–11 (2017)CrossRefGoogle Scholar
  110. 110.
    Han, S.H., Mallampalli, R.K.: The role of surfactant in lung disease and host defense against pulmonary infections. Ann. Am. Thorac. Soc. 12, 765–774 (2015)CrossRefGoogle Scholar
  111. 111.
    Nayak, A., Dodagatta-Marri, E., Tsolaki, A.G., et al.: An insight into the diverse roles of surfactant proteins, SP-A and SP-D in innate and adaptive immunity. Front. Immunol. 3, 1–21 (2012)CrossRefGoogle Scholar
  112. 112.
    Stein, S.W., Thiel, C.G.: The history of therapeutic aerosols: a chronological review. J. Aerosol. Med. Pulm. Drug. Deliv. 30, 20–41 (2017)CrossRefGoogle Scholar
  113. 113.
    Dalby, R.N., Eicher, J., Zierenberg, B.: Development of Respimat((R)) Soft Mist Inhaler and its clinical utility in respiratory disorders. Med. Devices (Auckland, N.Z.) 4, 145–155 (2011)Google Scholar
  114. 114.
    Edwards, D.A., Hanes, J., Caponetti, G., et al.: Large porous particles for pulmonary drug delivery. Science (New York, N.Y.) 276, 1868–1871 (1997)Google Scholar
  115. 115.
    Muralidharan, P., Malapit, M., Mallory, E., et al.: Inhalable nanoparticulate powders for respiratory delivery. Nanomed. Nanotechnol. Biol. Med. 11, 1189–1199 (2015)CrossRefGoogle Scholar
  116. 116.
    May, S., Jensen, B., Wolkenhauer, M., et al.: Dissolution techniques for in vitro testing of dry powders for inhalation. Pharm. Res. 29, 2157–2166 (2012)CrossRefGoogle Scholar
  117. 117.
    Forbes, B., Bäckman, P., Christopher, D., et al.: In vitro testing of orally inhaled products: development of science-based regulatory approaches. AAPSJ 17 (2015)Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Nicole Schneider-Daum
    • 1
    Email author
  • Marius Hittinger
    • 1
    • 2
  • Xabier Murgia
    • 1
  • Claus-Michael Lehr
    • 1
    • 2
  1. 1.Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)SaarbrückenGermany
  2. 2.PharmBioTec GmbHSaarbrückenGermany

Personalised recommendations