Skip to main content
SpringerLink
Log in
Book cover

Controlled Pulmonary Drug Delivery pp 417–442Cite as

In Vitro Cell Culture Models for Evaluating Controlled Release Pulmonary Drug Delivery

  • Chapter
  • First Online:

Part of the book series: Advances in Delivery Science and Technology ((ADST))

Abstract

A variety of cell culture systems for modeling the pulmonary system have been developed. They offer the potential to study various cell biology-related questions in the lung field. In this chapter primary cell cultures, continuous disease models, and coculture models are discussed. The use of these models in biopharmaceutical research is then reviewed along with discussion on drug permeability, transporters, aerosol deposition studies, and in vitro–in vivo correlation studies. Notwithstanding the difficulties and challenges surrounding various aspects of in vitro respiratory epithelial models, mechanistic studies of pulmonary drug delivery using various tracheobronchial and alveolar mucosae are expected to provide us with a wealth of information in the coming years that will lead to newer and more efficient methods to treat lung-specific diseases using controlled and targeted approaches.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Oreffo VI, Morgan A, Richards RJ (1990) Isolation of Clara cells from the mouse lung. Environ Health Perspect 85:51–64

    PubMed  CAS  Google Scholar 

  2. Kaufman DG (1976) Biochemical studies of isolated hamster tracheal epithelium. Environ Health Perspect 16:99–110

    PubMed  CAS  Google Scholar 

  3. Robison TW, Dorio RJ, Kim KJ (1993) Formation of tight monolayers of guinea pig airway epithelial cells cultured in an air-interface: bioelectric properties. Biotechniques 15(3):468–473

    PubMed  CAS  Google Scholar 

  4. Suda T, Sato A, Sugiura W, Chida K (1995) Induction of MHC class II antigens on rat bronchial epithelial cells by interferon-gamma and its effect on antigen presentation. Lung 173(2):127–137

    PubMed  CAS  Google Scholar 

  5. Chung Y, Kercsmar CM, Davis PB (1991) Ferret tracheal epithelial cells grown in vitro are resistant to lethal injury by activated neutrophils. Am J Respir Cell Mol Biol 5(2):125–132

    PubMed  CAS  Google Scholar 

  6. Liedtke CM (1988) Differentiated properties of rabbit tracheal epithelial cells in primary culture. Am J Physiol 255(6 pt 1):C760–C770

    PubMed  CAS  Google Scholar 

  7. Mathias NR, Kim KJ, Robison TW, Lee VH (1995) Development and characterization of rabbit tracheal epithelial cell monolayer models for drug transport studies. Pharm Res 12(10):1499–1505

    PubMed  CAS  Google Scholar 

  8. Welsh MJ (1985) Ion transport by primary cultures of canine tracheal epithelium: methodology, morphology, and electrophysiology. J Membr Biol 88(2):149–163

    PubMed  CAS  Google Scholar 

  9. Black PN, Ghatei MA, Takahashi K, Bretherton-Watt D, Krausz T, Dollery CT, Bloom SR (1989) Formation of endothelin by cultured airway epithelial cells. FEBS Lett 255(1):129–132

    PubMed  CAS  Google Scholar 

  10. Sisson JH, Tuma DJ, Rennard SI (1991) Acetaldehyde-mediated cilia dysfunction in bovine bronchial epithelial cells. Am J Physiol 260(2 pt 1):L29–L36

    PubMed  CAS  Google Scholar 

  11. Sime A, McKellar Q, Nolan A (1997) Method for the growth of equine airway epithelial cells in culture. Res Vet Sci 62(1):30–33

    PubMed  CAS  Google Scholar 

  12. Masui T, Wakefield LM, Lechner JF, LaVeck MA, Sporn MB, Harris CC (1986) Type beta transforming growth factor is the primary differentiation-inducing serum factor for normal human bronchial epithelial cells. Proc Natl Acad Sci USA 83(8):2438–2442

    PubMed  CAS  Google Scholar 

  13. de Jong PM, van Sterkenburg MA, Kempenaar JA, Dijkman JH, Ponec M (1993) Serial culturing of human bronchial epithelial cells derived from biopsies. In Vitro Cell Dev Biol Anim 29A(5):379–387

    PubMed  Google Scholar 

  14. Galietta LJ, Lantero S, Gazzolo A, Sacco O, Romano L, Rossi GA, Zegarra-Moran O (1998) An improved method to obtain highly differentiated monolayers of human bronchial epithelial cells. In Vitro Cell Dev Biol Anim 34(6):478–481

    PubMed  CAS  Google Scholar 

  15. Zabner J, Karp P, Seiler M, Phillips SL, Mitchell CJ, Saavedra M, Welsh M, Klingelhutz AJ (2003) Development of cystic fibrosis and noncystic fibrosis airway cell lines. Am J Physiol 284(5):L844–L854

    CAS  Google Scholar 

  16. Chemuturi NV, Hayden P, Klausner M, Donovan MD (2005) Comparison of human tracheal/bronchial epithelial cell culture and bovine nasal respiratory explants for nasal drug transport studies. J Pharm Sci 94(9):1976–1985

    PubMed  CAS  Google Scholar 

  17. Forbes B, Ehrhardt C (2005) Human respiratory epithelial cell culture for drug delivery applications. Eur J Pharm Biopharm 60(2):193–205

    PubMed  CAS  Google Scholar 

  18. Demling N, Ehrhardt C, Kasper M, Laue M, Knels L, Rieber EP (2006) Promotion of cell adherence and spreading: a novel function of RAGE, the highly selective differentiation marker of human alveolar epithelial type I cells. Cell Tissue Res 323(3):475–488

    PubMed  CAS  Google Scholar 

  19. Fuchs S, Hollins AJ, Laue M, Schaefer UF, Roemer K, Gumbleton M, Lehr CM (2003) Differentiation of human alveolar epithelial cells in primary culture – morphological characterisation and expression of caveolin-1 and surfactant protein-C. Cell Tissue Res 311:31–45

    PubMed  Google Scholar 

  20. Danto SI, Shannon JM, Borok Z, Zabski SM, Crandall ED (1995) Reversible transdifferentiation of alveolar epithelial cells. Am J Respir Cell Mol Biol 12(5):497–502

    PubMed  CAS  Google Scholar 

  21. Borok Z, Liebler JM, Lubman RL, Foster MJ, Zhou B, Li X, Zabski SM, Kim KJ, Crandall ED (2002) Na transport proteins are expressed by rat alveolar epithelial type I cells. Am J Physiol 282(4):L599–L608

    CAS  Google Scholar 

  22. Johnson MD, Widdicombe JH, Allen L, Barbry P, Dobbs LG (2002) Alveolar epithelial type I cells contain transport proteins and transport sodium, supporting an active role for type I cells in regulation of lung liquid homeostasis. Proc Natl Acad Sci USA 99(4):1966–1971

    PubMed  CAS  Google Scholar 

  23. Chen J, Chen Z, Narasaraju T, Jin N, Liu L (2004) Isolation of highly pure alveolar epithelial type I and type II cells from rat lungs. Lab Invest 84(6):727–735 [Erratum in: Lab Invest 85(9):1181 (2005)]

    Google Scholar 

  24. Corti M, Brody AR, Harrison JH (1996) Isolation and primary culture of murine alveolar type II cells. Am J Respir Cell Mol Biol 14:309–315

    PubMed  CAS  Google Scholar 

  25. Goodman BE, Crandall ED (1982) Dome formation in primary cultured monolayers of alveolar epithelial cells. Am J Physiol 243:C96–C100

    PubMed  CAS  Google Scholar 

  26. Shen J, Elbert KJ, Yamashita F, Lehr CM, Kim KJ, Lee VH (1999) Organic cation transport in rabbit alveolar epithelial cell monolayers. Pharm Res 16(8):1280–1287

    PubMed  CAS  Google Scholar 

  27. Steimer A, Franke H, Haltner-Ukomado E, Laue M, Ehrhardt C, Lehr CM (2007) Monolayers of porcine alveolar epithelial cells in primary culture as an in vitro model for drug absorption studies. Eur J Pharm Biopharm 66(3):372–382

    PubMed  CAS  Google Scholar 

  28. King LS, Agre P (2001) Man is not a rodent: aquaporins in the airways. Am J Respir Cell Mol Biol 24(3):221–223

    PubMed  CAS  Google Scholar 

  29. Wang J, Edeen K, Manzer R, Chang Y, Wang S, Chen X, Funk CJ, Cosgrove GP, Fang X, Mason RJ (2007) Differentiated human alveolar epithelial cells and reversibility of their phenotype in vitro. Am J Respir Cell Mol Biol 36(6):661–668

    PubMed  CAS  Google Scholar 

  30. Bingle L, Bull TB, Fox B, Guz A, Richards RJ, Tetley TD (1990) Type II pneumocytes in mixed cell culture of human lung: a light and electron microscopic study. Environ Health Perspect 85:71–80

    PubMed  CAS  Google Scholar 

  31. Ehrhardt C, Kim KJ, Lehr CM (2005) Isolation and culture of human alveolar epithelial cells. Methods Mol Med 107:207–216

    PubMed  CAS  Google Scholar 

  32. Gruenert DC, Finkbeiner WE, Widdicombe JH (1995) Culture and transformation of human airway epithelial cells. Am J Physiol 268(3 pt 1):L347–L360

    PubMed  CAS  Google Scholar 

  33. Ehrhardt C, Kneuer C, Fiegel J, Hanes J, Schaefer UF, Kim KJ, Lehr CM (2002) Influence of apical fluid volume on the development of functional intercellular junctions in the human epithelial cell line 16HBE14o−: implications for the use of this cell line as an in vitro model for bronchial drug absorption studies. Cell Tissue Res 308(3):391–400

    PubMed  CAS  Google Scholar 

  34. Forbes B (2000) Human airway epithelial cell lines for in vitro drug transport and metabolism studies. Pharm Sci Technol Today 3(1):18–27

    PubMed  CAS  Google Scholar 

  35. Sakagami M (2006) In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery. Adv Drug Deliv Rev 58(9–10):1030–1060

    PubMed  CAS  Google Scholar 

  36. Fogh J, Trempe G (1975) New human tumor cell lines. In: Fogh J (ed) Human tumor cells in vitro. Plenum, New York, pp 115–159

    Google Scholar 

  37. Shen BQ, Finkbeiner WE, Wine JJ, Mrsny RJ, Widdicombe JH (1994) Calu-3: a human airway epithelial cell line that shows cAMP-dependent Cl- secretion. Am J Physiol 266(5 pt 1):L493–L501

    PubMed  CAS  Google Scholar 

  38. Foster KA, Avery ML, Yazdanian M, Audus KL (2000) Characterization of the Calu-3 cell line as a tool to screen pulmonary drug delivery. Int J Pharm 208(1–2):1–11

    PubMed  CAS  Google Scholar 

  39. Mathia NR, Timoszyk J, Stetsko PI, Megill JR, Smith RL, Wall DA (2002) Permeability characteristics of calu-3 human bronchial epithelial cells: in vitro-in vivo correlation to predict lung absorption in rats. J Drug Target 10(1):31–40

    PubMed  Google Scholar 

  40. Grainger CI, Greenwell LL, Lockley DJ, Martin GP, Forbes B (2006) Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier. Pharm Res 23(7):1482–1490

    PubMed  CAS  Google Scholar 

  41. Florea BI, Cassara ML, Junginger HE, Borchard G (2003) Drug transport and metabolism characteristics of the human airway epithelial cell line Calu-3. J Control Release 87(1–3):131–138

    PubMed  CAS  Google Scholar 

  42. Fiegel J, Ehrhardt C, Schaefer UF, Lehr CM, Hanes J (2003) Large porous particle impingement on lung epithelial cell monolayers–toward improved particle characterization in the lung. Pharm Res 20(5):788–796

    PubMed  CAS  Google Scholar 

  43. Cooney D, Kazantseva M, Hickey AJ (2004) Development of a size-dependent aerosol deposition model utilising human airway epithelial cells for evaluating aerosol drug delivery. Altern Lab Anim 32(6):581–590

    PubMed  CAS  Google Scholar 

  44. Amidi M, Romeijn SG, Borchard G, Junginger HE, Hennink WE, Jiskoot W (2006) Preparation and characterization of protein-loaded N-trimethyl chitosan nanoparticles as nasal delivery system. J Control Release 111(1–2):107–116

    PubMed  CAS  Google Scholar 

  45. Cozens AL, Yezzi MJ, Kunzelmann K, Ohrui T, Chin L, Eng K, Finkbeiner KE, Widdicombe JH, Gruenert DC (1994) CFTR expression and chloride secretion in polarized immortal human bronchial epithelial cells. Am J Respir Cell Mol Biol 10(1):38–47

    PubMed  CAS  Google Scholar 

  46. Ehrhardt C, Kneuer C, Laue M, Schaefer UF, Kim KJ, Lehr CM (2003) 16HBE14o− human bronchial epithelial cell layers express P-glycoprotein, lung resistance-related protein, and caveolin-1. Pharm Res 20(4):545–551

    PubMed  CAS  Google Scholar 

  47. Forbes B, Lim S, Martin GP, Brown MB (2002) An in vitro technique for evaluating inhaled nasal delivery systems. STP Pharma Sci 12:75–79

    CAS  Google Scholar 

  48. Manford F, Tronde A, Jeppsson AB, Patel N, Johansson F, Forbes B (2005) Drug permeability in 16HBE14o− airway cell layers correlates with absorption from the isolated perfused rat lung. Eur J Pharm Sci 26(5):414–420

    PubMed  CAS  Google Scholar 

  49. Kudsiova L, Lawrence MJ (2008) A comparison of the effect of chitosan and chitosan-coated vesicles on monolayer integrity and permeability across Caco-2 and 16HBE14o− cells. J Pharm Sci 97(9):3998–4010

    PubMed  CAS  Google Scholar 

  50. Reddel RR, Ke Y, Gerwin BI, McMenamin MG, Lechner JF, Su RT, Brash DE, Park JB, Rhim JS, Harris CC (1988) Transformation of human bronchial epithelial cells by infection with SV40 or adenovirus-12 SV40 hybrid virus, or transfection via strontium phosphate coprecipitation with a plasmid containing SV40 early region genes. Cancer Res 48(7):1904–1909

    PubMed  CAS  Google Scholar 

  51. Atsuta J, Sterbinsky SA, Plitt J, Schwiebert LM, Bochner BS, Schleimer RP (1997) Phenotyping and cytokine regulation of the BEAS-2B human bronchial epithelial cell: demonstration of inducible expression of the adhesion molecules VCAM-1 and ICAM-1. Am J Respir Cell Mol Biol 17(5):571–582

    PubMed  CAS  Google Scholar 

  52. Sun W, Wu R, Last JA (1995) Effects of exposure to environmental tobacco smoke on a human tracheobronchial epithelial cell line. Toxicology 100(1–3):163–174

    PubMed  CAS  Google Scholar 

  53. Steerenberg PA, Zonnenberg JA, Dormans JA, Joon PN, Wouters IM, van Bree L, Scheepers PT, Van Loveren H (1998) Diesel exhaust particles induced release of interleukin 6 and 8 by (primed) human bronchial epithelial cells (BEAS 2B) in vitro. Exp Lung Res 24(1):85–100

    PubMed  CAS  Google Scholar 

  54. Veranth JM, Kaser EG, Veranth MM, Koch M, Yost GS (2007) ytokine responses of human lung cells (BEAS-2B) treated with micron-sized and nanoparticles of metal oxides compared to soil dusts. Part Fibre Toxicol 4(1):2

    PubMed  Google Scholar 

  55. Odoms K, Shanley TP, Wong HR (2004) Short-term modulation of interleukin-1beta signaling by hyperoxia: uncoupling of IkappaB kinase activation and NF-kappaB-dependent gene expression. Am J Physiol 286(3):L554–L562

    CAS  Google Scholar 

  56. Noah TL, Yankaskas JR, Carson JL, Gambling TM, Cazares LH, McKinnon KP, Devlin RB (1995) Tight junctions and mucin mRNA in BEAS-2B cells. In Vitro Cell Dev Biol Anim 31(10):738–740

    PubMed  CAS  Google Scholar 

  57. Eaton EA, Walle UK, Wilson HM, Aberg G, Walle T (1996) Stereoselective sulphate conjugation of salbutamol by human lung and bronchial epithelial cells. Br J Clin Pharmacol 41(3):201–206

    PubMed  CAS  Google Scholar 

  58. Proud D, Subauste MC, Ward PE (1994) Glucocorticoids do not alter peptidase expression on a human bronchial epithelial cell line. Am J Respir Cell Mol Biol 11(1):57–65

    PubMed  CAS  Google Scholar 

  59. Lieber M, Smith B, Szakal A, Nelson-Rees W, Todaro G (1976) A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int J Cancer 17(1):62–70

    PubMed  CAS  Google Scholar 

  60. Kim KJ, Borok Z, Crandall ED (2001) A useful in vitro model for transport studies of alveolar epithelial barrier. Pharm Res 18:253–255

    PubMed  CAS  Google Scholar 

  61. Forbes B, Ehrhardt C (2005) Human respiratory epithelial cell culture for drug delivery applications. Eur J Pharm Biopharm 60(2):193–205

    PubMed  CAS  Google Scholar 

  62. Foster KA, Oster CG, Mayer MM, Avery ML, Audus KL (1998) Characterization of the A549 cell line as a type II pulmonary epithelial cell model for drug metabolism. Exp Cell Res 243(2):359–366

    PubMed  CAS  Google Scholar 

  63. Elbert KJ, Schäfer UF, Schäfers HJ, Kim KJ, Lee VHL, Lehr CM (1999) Monolayers of human alveolar epithelial cells in primary culture for pulmonary absorption and transport studies. Pharm Res 16(5):601–608

    PubMed  CAS  Google Scholar 

  64. Kobayashi S, Kondo S, Juni K (1995) Permeability of peptides and proteins in human cultured alveolar A549 cell monolayer. Pharm Res 12(8):1115–1119

    PubMed  CAS  Google Scholar 

  65. Wang Z, Zhang Q (2004) Transport of proteins and peptides across human cultured alveolar A549 cell monolayer. Int J Pharm 269(2):451–456

    PubMed  CAS  Google Scholar 

  66. Forbes B, Wilson CG, Gumbleton M (1999) Temporal dependence of ectopeptidase expression in alveolar epithelial cell culture: implications for study of peptide absorption. Int J Pharm 180(2):225–234

    PubMed  CAS  Google Scholar 

  67. Anabousi S, Bakowsky U, Schneider M, Huwer H, Lehr CM, Ehrhardt C (2006) In vitro assessment of transferrin-conjugated liposomes as drug delivery systems for inhalation therapy of lung cancer. Eur J Pharm Sci 29(5):367–374

    PubMed  CAS  Google Scholar 

  68. Duncan JE, Whitsett JA, Horowitz AD (1997) Pulmonary surfactant inhibits cationic liposome-mediated gene delivery to respiratory epithelial cells in vitro. Hum Gene Ther 8(4):431–438

    PubMed  CAS  Google Scholar 

  69. Rehan VK, Torday JS, Peleg S, Gennaro L, Vouros P, Padbury J, Rao DS, Reddy GS (2002) 1Alpha,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of 1alpha,25-dihydroxy vitamin D3: production and biological activity studies in pulmonary alveolar type II cells. Mol Genet Metab 76(1):46–56

    PubMed  CAS  Google Scholar 

  70. Newton DA, Rao KM, Dluhy RA, Baatz JE (2006) Hemoglobin is expressed by alveolar epithelial cells. J Biol Chem 281(9):5668–5676

    PubMed  CAS  Google Scholar 

  71. Zhang L, Whitsett JA, Stripp BR (1997) Regulation of Clara cell secretory protein gene transcription by thyroid transcription factor-1. Biochim Biophys Acta 1350(3):359–367

    PubMed  CAS  Google Scholar 

  72. Shlyonsky V, Goolaerts A, Van Beneden R, Sariban-Sohraby S (2005) Differentiation of epithelial Na+ channel function. An in vitro model. J Biol Chem 280(25):24181–24187

    PubMed  CAS  Google Scholar 

  73. Woollhead AM, Baines DL (2006) Forskolin-induced cell shrinkage and apical translocation of functional enhanced green fluorescent protein-human alphaENaC in H441 lung epithelial cell monolayers. J Biol Chem 281(8):5158–5168

    PubMed  CAS  Google Scholar 

  74. Wikenheiser KA, Vorbroker DK, Rice WR, Clark JC, Bachurski CJ, Oie HK, Whitsett JA (1993) Production of immortalized distal respiratory epithelial cell lines from surfactant protein C/simian virus 40 large tumor antigen transgenic mice. Proc Natl Acad Sci USA 90(23):11029–11033

    PubMed  CAS  Google Scholar 

  75. Grek CL, Newton DA, Qiu Y, Wen X, Spyropoulos DD, Baatz JE (2009) Characterization of alveolar epithelial cells cultured in semipermeable hollow fibers. Exp Lung Res 35(2):155–174

    PubMed  CAS  Google Scholar 

  76. Douglas WH, Kaighn ME (1974) Clonal isolation of differentiated rat lung cells. In Vitro 10(3–4):230–237

    PubMed  CAS  Google Scholar 

  77. Helms MN, Chen XJ, Ramosevac S, Eaton DC, Jain L (2006) Dopamine regulation of amiloride-sensitive sodium channels in lung cells. Am J Physiol Lung Cell Mol Physiol 290(4):L710–L722

    PubMed  CAS  Google Scholar 

  78. Koslowski R, Barth K, Augstein A, Tschernig T, Bargsten G, Aufderheide M, Kasper M (2004) A new rat type I-like alveolar epithelial cell line R3/1: bleomycin effects on caveolin expression. Histochem Cell Biol 121(6):509–519

    PubMed  CAS  Google Scholar 

  79. Horalkova L, Radziwon A, Endter S, Andersen R, Koslowski RMW, Dolezal P, Ehrhardt C (2009) Characterisation of the R3/1 cell line as an alveolar epithelial cell model for drug disposition studies. Eur J Pharm Sci 36(4–5):444–450

    PubMed  CAS  Google Scholar 

  80. Kemp SJ, Thorley AJ, Gorelik J, Seckl MJ, O’Hare MJ, Arcaro A, Korchev Y, Goldstraw P, Tetley TD (2008) Immortalization of human alveolar epithelial cells to investigate nanoparticle uptake. Am J Respir Cell Mol Biol 39(5):591–597

    PubMed  CAS  Google Scholar 

  81. van den Bogaard EH, Dailey LA, Thorley AJ, Tetley TD, Forbes B (2009) Inflammatory response and barrier properties of a new alveolar type 1-like cell line (TT1). Pharm Res 26(5):1172–1180

    PubMed  Google Scholar 

  82. Laube BL (2005) The expanding role of aerosols in systemic drug delivery, gene therapy, and vaccination. Respir Care 50(9):1161–1176

    PubMed  Google Scholar 

  83. Boucher RC (2004) New concepts of the pathogenesis of cystic fibrosis lung. Eur Respir J 23(1):146–158

    PubMed  CAS  Google Scholar 

  84. Stutts MJ, Cotton CU, Yankaskas JR, Cheng E, Knowles MR, Gatzy JT, Boucher RC (1985) Chloride uptake into cultured airway epithelial cells from cystic fibrosis patients and normal individuals. Proc Natl Acad Sci USA 82(19):6677–6681

    PubMed  CAS  Google Scholar 

  85. Gruenert DC, Basbaum CB, Widdicombe JH (1990) Long-term culture of normal and cystic fibrosis epithelial cells grown under serum-free conditions. In Vitro Cell Dev Biol 26(4):411–418

    PubMed  CAS  Google Scholar 

  86. Gruenert DC, Willems M, Cassiman JJ, Frizzell RA (2004) Established cell lines used in cystic fibrosis research. J Cyst Fibros 3(suppl 2):191–196

    PubMed  CAS  Google Scholar 

  87. Scholte BJ, Kansen M, Hoogeveen AT, Willemse R, Rhim JS, van der Kamp AW, Bijman J (1989) Immortalization of nasal polyp epithelial cells from cystic fibrosis patients. Exp Cell Res 182(2):559–571

    PubMed  CAS  Google Scholar 

  88. Olsen JC, Johnson LG, Stutts MJ, Sarkadi B, Yankaskas JR, Swanstrom R, Boucher RC (1992) Correction of the apical membrane chloride permeability defect in polarized cystic fibrosis airway epithelia following retroviral-mediated gene transfer. Hum Gene Ther 3(3):253–266

    PubMed  CAS  Google Scholar 

  89. Ehrhardt C, Collnot EM, Baldes C, Becker U, Laue M, Kim KJ, Lehr CM (2006) Towards an in vitro model of cystic fibrosis small airway epithelium: characterisation of the human bronchial epithelial cell line CFBE41o-. Cell Tissue Res 323(3):405–415

    PubMed  CAS  Google Scholar 

  90. Rothen-Rutishauser BM, Kiama SG, Gehr P (2005) A three-dimensional cellular model of the human respiratory tract to study the interaction with particles. Am J Respir Cell Mol Biol 32(4):281–289

    PubMed  CAS  Google Scholar 

  91. Rothen-Rutishauser B, Mühlfeld C, Blank F, Musso C, Gehr P (2007) Translocation of particles and inflammatory responses after exposure to fine particles and nanoparticles in an epithelial airway model. Part Fibre Toxicol 25:4–9

    Google Scholar 

  92. Pohl C, Hermanns MI, Uboldi C, Bock M, Fuchs S, Dei-Anang J, Mayer E, Kehe K, Kummer W, Kirkpatrick CJ (2009) Barrier functions and paracellular integrity in human cell culture models of the proximal respiratory unit. Eur J Pharm Biopharm 72(2):339–349

    PubMed  CAS  Google Scholar 

  93. Hermanns MI, Kasper J, Dubruel P, Pohl C, Uboldi C, Vermeersch V, Fuchs S, Unger RE, Kirkpatrick CJ (2010) An impaired alveolar-capillary barrier in vitro: effect of proinflammatory cytokines and consequences on nanocarrier interaction. J R Soc Interface 7(suppl 1):S41–S54

    PubMed  CAS  Google Scholar 

  94. Lehmann T, Kohler C, Weidauer E, Taege C, Foth H (2001) Expression of MRP1 and related transporters in human lung cells in culture. Toxicology 167(1):59–72

    PubMed  CAS  Google Scholar 

  95. Madlova M, Bosquillon C, Asker D, Dolezal P, Forbes B (2009) In-vitro respiratory drug absorption models possess nominal functional P-glycoprotein activity. J Pharm Pharmacol 61(3):293–301

    PubMed  CAS  Google Scholar 

  96. Lin H, Li H, Cho HJ, Bian S, Roh HJ, Lee MK, Kim JS, Chung SJ, Shim CK, Kim DD (2007) Air-liquid interface (ALI) culture of human bronchial epithelial cell monolayers as an in vitro model for airway drug transport studies. J Pharm Sci 96(2):341–350

    PubMed  CAS  Google Scholar 

  97. Endter S, Francombe D, Ehrhardt C, Gumbleton M (2009) RT-PCR analysis of ABC, SLC and SLCO drug transporters in human lung epithelial cell models. J Pharm Pharmacol 61(5):583–591

    PubMed  CAS  Google Scholar 

  98. Brillault J, De Castro WV, Harnois T, Kitzis A, Olivier JC, Couet W (2009) P-glycoprotein-mediated transport of moxifloxacin in a Calu-3 lung epithelial cell model. Antimicrob Agents Chemother 53(4):1457–1462

    PubMed  CAS  Google Scholar 

  99. Hamilton KO, Backstrom G, Yazdanian MA, Audus KL (2001) P-glycoprotein efflux pump expression and activity in Calu-3 cells. J Pharm Sci 90(5):647–658

    PubMed  CAS  Google Scholar 

  100. Patel J, Pal D, Vangal V, Gandhi M, Mitra AL (2002) Transport of HIV-protease inhibitors across 1 alpha,25di-hydroxy vitamin D3-treated Calu-3 cell monolayers: modulation of P-glycoprotein activity. Pharm Res 19(11):1696–1703

    PubMed  CAS  Google Scholar 

  101. Florea BI, van der Sandt IC, Schrier SM, Kooiman K, Deryckere K, de Boer AG, Junginger HE, Borchard G (2001) Evidence of P-glycoprotein mediated apical to basolateral transport of flunisolide in human broncho-tracheal epithelial cells (Calu-3). Br J Pharmacol 134(7):1555–1563

    PubMed  CAS  Google Scholar 

  102. Yen WC, Corpuz MR, Prudente RY, Cooke TA, Bissonnette RP, Negro-Vilar A, Lamph WW (2004) A selective retinoid X receptor agonist bexarotene (Targretin) prevents and overcomes acquired paclitaxel (Taxol) resistance in human non-small cell lung cancer. Clin Cancer Res 10(24):8656–8664

    PubMed  CAS  Google Scholar 

  103. Hamilton KO, Topp E, Makagiansar I, Siahaan T, Yazdanian M, Audus KL (2001) Multidrug resistance-associated protein-1 functional activity in Calu-3 cells. J Pharmacol Exp Ther 298(3):1199–1205

    PubMed  CAS  Google Scholar 

  104. van der Deen M, Timmer-Bosscha H, Timens W, Postma DS, de Vries EG (2004) Effect of cigarette smoke extract on MRP1 function in bronchial epithelial cells. Proc Am Assoc Cancer Res 45:A508

    Google Scholar 

  105. van der Deen M, de Vries EG, Visserman H, Zandbergen W, Postma DS, Timens W, Timmer-Bosscha H (2007) Cigarette smoke extract affects functional activity of MRP1 in bronchial epithelial cells. J Biochem Mol Toxicol 21(5):243–251

    PubMed  Google Scholar 

  106. Paturi DK, Kwatra D, Ananthula HK, Pal D, Mitra AK (2010) Identification and functional characterization of breast cancer resistance protein in human bronchial epithelial cells (Calu-3). Int J Pharm 384(1–2):32–38

    PubMed  CAS  Google Scholar 

  107. Campbell L, Abulrob AN, Kandalaft LE, Plummer S, Hollins AJ, Gibbs A, Gumbleton M (2003) Constitutive expression of p-glycoprotein in normal lung alveolar epithelium and functionality in primary alveolar epithelial cultures. J Pharmacol Exp Ther 304(1):441–452

    PubMed  CAS  Google Scholar 

  108. Endter S, Becker U, Daum N, Huwer H, Lehr CM, Gumbleton M, Ehrhardt C (2007) P-glycoprotein (MDR1) functional activity in human alveolar epithelial cell monolayers. Cell Tissue Res 328(1):77–84

    PubMed  CAS  Google Scholar 

  109. Agassandian M, Mathur SN, Zhou J, Field FJ, Mallampalli RK (2004) Oxysterols trigger ABCA1-mediated basolateral surfactant efflux. Am J Respir Cell Mol Biol 31(2):227–233

    PubMed  CAS  Google Scholar 

  110. Mulugeta S, Gray JM, Notarfrancesco KL, Gonzales LW, Koval M, Feinstein SI, Ballard PL, Fisher AB, Shuman H (2002) Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3. J Biol Chem 277(25):22147–22155

    PubMed  CAS  Google Scholar 

  111. Matsuzaki Y, Besnard V, Clark JC, Xu Y, Wert SE, Ikegami M, Whitsett JA (2008) STAT3 regulates ABCA3 expression and influences lamellar body formation in alveolar type II cells. Am J Respir Cell Mol Biol 38(5):551–558

    PubMed  CAS  Google Scholar 

  112. Mamchaoui K, Makhloufi Y, Saumon G (2002) Glucose transporter gene expression in freshly isolated and cultured rat pneumocytes. Acta Physiol Scand 175(1):19–24

    PubMed  CAS  Google Scholar 

  113. Kalsi KK, Baker EH, Medina RA, Rice S, Wood DM, Ratoff JC, Philips BJ, Baines DL (2008) Apical and basolateral localisation of GLUT2 transporters in human lung epithelial cells. Pflugers Arch 5:991–1003

    Google Scholar 

  114. Ehrhardt C, Kneuer C, Bies C, Lehr CM, Kim KJ, Bakowsky U (2005) Salbutamol is actively absorbed across human bronchial epithelial cell layers. Pulm Pharmacol Ther 18(3):165–170

    PubMed  CAS  Google Scholar 

  115. Horvath G, Schmid N, Fragoso MA, Schmid A, Conner GE, Salathe M, Wanner A (2007) Epithelial organic cation transporters ensure pH-dependent drug absorption in the airway. Am J Respir Cell Mol Biol 36(1):53–60

    PubMed  CAS  Google Scholar 

  116. Miakotina OL, Agassandian M, Shi L, Look DC, Mallampalli RK (2005) Adenovirus stimulates choline efflux by increasing expression of organic cation transporter-2. Am J Physiol 288(1):L93–L102

    CAS  Google Scholar 

  117. Wang T, Li J, Chen F, Zhao Y, He X, Wan D, Gu J (2007) Choline transporters in human lung adenocarcinoma: expression and functional implications. Acta Biochim Biophys Sin (Shanghai) 39(9):668–674

    CAS  Google Scholar 

  118. Ishiguro N, Oyabu M, Sato T, Maeda T, Minami H, Tamai I (2008) Decreased biosynthesis of lung surfactant constituent phosphatidylcholine due to inhibition of choline transporter by gefitinib in lung alveolar cells. Pharm Res 25(2):417–427

    PubMed  CAS  Google Scholar 

  119. Søndergaard HB, Brodin B, Nielsen CU (2008) hPEPT1 is responsible for uptake and transport of Gly-Sar in the human bronchial airway epithelial cell-line Calu-3. Pflugers Arch 456(3):611–622

    PubMed  Google Scholar 

  120. Rotoli BM, Bussolati O, Sala R, Gazzola GC, Dall’Asta V (2005) The transport of cationic amino acids in human airway cells: expression of system y+L activity and transepithelial delivery of NOS inhibitors. FASEB J 19(7):810–812

    PubMed  CAS  Google Scholar 

  121. Granillo OM, Brahmajothi MV, Li S, Whorton AR, Mason SN, McMahon TJ, Auten RL (2008) Pulmonary alveolar epithelial uptake of S-nitrosothiols is regulated by L-type amino acid transporter. Am J Physiol Lung Cell Mol Physiol 295(1):L38–L43

    PubMed  CAS  Google Scholar 

  122. Sloan JL, Grubb BR, Mager S (2003) Expression of the amino acid transporter ATB 0+ in lung: possible role in luminal protein removal. Am J Physiol 284(1):L39–L49

    CAS  Google Scholar 

  123. Uchiyama T, Fujita T, Gukasyan HJ, Kim KJ, Borok Z, Crandall ED, Lee VH (2008) Functional characterization and cloning of amino acid transporter B(0,+) (ATB(0,+)) in primary cultured rat pneumocytes. J Cell Physiol 214(3):645–654

    PubMed  CAS  Google Scholar 

  124. Jin SN, Mun GH, Lee JH, Oh CS, Kim J, Chung YH, Kang JS, Kim JG, Hwang DH, Hwang YI, Shin DH, Lee WJ (2005) Immunohistochemical study on the distribution of sodium-dependent vitamin C transporters in the respiratory system of adult rat. Microsc Res Tech 68(6):360–367

    PubMed  CAS  Google Scholar 

  125. Seki S, Kobayashi M, Itagaki S, Hirano T, Iseki K (2009) Contribution of organic anion transporting polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells. Biochim Biophys Acta 1788(5):911–917

    PubMed  CAS  Google Scholar 

  126. Izquierdo MA, Scheffer GL, Flens MJ, Giaccone G, Broxterman HJ, Meijer CJ, van der Valk P, Scheper RJ (1996) Broad distribution of the multidrug resistance-related vault lung resistance protein in normal human tissues and tumors. Am J Pathol 148(3):877–887

    PubMed  CAS  Google Scholar 

  127. Bouhamyia L, Chantot-Bastaraud S, Zaidi S, Roynard P, Prengel C, Bernaudin JF, Fleury-Feith J (2007) Immunolocalization and cell expression of lung resistance-related protein (LRP) in normal and tumoral human respiratory cells. J Histochem Cytochem 55(8):773–782

    PubMed  CAS  Google Scholar 

  128. Berger W, Elbling L, Micksche M (2000) Expression of the major vault protein LRP in human non-small-cell lung cancer cells: activation by short-term exposure to antineoplastic drugs. Int J Cancer 88(2):293–300

    PubMed  CAS  Google Scholar 

  129. Meschini S, Marra M, Calcabrini A, Monti E, Gariboldi M, Dolfini E, Arancia G (2002) Role of the lung resistance-related protein (LRP) in the drug sensitivity of cultured tumor cells. Toxicol In Vitro 16(4):389–398

    PubMed  CAS  Google Scholar 

  130. Lips KS, Volk C, Schmitt BM, Pfeil U, Arndt P, Miska D, Ermert L, Kummer W, Koepsell H (2005) Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am J Respir Cell Mol Biol 33(1):79–88

    PubMed  CAS  Google Scholar 

  131. Groneberg DA, Fischer A, Chung KF, Daniel H (2004) Molecular mechanisms of pulmonary peptidomimetic drug and peptide transport. Am J Respir Cell Mol Biol 30(3):251–260

    PubMed  CAS  Google Scholar 

  132. Bahadduri PM, D’Souza VM, Pinsonneault JK, Sadee W, Bao S, Knoell DL, Swaan PW (2005) Functional characterization of the peptide transporter PEPT2 in primary cultures of human upper airway epithelium. Am J Respir Cell Mol Biol 32(4):319–325

    PubMed  CAS  Google Scholar 

  133. Florea BI, Thanou M, Junginger HE, Borchard G (2006) Enhancement of bronchial octreotide absorption by chitosan and N-trimethyl chitosan shows linear in vitro/in vivo correlation. J Control Release 110(2):353–361

    PubMed  CAS  Google Scholar 

  134. Grainger CI, Greenwell LL, Martin GP, Forbes B (2009) The permeability of large molecular weight solutes following particle delivery to air-interfaced cells that model the respiratory mucosa. Eur J Pharm Biopharm 71(2):318–324

    PubMed  CAS  Google Scholar 

  135. Cheek JM, Kim KJ, Crandall ED (1989) Tight monolayers of rat alveolar epithelial cells: bioelectric properties and active sodium transport. Am J Physiol 256(3 pt 1):C688–C693

    PubMed  CAS  Google Scholar 

  136. Kim KJ, Malik AB (2003) Protein transport across the lung epithelial barrier. Am J Physiol 284(2):L247–L259

    CAS  Google Scholar 

  137. Morimoto K, Yamahara H, Lee VH, Kim KJ (1993) Dipeptide transport across rat alveolar epithelial cell monolayers. Pharm Res 10(11):1668–1674

    PubMed  CAS  Google Scholar 

  138. Matsukawa Y, Yamahara H, Lee VH, Crandall ED, Kim KJ (1996) Horseradish peroxidase transport across rat alveolar epithelial cell monolayers. Pharm Res 13(9):1331–1335

    PubMed  CAS  Google Scholar 

  139. Widera A, Kim KJ, Crandall ED, Shen WC (2003) Transcytosis of GCSF-transferrin across rat alveolar epithelial cell monolayers. Pharm Res 20(8):1231–1238

    PubMed  CAS  Google Scholar 

  140. Bur M, Huwer H, Lehr CM, Hagen N, Guldbrandt M, Kim KJ, Ehrhardt C (2006) Assessment of transport rates of proteins and peptides across primary human alveolar epithelial cell monolayers. Eur J Pharm Sci 28(3):196–203

    PubMed  CAS  Google Scholar 

  141. Effros RM, Mason GR (1983) Measurements of pulmonary epithelial permeability in vivo. Am Rev Respir Dis 127(5 pt 2):S59–S65

    PubMed  CAS  Google Scholar 

  142. Matsukawa Y, Lee VH, Crandall ED, Kim KJ (1997) Size-dependent dextran transport across rat alveolar epithelial cell monolayers. J Pharm Sci 86(3):305–309

    PubMed  CAS  Google Scholar 

  143. Bosquillon C (2010) Drug transporters in the lung-do they play a role in the biopharmaceutics of inhaled drugs? J Pharm Sci 99:2240–2255

    PubMed  CAS  Google Scholar 

  144. van der Deen M, de Vries EG, Timens W, Scheper RJ, Timmer-Bosscha H, Postma DS (2005) ATP-binding cassette (ABC) transporters in normal and pathological lung. Respir Res 6:59

    PubMed  Google Scholar 

  145. Patel LN, Uchiyama T, Kim KJ, Borok Z, Crandall ED, Shen WC, Lee VH (2008) Molecular and functional expression of multidrug resistance-associated protein-1 in primary cultured rat alveolar epithelial cells. J Pharm Sci 97(6):2340–2349

    PubMed  CAS  Google Scholar 

  146. Bates SR, Tao JQ, Yu KJ, Borok Z, Crandall ED, Collins HL, Rothblat GH (2008) Expression and biological activity of ABCA1 in alveolar epithelial cells. Am J Respir Cell Mol Biol 38(3):283–292

    PubMed  CAS  Google Scholar 

  147. Groneberg DA, Paul H, Welte T (2006) Novel strategies of aerosolic pharmacotherapy. Exp Toxicol Pathol 57(suppl 2):49–53

    PubMed  Google Scholar 

  148. Rothenberg ME, Doepker MP, Lewkowich IP, Chiaramonte MG, Stringer KF, Finkelman FD, MacLeod CL, Ellies LG, Zimmermann N (2006) Cationic amino acid transporter 2 regulates inflammatory homeostasis in the lung. Proc Natl Acad Sci USA 103(40):14895–14900

    PubMed  CAS  Google Scholar 

  149. Shen J, Elbert KJ, Yamashita F, Lehr CM, Kim KJ, Lee VH (1999) Organic cation transport in rabbit alveolar epithelial cell monolayers. Pharm Res 16(8):1280–1287

    PubMed  CAS  Google Scholar 

  150. Ehrhardt C, Kneuer C, Baldes C, Kim KJ, Lehr CM (2006) Albuterol is net absorbed across human alveolar epithelial cell monolayers. Proc Am Thor Soc 3:A761

    Google Scholar 

  151. Matsukawa Y, Yamahara H, Yamashita F, Lee VH, Crandall ED, Kim KJ (2000) Rates of protein transport across rat alveolar epithelial cell monolayers. J Drug Target 7(5):335–342

    PubMed  CAS  Google Scholar 

  152. Kim KJ, Matsukawa Y, Yamahara H, Kalra VK, Lee VH, Crandall ED (2003) Absorption of intact albumin across rat alveolar epithelial cell monolayers. Am J Physiol 284(3):L458–L465

    CAS  Google Scholar 

  153. Kim KJ, Fandy TE, Lee VH, Ann DK, Borok Z, Crandall ED (2004) Net absorption of IgG via FcRn-mediated transcytosis across rat alveolar epithelial cell monolayers. Am J Physiol 287(3):L616–L622

    CAS  Google Scholar 

  154. Ikehata M, Yumoto R, Nakamura K, Nagai J, Takano M (2008) Comparison of albumin uptake in rat alveolar type II and type I-like epithelial cells in primary culture. Pharm Res 25(4):913–922

    PubMed  CAS  Google Scholar 

  155. Schanker LS (1978) Drug absorption from the lung. Biochem Pharmacol 27(4):381–385

    PubMed  CAS  Google Scholar 

  156. Lim ST, Forbes B, Martin GP, Brown MB (2001) In vivo and in vitro characterization of novel microparticulates based on hyaluronan and chitosan hydroglutamate. AAPS PharmSciTech 2(4):20

    PubMed  CAS  Google Scholar 

  157. Cooney D, Kazantseva M, Hickey AJ (2004) Development of a size-dependent aerosol deposition model utilising human airway epithelial cells for evaluating aerosol drug delivery. Altern Lab Anim 32(6):581–590

    PubMed  CAS  Google Scholar 

  158. Bur M, Rothen-Rutishauser B, Huwer H, Lehr CM (2009) A novel cell compatible impingement system to study in vitro drug absorption from dry powder aerosol formulations. Eur J Pharm Biopharm 72(2):350–357

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

STB is funded by an IRCSET Government of Ireland Postgraduate Scholarship in Science, Engineering and Technology. This work has been partly funded in part by a Strategic Research Cluster grant (07/SRC/B1154) under the National Development Plan co-funded by EU Structural Funds and Science Foundation Ireland (CE) and by Hastings Foundation, Whittier Foundation, and research grants ES017034, ES018782, HL038621, and HL064365 from the National Institutes of Health (KJK).

Author information

Authors and Affiliations

  1. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Panoz Institute, Dublin, Ireland

    Carsten Ehrhardt

Authors
  1. Stephen T. Buckley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kwang-Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carsten Ehrhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carsten Ehrhardt .

Editor information

Editors and Affiliations

  1. , Pharmaceutics Division - PHR 4.214, University of Texas, University Station 1, Austin, 78712, USA

    Hugh D.C. Smyth

  2. Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Anthony J. Hickey

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Controlled Release Society

About this chapter

Cite this chapter

Buckley, S.T., Kim, KJ., Ehrhardt, C. (2011). In Vitro Cell Culture Models for Evaluating Controlled Release Pulmonary Drug Delivery. In: Smyth, H., Hickey, A. (eds) Controlled Pulmonary Drug Delivery. Advances in Delivery Science and Technology. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9745-6_18

Download citation

Publish with us

Policies and ethics

Societies and partnerships

Search

Navigation