Airway Mucus: Its Components and Function

  • Lillehoj, Erik-P. (Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy) ;
  • Kim, K.-Chul (Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland, School of Medicine)
  • Published : 2002.12.01

Abstract

The airway surface liquid (ASL), often referred to as mucus, is a thin layer of fluid covering the luminal surface of the airway. The major function of mucus is to protect the lung through mucociliary clearance against foreign particles and chemicals entering the lung. The mucus is comprised of water, ions, and various kinds of macromolecules some of which possess the protective functions such as anti-microbial, anti-protease, and anti-oxidant activity. Mucus glycoproteins or mucins are mainly responsible for the viscoelastic property of mucus, which is crucial for the effective mucociliary clearance. There are at least eight mucin genes identified in the human airways, which will potentially generate various kinds of mucin molecules. At present, neither the exact structures of mucin proteins nor their regulation are understood although it seems likely that different types of mucins are involved in different functions and might also be associated with certain airway diseases. The fact that mucins are tightly associated with various macromolecules present in ASL seems to suggest that the defensive role of ASL is determined not only by these individual components but rather by a combination of these components. Collectively, mucins in ASL may be compared to aircraft carriers carrying various types of weapons in defense of airborne enemies.

Keywords

References

  1. An, G., Luo, G., Wu, R, Expression of MUC2 gene is downregulated by vitamin A at the transcriptional level in vitro in tracheobronchial epithelial cells. Am. J. Respir Cell Mol. Biol., 10, 546-551 (1994) https://doi.org/10.1165/ajrcmb.10.5.8179918
  2. Baraniuk, J. N., Shizari, T, Sabol, M., Ali, M., Underhill, C. B., Hyaluronan is exocytosed from serous, but not mucous cells, of human nasal and tracheobronchial submucosal glands. J. Investig. Med., 44, 47-52 (1996)
  3. Baruch, A., Hartmann, M. L., Yoeli, M., Adereth, Y, Greenstein, S., Stadler, Y., Skomik, Y, Zaretsky, J., Smorodinsky, N. I., Keydar, I., Wreschner, D. H., The breast cancer-associated MUC1 qene qenerates both a receptor and its cognate binding protein. Cancer Res., 59, 1552-1561 (1999)
  4. Bemacki, S. H., Nelson, A. L., Abdullah, L., Sheehan, J. K., Harris, A, William-Davis, C., Randell, S. H., Mucin gene expression during differentiation of human airway epithelia in vitro. MUC4 and MUC5b are strongly induced. Am. J. Respir Cell Mol. Biol., 20, 595-604 (1999) https://doi.org/10.1165/ajrcmb.20.4.3442
  5. Bhaskar, K. R, O'Sullivan, D. D., Seltzer, J., Rossing, T H., Drazen, J. M., Reid, L. M., Density gradient study of bronchial mucus aspirates from healthy volunteers (smokers and nonsmokers) and from patients with tracheostomy. Exp. Lung Res., 9, 289-308 (1985) https://doi.org/10.3109/01902148509057529
  6. Bhaskar, K. R., O'Sullivan, D. D., Opaskar-Hincman, H., Reid, L. M., Coles, S. J., Density gradient analysis of secretions produced in vitro by human and canine airway mucosa: identification of lipids and proteoglycans in such secretions. Exp. Lung Res., 10, 401-422 (1986) https://doi.org/10.3109/01902148609058290
  7. Bhaskar, K. R, O'Sullivan, D. D., Opaskar-Hincman, H., Reid, L. M., Lipids in airway secretions. Eur. J. Respir. Dis. (Suppl), 153, 215-221 (1987)
  8. Boman, H. G., Peptide antibiotics and their role in innate immunity. Annu. Rev. Immunol., 13, 61-92 (1995) https://doi.org/10.1146/annurev.iy.13.040195.000425
  9. Braga, V. M. M., Pemberton, L. F., Duhig, T, Gendler, S. J., Spatial and temporal expression of an epithelial mucin, Muc1, during mouse development. Development, 115, 427-437 (1992)
  10. Breuer, R, Christensen, T. G., Niles, R. M., Stone, P. J., Snider, G. L., Human neutrophil elastase causes glycoconjugate release from the epithelial cell surface of hamster trachea in organ culture. Am. Rev. Respir. Dis., 139, 779-782 (1989) https://doi.org/10.1164/ajrccm/139.3.779
  11. Buisine, M. P., Devisme, L., Copin, M. C., Durand-Reville, M., Gosselin, B., Aubert, J. P., Porchet, N., Developmental mucin gene expression in the human respiratory tract. Am. J. Respil. Cell Mol. BioI., 20, 209-218 (1999) https://doi.org/10.1165/ajrcmb.20.2.3259
  12. Carraway, K. L., Price-Schiavi, S. A, Komatsu, M., Idris, N., Perez, A, Li, P., Jepson, S., Zhu, X., Carvajal, M. E., Carraway, C. A, Multiple facets of sialomucin complexl MUC4, a membrane mucin and ErbB2 ligand, in tumors and tissues (Y2K update). Front Biosci., 5, D95-D107 (2000) https://doi.org/10.2741/Carraway
  13. Chen, Y., Zhao, Y. H., Wu, R., In silico cloning of mouse Muc5b gene and upregulation of its expression in mouse asthma model. Am. J. Respir. Crit. Care Med., 164, 1059-1066 (2001) https://doi.org/10.1164/ajrccm.164.6.2012114
  14. Christensen, T. G., Blanchard, G. C., Nolley, G., Hayes, J. A, Ultrastructural localization of endogenous peroxidase in the lower respiratory tract of the guinea pig. Cell Tissue Res., 214, 407-415 (1981)
  15. Copin, M. C., Devisme, L., Buisine, M. P, Marquette, C. H., Wurtz, A., Aubert, J. P., Gosselin, B., Porchet, N., From normal respiratory mucosa to epidermoid carcinoma: expression of human mucin genes. Int. J. Cancer, 86, 162-168 (2000) https://doi.org/10.1002/(SICI)1097-0215(20000415)86:2<162::AID-IJC3>3.0.CO;2-R
  16. Dabbagh, K., Takeyama, K., Lee, H. M., Ueki, I. F., Lausier, J. A., Nadel, J. A., IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J. Immunol., 162, 6233-6237 (1999)
  17. Desseyn, J. L., Aubert, J. P., Van Seuningen, I., Porchet, N., Laine, A., Genomic organization of the 3' region of the human mucin gene MUC5B. J. Biol. Chem., 272, 16873-16833 (1997) https://doi.org/10.1074/jbc.272.27.16873
  18. De Watel, R, Willems, L. N., Van Muijen, G. N., Franken, C., Fransen, J. A., Dijkman, J. H., Kramps, J. A.,Ultrastructural localization of bronchial antileukoprotease in central and per pneral human airways by a gold-labeling technique using monoclonal antibodies. Am. Rev. Respir. Dis., 133, 882-890 (1986)
  19. Dohrman, A., Tsuda, T., Escudier, E., Cardone, M., Jany, B., Gum, J., Kim, Y., Basbaum, C., Distribution of lysozyme and mucin (MUC2 and MUC3) mRNA in human bronchus. Exp. Lurg Res., 20, 367-380 (1994) https://doi.org/10.3109/01902149409064393
  20. Dohrman, A, Miyata, S., Gallup, M., Li, J. D., Chapelin, C., Corte, A, Escudier, E., Nadel, J., Basbaum, C., Mucin gene (MUC2 and MUC5AC) upregulation by Gram-positive and Gram-jeqative bacteria. Biochim. Biophys. Acta., 1406, 251-259 (1998) https://doi.org/10.1016/S0925-4439(98)00010-6
  21. Dufosse, J., Porchet, N., Audie, J. P., Guyonnet-Duperat, V., Laine, A., Van Seuningen, I., Marrakchi, S., Degand, P., Aubert, J. P., Degenerate 87-base pair tandem repeats create hydrophilic/hydrophobic alternating domains in human mucin peptides mapped to 11p15. Biochem. J., 293, 329-337 (1933)
  22. Ellison, R. T., Boose, D., LaForce, F. M., Isolation of an ant bacterial peptide from human lung lavage fluid. J. Infect. Dis., 151, 1123-1129 (1985) https://doi.org/10.1093/infdis/151.6.1123
  23. Elrod, K. C., Moore, W. R., Abraham, W. M., Tanaka, R. D., Lactoferrin, a potent tryptase inhibitor, abolishes late-phase airway responses in allergic sheep. Am. J. Respir. Crit. Care Med., 156, 375-381 (1997) https://doi.org/10.1164/ajrccm.156.2.9607012
  24. Forteza, R., Lieb, T., Aoki, T., Savani, R. C., Conner, G. E., Salathe, M., Hyaluronan serves a novel role in airway mucosal host defense. FASEB J., 15, 2179-2186 (2001) https://doi.org/10.1096/fj.01-0036com
  25. Gend er, S. J., Lancaster, C. A., Taylor-Papadimitriou, J., Duhig, T., Peat, N., Burchell, J., Pemberton, L., Lalani, E. N., Wilson, D., Molecular cloning and expression of human tumorassociated polymorphic epithelial mucin. J. Biol. Chem., 265, 15286-15293 (1990)
  26. Gend er, S. J., Spicer, A. P., Epithelial mucin genes. Annu. Rev.Physiol., 57, 607-634 (1995) https://doi.org/10.1146/annurev.ph.57.030195.003135
  27. Gerson, C., Sabater, J., Scuri, M., Torbati, A., Coffey, R., Ab aharn, J. W., Lauredo, I., Forteza, R., Wanner, A., Sa athe, M., Abraham, W. M., Conner, G. E., The lac operoxidase system functions in bacterial clearance of ainvays. Am. J. Respir. Cell Mol. Biol., 22, 665-671 (2000) https://doi.org/10.1165/ajrcmb.22.6.3980
  28. Gray, T. E., Guzman, K., Davis, C. W., Abdullah, L. H., Ne tesheim, P., Mucociliary differentiation of serially passaged normal human tracheobronchial epithelial cells. Am. J. Respir. Cell Mol. Biol., 14, 104-112 (1996) https://doi.org/10.1165/ajrcmb.14.1.8534481
  29. Gray, T Koo, J. S., Nettesheim, P., Regulation of mucous differentiation and mucin gene expression in the tracheobronchial epithelium. Toxicology, 160, 35-46 (2001) https://doi.org/10.1016/S0300-483X(00)00455-8
  30. Gruttor, M. G., Fendrich, G., Huber, R., Bode, W., The 2.5 A X-ray crystal structure of the acid-stable proteinase inhibitor from human mucous secretions analyzed in its complex with bovine alpha-chymotrypsin. EMBO J., 7, 345-351 (1988)
  31. Gum, J. R., Hicks, J. W., Toribara, N. W., Siddiki, B., Kim, Y. S., Molecular cloning of human intestinal mucin (MUC2) cDNA. J. Biol. Chem., 269, 2440-2446 (1994)
  32. Guyonnet-Duperat, V., Audie, J. P., Debailleul, V., Laine, A., Buisine, M. P., Galiegue-Zouitina, S., Pigny, P., Degand, P., Aubert, J. P., Porchet, N., Characterization of the human mucin gene MUC5AC: a consensus cysteine-rich domain for 11p15 mucin qenes? Biochem. J., 305, 211-219 (1995) https://doi.org/10.1042/bj3050211
  33. Guzman, K., Gray, T. E., Yoon, J. H., Nettesheim, P., Quantitation of mucin RNA by PCR reveals induction of both MUC2 and MUC5AC mRNA levels by retinoids. Am. J. Physiol. (Lung Cell Mol Physiol), 271, L1023-L1028 (1996) https://doi.org/10.1152/ajplung.1996.271.6.L1023
  34. Hayashi, T., Takahashi, T., Motoya, S., Ishida, T, Itoh, F., Adachi, M., Hinoda, Y., Imai, K., MUC1 mucin core protein binds to the domain 1 of ICAM-1. Digestion, 63, 87-92 (2001) https://doi.org/10.1159/000051917
  35. Hilkens, J., Ligtenberg, M. J. L., Vos, H. L., Litvinov, S. V, Cell membrane-associated mucins and their adhesion-modulating property. Trends Biochem. Sci., 17, 359-363 (1992) https://doi.org/10.1016/0968-0004(92)90315-Z
  36. Holgate, S. T., Epithelial damage and response. Clin. Exp. Allergy, 30, 37-41 (2000) https://doi.org/10.1046/j.1365-2222.2000.00095.x
  37. Houdret, N., Perini, J. M., Galabert, C., Scharfman, A., Humbert, P., Lamblin, G., Roussel, P., The high lipid content of respiratory mucins in cystic fibrosis is related to infection. Biochim. Biophys. Acta, 880, 54-61 (1986) https://doi.org/10.1016/0304-4165(86)90119-4
  38. Huang, J., Olivenstein, R., Taha, R., Hamid, Q., Ludwig, M., Enhanced proteoglycan deposition in the airway wall of atopic asthmatics. Am. J. Respir. Crit. Care Med., 160, 725-729 (1999) https://doi.org/10.1164/ajrccm.160.2.9809040
  39. Jacquot, J., Hayem, A, Galabert, C., Functions of proteins and lipids in airway secretions. Eur. Respir. J., 5, 343-358 (1992)
  40. Karlsson, N. G., Johansson, M. E., Asker. N., Karlsson, H., Gendler, S. J., Carlstedt, I., Hansson, G. C., Molecular characterization of the large heavily glycosylated domain glycopeptide from the rat small intestinal Muc2 mucin. Glycoconj. J., 13, 823-831 (1996) https://doi.org/10.1007/BF00702346
  41. Kim, K. C., Possible requirement of collagen gel substratum for production of mucin-like glycoproteins by primary rabbit tracheal epithelial cells in culture. In Vitro, 21, 617-621 (1985)
  42. Kim, K. C., Wasano, K., Niles, R. M., Schuster, J. E., Stone, P. J., Brody, J. S., Human neutrophil elastase releases cell surface mucins from primary cultures of hamster tracheal epithelial cells. Proc. Natl. Acad. Sci. USA, 84, 9304-08 (1987) https://doi.org/10.1073/pnas.84.24.9304
  43. Kim, K. C., Hincman, H. O., Bhaskar, K. R., Secretions from primary hamster tracheal epithelial cells in culture: Mucin-like glycoproteins, proteoglycans and lipids. Exp. Lung Res., 15, 299-314 (1989) https://doi.org/10.3109/01902148909087860
  44. Kim, K. C., Singh, B. N., Hydrophobicity of mucin-like glycoproteins secreted by cultured tracheal epithelial cells: Association with lipids. Exp. Lung Res., 16, 279-292 (1990a) https://doi.org/10.3109/01902149009108845
  45. Kim, K. C., Singh, B. N., Association of lipids with mucins may take place prior to secretion: Studies with primary tracheal epithelial cells in culture. Biorheology, 27, 491-501 (1990b) https://doi.org/10.3233/BIR-1990-273-428
  46. Kim, K. C., Mucin-like glycoproteins secreted from cultured hamster tracheal surface epithelial cells: Their hydrophobic nature and amino acid composition. Exp. Lung Res., 17, 65-76 (1991) https://doi.org/10.3109/01902149109063282
  47. Kim, K. C., Regulation of airway goblet cell mucin secretion. In, Airway Secretion: Physiological Bases for the Control of Mucus Hypersecretion. Takishima T and Shimura S (eds). Lung Biology in Health and Disease, Vol. 72, Marcel Dekker, New York, NY, pp.433-449, (1994)
  48. Kim, K. C., Hyun, S. W., Kim, B. T., Meerzaman, D., Lee, M. K., Lillehoj, E. P., Pseudomonas adhesion to MUC1 mucins: A potential role of MUC1 mucins in clearance of inhaled bacteria. In, Cilia, Mucus and Mucociliary Interactions. Salathe, M (ed). Marcel Dekker, New York, NY, pp. 217-224, (2001)
  49. Kim, Y. D., Kwon, E. J., Kwon, T. K., Baek, S. H., Song, S. Y., Suh, J. S., Regulation of IL-1$\beta$-mediated MUC2 gene in NCIH292 human airway epithelial cells. Biochem. Biophys. Res. Commun., 274, 112-116 (2000) https://doi.org/10.1006/bbrc.2000.3107
  50. Kirkham, S., Sheehan, J. K., Knight, D., Richardson, P. S., Thornton, D. J., Heterogeneity of airways mucus: variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B. Biochem. J., 361, 537-546 (2002) https://doi.org/10.1042/0264-6021:3610537
  51. Konstan, M. W., Walenga, R. W., Hilliard, K. A., Hilliard, J. B., Leukotriene B4 markedly elevated in the epithelial lining fluid of patients with cystic fibrosis. Am. Rev. Respir. Dis., 148, 896-901 (1993) https://doi.org/10.1164/ajrccm/148.4_Pt_1.896
  52. LaForce, F. M., Boose, D. S., Effect of zinc and phosphate on an antibacterial peptide isolated from lung lavage. Infect. Immun, 45, 692-696 (1984)
  53. Lan, M. S., Batra, S. K., Qi, W. N., Metzgar, R. S., Hollingsworth, M. A., Cloning and sequencing of a human pancreatic tumor mucin cDNA. J. Biol. Chem., 265, 15294-15299 (1990)
  54. Li, J. D., Dohrman, A. F., Gallup, M., Miyata, S., GUill, J. R., Kim, Y. S., Nadel, J. A., Prince, A., Basbaum, C. B., Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc. Natl. Acad. Sci. USA, 94, 967-72 (1997) https://doi.org/10.1073/pnas.94.3.967
  55. Li, Y., Bharti, A., Chen, D., Gong, J., Kufe, D., Interaction of glycogen synthase kinase 3$\beta$ with the DF3/MUC1 carcinomaassociated antigen and $\beta$-catenin. Mol. Cell Biol., 18, 7216-7224 (1998) https://doi.org/10.1128/MCB.18.12.7216
  56. Li, Y, Kuwahara, H., Ren, J., Wen, G., Kufe, D., The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3$\beta$3$\beta$ and $\beta$-catenin. J. Biol. Chem., 276, 6061-6064 (2001a) https://doi.org/10.1074/jbc.C000754200
  57. Li, Y., Martin, L. D., Minnicozzi, M., Greenfeder, S., Fine, J., Pettersen, C. A., Chorley, B., Adler, K. B., Enhanced expression of mucin genes in a guinea pig model of allergic asthma. Am. J. Respir. Cell Mol. Biol., 25, 644-651 (2001b) https://doi.org/10.1165/ajrcmb.25.5.4485
  58. Ligtenberg, M. J. L., Vos, H. L., Gennissen, A. M., Hilkens, J., Episialin, a carcinoma-associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini. J. Biol. Chem., 265, 5573-5578(1990)
  59. Ligtenberg, M. J. L., Kruijshaar, L., Buijs, F, van Meijer, M., Litvinov, S. V., Hilkens, J., Cell-associated episialin is a complex containing two proteins derived from a common precursor. J. Biol. Chem., 267, 6171-6177 (1992)
  60. Lillehoj, E. P., Hyun, S. W., Kim, B. T., Zhang, X. G., Lee, D. I., Rowland, S., Kim, K. C., Muc1 mucins on the cell surface are adhesion sites for Pseudomonas aeruginosa. Am. J. Physiol. (Lung Cell Mol Physiol), 280, L181-L187 (2001) https://doi.org/10.1152/ajplung.2001.280.1.L181
  61. Lillehoj, E. P., Kim, B. T., Kim, K. C., Identification of Pseudomonas aeruginosa flagellin as an adhesin for Muc1 mucin. Am. J. Physiol. (Lung Cell Mol Physiol), 282, L751-L756 (2002) https://doi.org/10.1152/ajplung.00383.2001
  62. Longphre, M., Li, D., Gallup, M., Drori, E., Ordonez, C. L., Redman, T., Wenzel, S., Bice, D. E., Fahy, J. V.. Basbaum, C., Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells. J. Clin. Invest., 104, 1375-1382 (1999) https://doi.org/10.1172/JCI6097
  63. Lopez-Ferrer, A., Curull, V., Barranco, C., Garrido, M., Lloreta, J., Real, F X., de Bolos, C., Mucins as differentiation markers in bronchial epithelium. Squamous cell carcinoma and adenocarcinoma display similar expression patterns. Am. J. Respir. Cell Mol. Biol., 24, 22-29 (2001) https://doi.org/10.1165/ajrcmb.24.1.4294
  64. Louahed, J., Toda, M., Jen, J., Hamid, Q., Renauld, J. C., Levitt, R. C., Nicolaides, N. C., Interleukin-9 upregulates mucus expression in the airways. Am. J. Respir. Cell Mol. Biol., 22, 649-656 (2000) https://doi.org/10.1165/ajrcmb.22.6.3927
  65. Lukacs, N. W., Strieter, R. M., Chensue, S. W., Kunkel, S. L., Activation and regulation of chemokines in allergic airway inflammation. J. Leukoc. Biol., 59, 13-17 (1996) https://doi.org/10.1002/jlb.59.1.13
  66. Lundgren, J. D., Rieves, R. D., Mullol, J., Logun, C., Shelhamer, J. H., The effect of neutrophil protenase enzymes on the release of mucus from feline and human airway cultures. Respir. Med., 88, 511-518 (1994) https://doi.org/10.1016/S0954-6111(05)80333-6
  67. Meezaman, D., Charles, P., Daskal, E., Polymeropoulos, M. H., Martin, B. M., Rose, M. C., Cloning and analysis of cDNA encoding a major airway glycoprotein, human tracheobronchial mucin (MUC5). J. Biol. Chem., 269, 12932-12939 (1994)
  68. Meerzaman, D., Xing, P. X., Kim, K. C., Construction and characterization of a chimeric receptor containing the cytoplasmic domain of MUC1 mucin. Am. J. Physiol. (Lung Cell Mol Physiol), 278, L625-L629 (2000) https://doi.org/10.1152/ajplung.2000.278.3.L625
  69. Moniaux, N., Escande, F., Porchet, N., Aubert, J. P., Batra, S. K., Structural organization and classification of the human mucin genes. Front. Biosci., 6, D1192-D1206 (2001) https://doi.org/10.2741/Moniaux
  70. Nadziejkc, C. E., Siomiany, B. L., Siomiany, A., Most of the lipid in punulent sputum is bound to mucus glycoprotein. Exp. Lung Res., 19, 671-684 (1993) https://doi.org/10.3109/01902149309064364
  71. Nadzkejkc, C., Finkelstein, Inhibition of neutrophil elastase by mucus glycoprotein. Am. J Respir. Cell Mol. Biol., 11, 103-107 (1994) https://doi.org/10.1165/ajrcmb.11.1.7912511
  72. Nakamura, H., Yoshimura, K., McElvaney, N. G., Crystal, R. G., NeLtroohil elastase in respiratory epithelial lining fluid of individuais with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J. Clin. lnvest. 89, 1478-1484 (1992) https://doi.org/10.1172/JCI115738
  73. Noah, T. I., Blach, R., Cheng, P. W., Wood, R. E., Leigh, M. W., Nasal and bronchoalveolar lavage fluid cytokines in early cys'ic f brosis. J. Infect. Dis., 175, 638-647 (1997) https://doi.org/10.1093/infdis/175.3.638
  74. Ohkavrara, Y., Tamura, G., Iwasaki, T., Tanaka, A., Kikuchi, T., Shitate, K., Activation and transforming growth factor-beta production in eosinophils by hyaluronan. Am. J. Respir. Cell Mol Biol., 23, 444-451 (2000) https://doi.org/10.1165/ajrcmb.23.4.3875
  75. O'Riordan, T. G., Otero, R., Mao, Y., Lauredo, I., Abraham, W. M., Elastase contributes to antigen-induced mucociliary dysiunction in ovine airways. Am. J. Respir. Crit. Care Med., 155, 1522-1528 (1997) https://doi.org/10.1164/ajrccm.155.5.9154852
  76. Pandey, P., Kharbanda, S., Kufe, D., Association of the DF3/ MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein. Cancer Res., 55, 4000-4003 (1995)
  77. Park, H. R., Hyun, S. W., Kim, K. C., Expression of MUC1 mucin gene by hamster tracheal surface epithelial cells in primarv culture. Am. J . Respir. Cell Mol. Biol., 15, 237-244 (1996) https://doi.org/10.1016/S1569-2558(08)60312-4
  78. Paul, E., Lee, D. I., Hyun, S. W., Gendler, S. J., Kim, K. C., ldentiflcation and characterization of high molecular-mass mucin-like glycoproteins in the plasma membrane of airway epithel al cells. Am. J. Respir. Cell Mol. Biol., 19, 681-690 (1998) https://doi.org/10.1165/ajrcmb.19.4.2908
  79. Paul, A., Picard, J., Mergey, M., Veissiere, D., Finkbeiner, W. E., Bas ba um, C. B., Glycoconjugates secreted by bovine traoheal serous cells in culture. Arch. Biochem. Biophys., 260, 75-84 (1988) https://doi.org/10.1016/0003-9861(88)90426-2
  80. Perlmutter, D. H., Pierce, J. A., The alpha 1-antitrypsin gene and em physema. Am. J. Physiol., 257, L147-L162 (1989) https://doi.org/10.1152/ajpcell.1989.257.1.C147
  81. Pigny, P, Guyonnet-Duperat, V., Hill, A. S., Pratt, W. S., Gal eque- Zouitina, S., d'Hooge, M. C., Laine, A., Van Sellnirigen, I., Degand, P., Gum, J. R., Kim, Y. S., Swallow, D. M. Aubert, J. P., Porchet, N., Human mucin qenes assigned to 11p15.5: Identification and organization of a cluster of qenes. Genomics, 38, 340-352 (1996) https://doi.org/10.1006/geno.1996.0637
  82. Quinn, R. J., McGuckin, M. A., Phosphorylation of the cytoplasmtc domain of the MUC1 mucin correlates with chanqes in cell-cell adhesion. Int. J. Cancer, 87, 499-506 (2000) https://doi.org/10.1002/1097-0215(20000815)87:4<499::AID-IJC6>3.0.CO;2-9
  83. Renauld, J. C., New insights into the role of cytokines in asthma. J. Clin. Pathol., 54, 577-589 (2001) https://doi.org/10.1136/jcp.54.8.577
  84. Roca-Ferrer, J., Mullol, J., Xaubet, A., Benitez, P., BernalSprekelsen, M., Shelhamer, J., Picado, C., Proinflammatory cytokines and eosinophil cationic protein on glandular secretion from human nasal mucosa: regulation by corticosteroids. J. Allergy Clin. Immunol., 108, 87-93 (2001) https://doi.org/10.1067/mai.2001.115485
  85. Rose, M. C., Piazza, F. M., Chen, Y. A., Ailmam, M. Z., Bautista, M. V., Letwin, N., Rajput, B., Model systems for investigating mucin gene expression in airway diseases. J. Aerosol Med., 13, 245-261 (2000) https://doi.org/10.1089/jam.2000.13.245
  86. Sala, A., Murphy, R. C., Voelkel, N. F., Direct airway injury results in elevated levels of sulfidopeptide leukotrienes, detectable in airway secretions. Prostaglandins, 42, 1-7 (1991) https://doi.org/10.1016/0090-6980(91)90088-W
  87. Salathe, M., Guldimann, P., Conner, G. E., Wanner, A., Hydrogen peroxide-scavenging properties of sheep airway mucus. Am. J. Respir. Crit. Care Med., 151, 1543-1550 (1995) https://doi.org/10.1164/ajrccm.151.5.7735613
  88. Salathe, M., Holderby, M, Forteza, R, Abraham, W. M., Wanner, A., Conner, G. E., Isolation and characterization of a peroxidase from the airway. Am. J. Respir. Cell Mol. Biol., 17, 97-105 (1997) https://doi.org/10.1165/ajrcmb.17.1.2719
  89. Sallenave, J. M., Silva, A., Marsden, M. E., Ryle, A. P., Secretion of mucus proteinase inhibitor and elafin by Clara cell and type II pneumocyte cell lines. Am. J Respir. Cell Mol. Biol., 8, 126-33 (1993) https://doi.org/10.1165/ajrcmb/8.2.126
  90. Shankar, V., Gilmore, M. S., Elkins, R. C., Sachdev, G. P., A novel human airway mucin cDNA encodes a protein with unique tandem-repeat organization. Biochem. J., 300, 295-298 (1994) https://doi.org/10.1042/bj3000295
  91. Sharma, P., Dudus, L., Nielsen, P. A., Clausen, H., Yankaskas, J. R., Hollingsworth, M. A., Engelhardt, J. F., MUC5B and MUC7 are differentially expressed in mucous and serous cells of submucosal glands in human bronchial airways. Am. J. Respir. Cell Mol. Biol., 19, 30-37(1998) https://doi.org/10.1165/ajrcmb.19.1.3054
  92. Sims, D. E., Horne, M. M., Heterogeneity of the composition and thickness of tracheal mucus in rats. Am. J. Physiol., 273, L1036-L1041(1997)
  93. Singh, P. K., Jia, H. P., Wiles, K., Hesselberth, J., Liu, L., Conway, B. A., Greenberq, E. P., Valore, E. V., Welsh, M. J., Ganz, T., Tack, B. F., McCray, P. B. Jr, Production of betadefensins by human airway epithelia. Proc. Natl. Acad. Sci. USA, 95, 14961-14966 (1998) https://doi.org/10.1073/pnas.95.25.14961
  94. Singh, P. K., Tack B. F., McCray, P. B. Jr, Welsh, M. J.,Synergistic and additive killing by antimicrobial factors found in human airway surface liquid. Am. J Physiol. Lung Cell Mol. Physiol., 279, L799-L805 (2000) https://doi.org/10.1152/ajplung.2000.279.5.L799
  95. Smith, J., Travis, J. S. M., Greenberg, E. P., Welsh, M. J., Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface liquid. Cell, 85, 229-236 (1996) https://doi.org/10.1016/S0092-8674(00)81099-5
  96. Snider, G. L., Lucey, E. C., Christensen, T. G., Stone, P. J., Calore, J. D., Catanese, A., Franzblau, C., Emphysema and bronchial secretory cell metaplasia induced in hamsters by human neutrophil products. Am. Rev. Respir. Dis., 129, 155-60 (1984)
  97. Sommerhoff, C. P., Caughey, G. H., Finkbeiner, W. E., Lazarus, S. C., Basbaum, C. B., Nadel, J. A., Mast cell chymase. A potent secretagogue for airway gland serous cells. J. Immunol., 142, 2450-2456 (1989)
  98. Sommerhoff, C. P., Nadel, J. A., Basbaum, C. B., Caughey, G. H., Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J. Clin. Invest., 85, 682-689 (1990) https://doi.org/10.1172/JCI114492
  99. Taipale, J., Lohi, J., Saarinen, J., Kovanen, P. T., Keski-Oja, J., Human mast cell chymase and leukocyte elastase release latent transforming growth factor-beta 1 from the extracellular matrix of cultured human epithelial and endothelial cells. J. Biol. Chem., 270, 4689-4696 (1995) https://doi.org/10.1074/jbc.270.9.4689
  100. Thompson, A. B., Bohling, T., Payvandi, F., Rennard, S. I., Lower respiratory tract lactoferrin and lysozyme arise primarily in the airways and are elevated in association with chronic bronchitis. J. Lab. Clin. Med., 115, 148-158 (1990)
  101. Thompson, R. C., Ohlsson, K., Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc. Natl. Acad. Sci. USA, 83, 6692-6696 (1986) https://doi.org/10.1073/pnas.83.18.6692
  102. van de Bovenkamp, J. H., Hau, C. M., Strous, G. J., Buller, H. A., Dekker, J., Einerhand, A. W., Molecular cloning of human gastric mucin MUC5AC reveals conserved cysteine-rich Ddomains and a putative leucine zipper motif. Biochem. Biophys. Res. Commun., 245, 853-859 (1998) https://doi.org/10.1006/bbrc.1998.8535
  103. van de Graaf, E. A., Out, T. A., Kobesen, A., Jansen, H. M., Lactoferrin and secretory lgA in the bronchoalveolar lavage fluid from patients with a stable asthma. Lung, 169, 275-283 (1991) https://doi.org/10.1007/BF02714163
  104. Vogelmeier, C., Hubbard, R. C., Fells, G. A., Schnebli, H. P., Thompson, R. C., Fritz, H., Crystal, R. G., Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor. J. Clin. Invest., 87, 482-488 (1991) https://doi.org/10.1172/JCI115021
  105. Voynow, J. A., Selby, D. M., Rose, M. C., Mucin gene expression (MUC1, MUC2, and MUC5/5AC) in nasal epithelial cells of cystic fibrosis, allergic rhinitis, and normal individuals. Lung, 176, 345-354 (1998) https://doi.org/10.1007/PL00007616
  106. Wang, B., Lim, D. J., Han, J., Kim, Y. S., Basbaum, C, B., Li, J. D., Novel cytoplasmic proteins of nontypeable Haemophilus influenzae up-regulate human MUC5AC mucin transcription via a positive p38 mitogen-activated protein kinase pathway and a negative phosphoinositide 3-kinase-Akt pathway. J. Biol. Ghem., 277, 949-957 (2002)
  107. Wickstrom, C., Davies, J. R., Eriksen, G. V., Veerman, E. C., Carlstedt, I., 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, 685-693 (1998) https://doi.org/10.1042/bj3340685
  108. Widdicombe, J. G., Role of lipids in airway function. Eur. J. Respir. Dis., 153, 197-204 (1987)
  109. Williams, S. J., Wreschner, D. H., Tran, M., Eyre, H. J., Sutherland, G. R., McGuckin, M. A., MUC13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J. Biol. Chem., 276, 18327-18336 (2001) https://doi.org/10.1074/jbc.M008850200
  110. Wu, R., Yankaskas, J., Cheng, E., Knowles, M. R., Boucher, R., Growth and differentiation of human nasal epithelial cells in culture, Serum-free, hormone-supplemented medium and proteoglycan synthesis. Am. Rev. Respir. Dis., 132, 311-320 (1985)
  111. Yoon, J. H., Kim, K. S., Kim, H. U., Linton, J. A., Lee, J. G., Effects of TNF-alpha and IL-1 beta on mucin, lysozyme, IL-6 and IL-8 in passage-2 normal human nasal epithelial cells. Acta Otolaryngol., 119, 905-910 (1999) https://doi.org/10.1080/00016489950180261
  112. Yoon, J. H., Kim, K. S., Kim, S. S., Lee, J. G., Park, I. Y.,Secretory differentiation of serially passaged normal human nasal epithelial cells by retinoic acid: expression of mucin and lysozyme. Ann. Otol. Rhinal. Laryngol., 109, 594-601 (2000) https://doi.org/10.1177/000348940010900612
  113. Zhao, J., Sime, P. J., Bringas, P. Jr, Gauldie, J., Warburton, D., Adenovirus-mediated decorin gene transfer prevents TGF-beta-induced inhibition of lung morphogenesis. Am. J. Physiol., 277, L412-L422 (1999) https://doi.org/10.1152/ajpcell.1999.277.3.C412
  114. Zrihan-Licht, S., Baruch, A., Elroy-Stein, O., Keydar, I., Wreschner, D. H., Tyrosine phosphorylation of the MUC1 breast cancer membrane proteins. Cytokine receptor-like molecules. FEBS Lettr., 356, 130-136 (1994) https://doi.org/10.1016/0014-5793(94)01251-2
  115. Zuhdi Alimam, M., Piazza, F. M., Selby, D. M., Letwin. N., Huang, L., Rose, M. C., Muc-5/5ac mucin messenger RNA and protein expression is a marker of goblet cell metaplasia in murine airways. Am. J. Respir. Cell Mol. Biol., 22, 253-260 (2000) https://doi.org/10.1165/ajrcmb.22.3.3768
  116. Kai, H., Yoshitake, K., Hisatsune, A., Kido, T., Isohama, Y., Takahama, K., Miyata, T., Dexamethasone suppresses mucus production and MUC-2 and MUC-5AC gene expression by NCI-H292 cells. Am. J. Physiol., 271, L484-L488 (1996)