Skip to main content
SpringerLink
Log in

Role of hyaluronan and CD44 in reactive oxygen species-induced mucus hypersecretion

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Mucus hypersecretion is an important manifestation in patients with chronic inflammatory airway diseases. Mucin 5AC (MUC5AC) is a major component of airway mucus. MUC5AC expression is regulated by epidermal growth factor receptor (EGFR) which can be activated by reactive oxygen species (ROS). Hyaluronan (HA), a linear glycosaminoglycan with molecular weights ranging from 2 × 105 to 1 × 107, is expressed in airway epithelium and can be depolymerized by ROS into hyaluronan fragments. The mechanisms through which fragmented HA exerts its biologic functions have been elucidated by interactions with its receptor CD44. The aim of our study was to examine the role of HA and CD44 in ROS-induced EGFR activation and MUC5AC expression. We exposed NCI-H292 cells to ROS generated by xanthine/xanthine oxidase (X/XO). ROS-induced EGFR phosphorylation, which was activated by tissue kallekrein (TK) activation and EGF release. We found ROS promoted CD44 co-immunoprecipitation with EGFR and MUC5AC up-regulation. These effects were mimicked by hyaluronan fragments. All the effects were inhibited by blocking CD44 or EGFR, suggesting that CD44 plays a critical role in ROS-induced MUC5AC up-regulation. These results show that ROS depolymerizes hyaluronan into fragments, and these fragments bind their receptor CD44 to induce TK activation, which cleaves EGF precursors into mature EGF to activate its receptor EGFR. Furthermore, we provide evidence that hyaluronan fragments are sufficient to induce CD44/EGFR interaction and EGFR signaling which lead to MUC5AC expression. The results indicate that the regulation of ROS-induced MUC5AC expression by hyaluronan and CD44 may provide important insights in the mechanism of mucus hypersecretion.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Caramori G, Casolari P, Di Gregorio C, Saetta M, Baraldo S, Boschetto P, Ito K, Fabbri LM, Barnes PJ, Adcock IM, Cavallesco G, Chung KF, Papi A (2009) MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients. Histopathology 55:321–331

    Article  PubMed  Google Scholar 

  2. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Paré PD (2004) The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 350:2645–2653

    Article  PubMed  CAS  Google Scholar 

  3. Rose MC, Voynow JA (2006) Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev 86:245–278

    Article  PubMed  CAS  Google Scholar 

  4. Vestbo J (2002) Epidemiological studies in mucus hypersecretion. Novartis Found Symp 248:3–12

    Article  PubMed  Google Scholar 

  5. Shao MX, Nakanaga T, Nadel JA (2004) Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. Am J Physiol Lung Cell Mol Physiol 287:L420–L427

    Article  PubMed  CAS  Google Scholar 

  6. Binker MG, Binker-Cosen AA, Richards D, Oliver B, Cosen-Binker LI (2009) LPS-stimulated MUC5AC production involves Rac1-dependent MMP-9 secretion and activation in NCI-H292 cells. Biochem Biophys Res Commun 386:124–129

    Article  PubMed  CAS  Google Scholar 

  7. Cervantes-Sandoval I, Serrano-Luna Jde J, Meza-Cervantez P, Arroyo R, Tsutsumi V, Shibayama M (2009) Naegleria fowleri induces MUC5AC and pro-inflammatory cytokines in human epithelial cells via ROS production and EGFR activation. Microbiology 155:3739–3747

    Article  PubMed  CAS  Google Scholar 

  8. Lemjabbar H, Li D, Gallup M, Sidhu S, Drori E, Basbaum C (2003) Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. J Biol Chem 278:26202–26207

    Article  PubMed  CAS  Google Scholar 

  9. Li Q, Zhou XD, Yu HM, Nie XH, Xu XY (2010) Regulation of neutrophil elastase-induced MUC5AC expression by nuclear factor erythroid-2 related factor 2 in human airway epithelial cells. J Investig Med 58:730–736

    CAS  Google Scholar 

  10. Zheng S, Byrd AS, Fischer BM, Grover AR, Ghio AJ, Voynow JA (2007) Regulation of MUC5AC expression by NAD(P)H:quinone oxidoreductase 1. Free Radic Biol Med 42:1398–1408

    Article  PubMed  CAS  Google Scholar 

  11. Yan F, Li W, Jono H, Li Q, Zhang S, Li JD, Shen H (2008) Reactive oxygen species regulate Pseudomonas aeruginosa lipopolysaccharide-induced MUC5AC mucin expression via PKC-NADPH oxidase-ROS-TGF-alpha signaling pathways in human airway epithelial cells. Biochem Biophys Res Commun 366:513–519

    Article  PubMed  CAS  Google Scholar 

  12. Casalino-Matsuda SM, Monzón ME, Forteza RM (2006) Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. Am J Respir Cell Mol Biol 34:581–591

    Article  PubMed  CAS  Google Scholar 

  13. Forteza R, Lieb T, Aoki T, Savani RC, Conner GE, Salathe M (2001) Hyaluronan serves a novel role in airway mucosal host defense. FASEB J 15:2179–2186

    Article  PubMed  CAS  Google Scholar 

  14. Casalino-Matsuda SM, Monzon ME, Conner GE, Salathe M, Forteza RM (2004) Role of hyaluronan and reactive oxygen species in tissue kallikrein-mediated epidermal growth factor receptor activation in human airways. J Biol Chem 279:21606–21616

    Article  PubMed  CAS  Google Scholar 

  15. Forteza R, Lauredo I, Abraham WM, Conner GE (1999) Bronchial tissue kallikrein activity is regulated by hyaluronic acid binding. Am J Respir Cell Mol Biol 21:666–674

    PubMed  CAS  Google Scholar 

  16. Tsatas D, Kanagasundaram V, Kaye A, Novak U (2002) EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines. J Clin Neurosci 9:282–288

    Article  PubMed  CAS  Google Scholar 

  17. Wakahara K, Kobayashi H, Yagyu T, Matsuzaki H, Kondo T, Kurita N, Sekino H, Inagaki K, Suzuki M, Kanayama N, Terao T (2005) Bikunin down-regulates heterodimerization between CD44 and growth factor receptors and subsequently suppresses agonist-mediated signaling. J Cell Biochem 94:995–1009

    Article  PubMed  CAS  Google Scholar 

  18. Kim Y, Lee YS, Choe J, Lee H, Kim YM, Jeoung D (2008) CD44-epidermal growth factor receptor interaction mediates hyaluronic acid-promoted cell motility by activating protein kinase C signaling involving Akt, Rac1, Phox, reactive oxygen species, focal adhesion kinase, and MMP-2. J Biol Chem 283:22513–22528

    Article  PubMed  CAS  Google Scholar 

  19. Wang SJ, Bourguignon LY (2006) Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer. Arch Otolaryngol Head Neck Surg 132:771–778

    Article  PubMed  Google Scholar 

  20. Casalino-Matsuda SM, Monzon ME, Day AJ, Forteza RM (2009) Hyaluronan fragments/CD44 mediate oxidative stress-induced MUC5B up-regulation in airway epithelium. Am J Respir Cell Mol Biol 40:277–285

    Article  PubMed  CAS  Google Scholar 

  21. Mahoney DJ, Aplin RT, Calabro A, Hascall VC, Day AJ (2001) Novel methods for the preparation and characterization of hyaluronan oligosaccharides of defined length. Glycobiology 11:1025–1033

    Article  PubMed  CAS  Google Scholar 

  22. Garrett JR, Kidd A, Kyriacou K, Smith RE (1985) Use of different derivatives of D-Val-Leu-Arg for studying kallikrein activities in cat submandibular glands and saliva. Histochem J 17:805–818

    Article  PubMed  CAS  Google Scholar 

  23. Geiger R, Miska W (1988) Human tissue kallikrein. Methods Enzymol 163:102–115

    Article  PubMed  CAS  Google Scholar 

  24. Camenisch TD, McDonald JA (2000) Hyaluronan: is bigger better? Am J Respir Cell Mol Biol 23:431–433

    PubMed  CAS  Google Scholar 

  25. Repine JE, Bast A, Lankhorst I, Oxidative Stress Study Group (1997) Oxidative stress in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 156:341–357

    PubMed  CAS  Google Scholar 

  26. Loukides S, Horvath I, Wodehouse T, Cole PJ, Barnes PJ (1998) Elevated levels of expired breath hydrogen peroxide in bronchiectasis. Am J Respir Crit Care Med 158:991–994

    PubMed  CAS  Google Scholar 

  27. Brown RK, Wyatt H, Price JF, Kelly FJ (1996) Pulmonary dysfunction in cystic fibrosis is associated with oxidative stress. Eur Respir J 9:334–339

    Article  PubMed  CAS  Google Scholar 

  28. Shao MX, Nadel JA (2005) Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. J Immunol 175:4009–4016

    PubMed  CAS  Google Scholar 

  29. Yasuo M, Fujimoto K, Imamura H, Ushiki A, Kanda S, Tsushima K, Kubo H, Yamaya M, Kubo K (2009) l-carbocisteine reduces neutrophil elastase-induced mucin production. Respir Physiol Neurobiol 167:214–216

    Article  PubMed  CAS  Google Scholar 

  30. Fischer B, Voynow J (2000) Neutrophil elastase induces MUC5AC messenger RNA expression by an oxidant-dependent mechanism. Chest 117:317S–320S

    Article  PubMed  CAS  Google Scholar 

  31. Jang MK, Kim SH, Lee KY, Kim TB, Moon KA, Park CS, Bae YJ, Zhu Z, Moon HB, Cho YS (2010) The tyrosine phosphatase, SHP-1, is involved in bronchial mucin production during oxidative stress. Biochem Biophys Res Commun 393:137–143

    Article  PubMed  CAS  Google Scholar 

  32. Takeyama K, Dabbagh K, Jeong Shim J, Dao-Pick T, Ueki IF, Nadel JA (2000) Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils. J Immunol 164:1546–1552

    PubMed  CAS  Google Scholar 

  33. Kim HJ, Park YD, Moon UY, Kim JH, Jeon JH, Lee JG, Bae YS, Yoon JH (2008) The role of Nox4 in oxidative stress-induced MUC5AC overexpression in human airway epithelial cells. Am J Respir Cell Mol Biol 39:598–609

    Article  PubMed  CAS  Google Scholar 

  34. Shao MX, Nadel JA (2005) Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci USA 102:767–772

    Article  PubMed  CAS  Google Scholar 

  35. Hisaka T, Yano H, Haramaki M, Utsunomiya I, Kojiro M (1999) Expressions of epidermal growth factor family and its receptor in hepatocellular carcinoma cell lines: relationship to cell proliferation. Int J Oncol 14:453–460

    PubMed  CAS  Google Scholar 

  36. Strachan L, Murison JG, Prestidge RL, Sleeman MA, Watson JD, Kumble KD (2001) Cloning and biological activity of epigen, a novel member of the epidermal growth factor superfamily. J Biol Chem 276:18265–18271

    Article  PubMed  CAS  Google Scholar 

  37. Sunnarborg SW, Hinkle CL, Stevenson M, Russell WE, Raska CS, Peschon JJ, Castner BJ, Gerhart MJ, Paxton RJ, Black RA, Lee DC (2002) Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J Biol Chem 277:12838–12845

    Article  PubMed  CAS  Google Scholar 

  38. Jahnke GD, Chao J, Walker MP, Diaugustine RP (1994) Detection of a kallikrein in the mouse lactating mammary gland: a possible processing enzyme for the epidermal growth factor precursor. Endocrinology 135:2022–2029

    Article  PubMed  CAS  Google Scholar 

  39. Forteza R, Lauredo I, Abraham WM, Conner GE (1992) Bronchial tissue kallikrein activity is regulated by hyaluronic acid binding. Am J Respir Cell Mol Biol 21:666–674

    Google Scholar 

  40. Zhang M, Peng B, Niehus J, Baumgarten CR, Brunnée T, Thalhofer S, Dorow P, Kunkel G (1997) Kinin generation in acute pneumonia and chronic bronchitis. Eur Respir J 10:1747–1753

    Article  PubMed  CAS  Google Scholar 

  41. Halliwell B, Hoult JR, Blake DR (1988) Oxidants, inflammation, and anti-inflammatory drugs. FASEB J 2:2867–2873

    PubMed  CAS  Google Scholar 

  42. McKee CM, Penno MB, Cowman M, Burdick MD, Strieter RM, Bao C, Noble PW (1996) Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Investig 98:2403–2413

    Article  PubMed  CAS  Google Scholar 

  43. Olayioye MA, Neve RM, Lane HA, Hynes NE (2000) The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19:3159–3167

    Article  PubMed  CAS  Google Scholar 

  44. Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45

    Article  PubMed  CAS  Google Scholar 

  45. McNeil JD, Wiebkin OW, Betts WH, Cleland LG (1985) Depolymerisation products of hyaluronic acid after exposure to oxygen-derived free radicals. Ann Rheum Dis 44:780–789

    Article  PubMed  CAS  Google Scholar 

  46. Sampson PM, Rochester CL, Freundlich B, Elias JA (1992) Cytokine regulation of human lung fibroblast hyaluronan (hyaluronic acid) production. Evidence for cytokine-regulated hyaluronan (hyaluronic acid) degradation and human lung fibroblast-derived hyaluronidase. J Clin Investig 90:1492–1503

    Article  PubMed  CAS  Google Scholar 

  47. Bartolazzi A, Peach R, Aruffo A, Stamenkovic I (1994) Interaction between CD44 and hyaluronate is directly implicated in the regulation of tumor development. J Exp Med 180:53–66

    Article  PubMed  CAS  Google Scholar 

  48. Knudson W, Knudson CB (1991) Assembly of a chondrocyte-like pericellular matrix on non-chondrogenic cells. Role of the cell surface hyaluronan receptors in the assembly of a pericellular matrix. J Cell Sci 99:227–235

    PubMed  Google Scholar 

  49. Manzanares D, Monzon ME, Savani RC, Salathe M (2007) Apical oxidative hyaluronan degradation stimulates airway ciliary beating via RHAMM and RON. Am J Respir Cell Mol Biol 37:160–168

    Article  PubMed  CAS  Google Scholar 

  50. Tammi R, MacCallum D, Hascall VC, Pienimaki JP, Hyttinen M, Tammi M (1998) Hyaluronan bound to CD44 on keratinocytes is displaced by hyaluronan decasaccharides and not hexasaccharides. J Biol Chem 273:28878–28888

    Article  PubMed  CAS  Google Scholar 

  51. Banerji S, Wright AJ, Noble M, Mahoney DJ, Campbell ID, Day AJ, Jackson DG (2007) Structures of the Cd44-hyaluronan complex provide insight into a fundamental carbohydrate-protein interaction. Nat Struct Mol Biol 14:234–239

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grant from the National Nature Science Foundation of China (No.30770951), and China-Russia Cooperation Research Foundation (NSFC81011120108; RFBR10-04-91160).

Author information

Authors and Affiliations

  1. Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing, 400010, China

    Hongmei Yu, Qi Li & Xiangdong Zhou

  2. Far Eastern Scientific Center of Physiology and Pathology of Respiration, Siberian Branch, Russian Academy of Medical Sciences, Blagoveshchensk, Russia

    Victor P. Kolosov & Juliy M. Perelman

Authors
  1. Hongmei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiangdong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Victor P. Kolosov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juliy M. Perelman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiangdong Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, H., Li, Q., Zhou, X. et al. Role of hyaluronan and CD44 in reactive oxygen species-induced mucus hypersecretion. Mol Cell Biochem 352, 65–75 (2011). https://doi.org/10.1007/s11010-011-0740-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-0740-6

Keywords

Search

Navigation