Skip to main content

Advertisement

SpringerLink
Log in

Prevention of lung injury by Muc1 mucin in a mouse model of repetitive Pseudomonas aeruginosa infection

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective and design

To determine whether repetitive airway Pseudomonas aeruginosa (Pa) infection results in lung inflammation and injury and, if so, whether these responses are affected by Muc1 mucin. Muc1 wild type (WT) and knockout (KO) mice were compared for body weights, lung inflammatory responses, and airspace enlargement using a chronic lung infection model system.

Materials

Mice were treated intranasally with Pa (107 CFU) on days 0, 4, 7 and 10. On day 14, body weights, inflammatory cell numbers in bronchoalveolar lavage fluid (BALF), and airspace enlargement were measured. Differences in inflammatory responses between groups were statistically analyzed by the Student’s t test and ANOVA.

Results

Muc1 WT mice exhibited mild degrees of both inflammation and airspace enlargement following repetitive airway Pa infection. However, Muc1 KO mice exhibited significantly decreased body weights, greater macrophage numbers in the BALF, and increased airspace enlargement compared with Muc1 WT mice.

Conclusions

This is the first report demonstrating that Muc1 deficiency can lead to lung injury during chronic Pa infection in mice. These results suggest that MUC1 may play a crucial role in the resolution of inflammation during chronic respiratory infections and that MUC1 dysfunction likely contributes to the pathogenesis of chronic inflammatory respiratory disease.

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

Similar content being viewed by others

References

  1. Levison ME, Kaye D. Pneumonia caused by gram-negative bacilli: an overview. Rev Infect Dis 1985;7 Suppl 4:S656–65.

    Google Scholar 

  2. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168(8):918–51.

    Article  PubMed  Google Scholar 

  3. Afessa B, Green B. Bacterial pneumonia in hospitalized patients with HIV infection: the Pulmonary Complications, ICU Support, and Prognostic Factors of Hospitalized Patients with HIV (PIP) Study. Chest. 2000;117(4):1017–22.

    Article  PubMed  CAS  Google Scholar 

  4. Eller J, Ede A, Schaberg T, Niederman MS, Mauch H, Lode H. Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function. Chest. 1998;113(6):1542–8.

    Article  PubMed  CAS  Google Scholar 

  5. Soler N, Ewig S, Torres A, Filella X, Gonzalez J, Zaubet A. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur Respir J. 1999;14(5):1015–22.

    Article  PubMed  CAS  Google Scholar 

  6. Miravitlles M, Espinosa C, Fernandez-Laso E, Martos JA, Maldonado JA, Gallego M. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD. Chest. 1999;116(1):40–6.

    Article  PubMed  CAS  Google Scholar 

  7. Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 2002;347(7):465–71.

    Article  PubMed  Google Scholar 

  8. Groenewegen KH, Wouters EF. Bacterial infections in patients requiring admission for an acute exacerbation of COPD; a 1-year prospective study. Respir Med. 2003;97(7):770–7.

    Article  PubMed  Google Scholar 

  9. Eidelman D, Saetta MP, Ghezzo H, Wang NS, Hoidal JR, King M, et al. Cellularity of the alveolar walls in smokers and its relation to alveolar destruction: functional implications. Am Rev Respir Dis. 1990;141(6):1547–52.

    PubMed  CAS  Google Scholar 

  10. Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med. 1995;152(5 Pt 1):1666–72.

    PubMed  CAS  Google Scholar 

  11. Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med. 1998;158(4):1277–85.

    PubMed  Google Scholar 

  12. Betsuyaku T, Nishimura M, Takeyabu K, Tanino M, Venge P, Xu S, et al. Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema. Am J Respir Crit Care Med. 1999;159(6):1985–91.

    PubMed  CAS  Google Scholar 

  13. Tetley TD. Macrophages and the pathogenesis of COPD. Chest. 2002;121(5 Suppl):156S–9S.

    Article  PubMed  CAS  Google Scholar 

  14. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science. 1997;277(5334):2002–4.

    Article  PubMed  CAS  Google Scholar 

  15. Owen CA. Roles for proteinases in the pathogenesis of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2008;3(2):253–68.

    PubMed  CAS  Google Scholar 

  16. Gendler SJ. MUC1, the renaissance molecule. J Mammary Gland Biol Neoplasia. 2001;6(3):339–53.

    Article  PubMed  CAS  Google Scholar 

  17. Hirasawa Y, Kohno N, Yokoyama A, Inoue Y, Abe M, Hiwada K. KL-6, a human MUC1 mucin, is chemotactic for human fibroblasts. Am J Respir Cell Mol Biol. 1997;17(4):501–7.

    PubMed  CAS  Google Scholar 

  18. Lu W, Hisatsune A, Koga T, Kato K, Kuwahara I, Lillehoj EP, et al. Cutting edge: enhanced pulmonary clearance of Pseudomonas aeruginosa by Muc1 knockout mice. J Immunol. 2006;176(7):3890–4.

    PubMed  CAS  Google Scholar 

  19. Lillehoj EP, Hyun SW, Kim BT, Zhang XG, Lee DI, Rowland S, et al. Muc1 mucins on the cell surface are adhesion sites for Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol. 2001;280(1):L181–7.

    PubMed  CAS  Google Scholar 

  20. Kato K, Lillehoj EP, Kai H, Kim KC. MUC1 expression by human airway epithelial cells mediates Pseudomonas aeruginosa adhesion. Front Biosci (Elite Ed). 2010;1(2):68–77.

    Article  Google Scholar 

  21. Lillehoj EP, Kim H, Chun EY, Kim KC. Pseudomonas aeruginosa stimulates phosphorylation of the airway epithelial membrane glycoprotein Muc1 and activates MAP kinase. Am J Physiol Lung Cell Mol Physiol. 2004;287(4):L809–15.

    Article  PubMed  CAS  Google Scholar 

  22. Choi S, Park YS, Koga T, Treloar A, Kim KC. TNF-alpha is a key regulator of MUC1, an anti-inflammatory molecule, during airway Pseudomonas aeruginosa infection. Am J Respir Cell Mol Biol. 2011;44(2):255–60.

    Article  PubMed  CAS  Google Scholar 

  23. Spicer AP, Rowse GJ, Lidner TK, Gendler SJ. Delayed mammary tumor progression in Muc-1 null mice. J Biol Chem. 1995;270(50):30093–101.

    Article  PubMed  CAS  Google Scholar 

  24. Ho MK, Springer TA. Tissue distribution, structural characterization, and biosynthesis of Mac-3, a macrophage surface glycoprotein exhibiting molecular weight heterogeneity. J Biol Chem. 1983;258(1):636–42.

    PubMed  CAS  Google Scholar 

  25. Flotte TJ, Springer TA, Thorbecke GJ. Dendritic cell and macrophage staining by monoclonal antibodies in tissue sections and epidermal sheets. Am J Pathol. 1983;111(1):112–24.

    PubMed  CAS  Google Scholar 

  26. Kato K, Lillehoj EP, Park YS, Umehara T, Hoffman NE, Madesh M, et al. Membrane-Tethered MUC1 Mucin Is Phosphorylated by Epidermal Growth Factor Receptor in Airway Epithelial Cells and Associates with TLR5 To Inhibit Recruitment of MyD88. J Immunol. 2012;16(188):2014–22.

    Article  Google Scholar 

  27. Dunnill MS. Quantitative methods in the study of pulmonary pathology. Thorax. 1962;17:320–8.

    Article  Google Scholar 

  28. Li Y, Dinwiddie DL, Harrod KS, Jiang Y, Kim KC. Anti-inflammatory effect of MUC1 during respiratory syncytial virus infection of lung epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol. 2010;298(4):L558–63.

    Article  PubMed  CAS  Google Scholar 

  29. van Heeckeren AM, Tscheikuna J, Walenga RW, Konstan MW, Davis PB, Erokwu B, et al. Effect of Pseudomonas infection on weight loss, lung mechanics, and cytokines in mice. Am J Respir Crit Care Med. 2000;161(1):271–9.

    PubMed  Google Scholar 

  30. Lagente V, Le Quement C, Boichot E. Macrophage metalloelastase (MMP-12) as a target for inflammatory respiratory diseases. Expert Opin Ther Targets. 2009;13(3):287–95.

    Article  PubMed  CAS  Google Scholar 

  31. Kim KC, Lillehoj EP. MUC1 mucin: a peacemaker in the lung. Am J Respir Cell Mol Biol. 2008;39(6):644–7.

    Article  PubMed  CAS  Google Scholar 

  32. Cash HA, Woods DE, McCullough B, Johanson WG Jr, Bass JA. A rat model of chronic respiratory infection with Pseudomonas aeruginosa. Am Rev Respir Dis. 1979;119(3):453–9.

    PubMed  CAS  Google Scholar 

  33. Starke JR, Edwards MS, Langston C, Baker CJ. A mouse model of chronic pulmonary infection with Pseudomonas aeruginosa and Pseudomonas cepacia. Pediatr Res. 1987;22(6):698–702.

    Article  PubMed  CAS  Google Scholar 

  34. Heeckeren A, Walenga R, Konstan MW, Bonfield T, Davis PB, Ferkol T. Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa. J Clin Invest. 1997;100(11):2810–5.

    Article  PubMed  CAS  Google Scholar 

  35. Koga T, Kuwahara I, Lillehoj EP, Lu W, Miyata T, Isohama Y, et al. TNF-alpha induces MUC1 gene transcription in lung epithelial cells: its signaling pathway and biological implication. Am J Physiol Lung Cell Mol Physiol. 2007;293(3):L693–701.

    Article  PubMed  CAS  Google Scholar 

  36. Zhang Z, Louboutin JP, Weiner DJ, Goldberg JB, Wilson JM. Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5. Infect Immun. 2005;73(11):7151–60.

    Article  PubMed  CAS  Google Scholar 

  37. Ueno K, Koga T, Kato K, Golenbock DT, Gendler SJ, Kai H, et al. MUC1 mucin is a negative regulator of toll-like receptor signaling. Am J Respir Cell Mol Biol. 2008;38(3):263–8.

    Article  PubMed  CAS  Google Scholar 

  38. Kato K, Lu W, Kai H, Kim KC. Phosphoinositide 3-kinase is activated by MUC1 but not responsible for MUC1-induced suppression of Toll-like receptor 5 signaling. Am J Physiol Lung Cell Mol Physiol. 2007;293(3):L686–92.

    Article  PubMed  CAS  Google Scholar 

  39. Kyo Y, Kato K, Park YS, Gajhate S, Umehara T, Lillehoj EP, et al. Anti-inflammatory role of MUC1 mucin during nontypeable Haemophilus influenzae infection. Am J Respir Cell Mol Biol. 2012;46(2):149–56.

    Article  PubMed  CAS  Google Scholar 

  40. Jarrard JA, Linnoila RI, Lee H, Steinberg SM, Witschi H, Szabo E. MUC1 is a novel marker for the type II pneumocyte lineage during lung carcinogenesis. Cancer Res. 1998;58(23):5582–9.

    PubMed  CAS  Google Scholar 

  41. Nagai A, Inano H, Matsuba K, Thurlbeck WM. Scanning electronmicroscopic morphometry of emphysema in humans. Am J Respir Crit Care Med. 1994;150(5 Pt 1):1411–5.

    PubMed  CAS  Google Scholar 

  42. Snider GL. Emphysema: the first two centuries–and beyond: A historical overview, with suggestions for future research: Part 1. Am Rev Respir Dis. 1992;146(5 Pt 1):1334–44.

    PubMed  CAS  Google Scholar 

  43. Barnes PJ. Medicine. Neutrophils find smoke attractive. Science. 2010;330(6000):40–1.

    CAS  Google Scholar 

  44. Russell REK, Thorley A, Culpitt SV, Dodd S, Donnelly LE, Demattos C, et al. Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases. Am J Physiol—Lung Cell Mol Physiol. 2002;283(4):L867–73.

    PubMed  CAS  Google Scholar 

  45. Shapiro SD, Goldstein NM, Houghton AM, Kobayashi DK, Kelley D, Belaaouaj A. Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am J Pathol. 2003;163(6):2329–35.

    Article  PubMed  CAS  Google Scholar 

  46. Leco KJ, Waterhouse P, Sanchez OH, Gowing KL, Poole AR, Wakeham A, et al. Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). J Clin Invest. 2001;108(6):817–29.

    PubMed  CAS  Google Scholar 

  47. da Hora K, Valenca SS, Porto LC. Immunohistochemical study of tumor necrosis factor-alpha, matrix metalloproteinase-12, and tissue inhibitor of metalloproteinase-2 on alveolar macrophages of BALB/c mice exposed to short-term cigarette smoke. Exp Lung Res. 2005;31(8):759–70.

    Article  PubMed  Google Scholar 

  48. Pons AR, Sauleda J, Noguera A, Pons J, Barcelo B, Fuster A, et al. Decreased macrophage release of TGF-beta and TIMP-1 in chronic obstructive pulmonary disease. Eur Respir J. 2005;26(1):60–6.

    Article  PubMed  CAS  Google Scholar 

  49. Taraseviciene-Stewart L, Douglas IS, Nana-Sinkam PS, Lee JD, Tuder RM, Nicolls MR, et al. Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease? Proc Am Thorac Soc. 2006;3(8):687–90.

    Article  PubMed  CAS  Google Scholar 

  50. Aoshiba K, Yokohori N, Nagai A. Alveolar wall apoptosis causes lung destruction and emphysematous changes. Am J Respir Cell Mol Biol. 2003;28(5):555–62.

    Article  PubMed  CAS  Google Scholar 

  51. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest. 2000;106(11):1311–9.

    Article  PubMed  CAS  Google Scholar 

  52. Mahoney JA, Rosen A. Apoptosis and autoimmunity. Curr Opin Immunol. 2005;17(6):583–8.

    Article  PubMed  CAS  Google Scholar 

  53. Agata N, Ahmad R, Kawano T, Raina D, Kharbanda S, Kufe D. MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8. Cancer Res. 2008;68(15):6136–44.

    Article  PubMed  CAS  Google Scholar 

  54. Kuwahara I, Lillehoj EP, Koga T, Isohama Y, Miyata T, Kim KC. The signaling pathway involved in neutrophil elastase stimulated MUC1 transcription. Am J Respir Cell Mol Biol. 2007;37(6):691–8.

    Article  PubMed  CAS  Google Scholar 

  55. Guo X, Verkler TL, Chen Y, Richter PA, Polzin GM, Moore MM, et al. Mutagenicity of 11 cigarette smoke condensates in two versions of the mouse lymphoma assay. Mutagenesis. 2011;26(2):273–81.

    Article  PubMed  CAS  Google Scholar 

  56. Pleasance ED, Stephens PJ, O’Meara S, McBride DJ, Meynert A, Jones D, et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2010;463(7278):184–90.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from National Institute of Health, HL-47125 and HL-81825 (KCK).

Author information

Author notes

  1. Tsuyoshi Umehara

    Present address: Department of Otorhinolaryngology, Faculty of Medicine, Shimane University, Izumo, Japan

Authors and Affiliations

  1. Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, PA, USA

    Tsuyoshi Umehara, Kosuke Kato, Yong Sung Park & Kwang Chul Kim

  2. Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA

    Erik P. Lillehoj

  3. Department of Otorhinolaryngology, Faculty of Medicine, Shimane University, Izumo, Japan

    Hideyuki Kawauchi

  4. Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA

    Kwang Chul Kim

Authors
  1. Tsuyoshi Umehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kosuke Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong Sung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erik P. Lillehoj
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hideyuki Kawauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kwang Chul Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kwang Chul Kim.

Additional information

Responsible Editor: Michael Parnham.

T. Umehara and K. Kato contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Umehara, T., Kato, K., Park, Y.S. et al. Prevention of lung injury by Muc1 mucin in a mouse model of repetitive Pseudomonas aeruginosa infection. Inflamm. Res. 61, 1013–1020 (2012). https://doi.org/10.1007/s00011-012-0494-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-012-0494-y

Keywords

Search

Navigation