Skip to main content
SpringerLink
Log in

Calgranulin B (S100A9/MRP14): A Key Molecule in Idiopathic Pulmonary Fibrosis?

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Calgranulin B is a small calcium-binding protein with several immunological functions mainly involved in chronic inflammation and cancer. It can participate in recruitment of neutrophils and leukocytes in inflamed tissue, oxidant/antioxidant balance, adhesion of neutrophils to fibronectin, and regulation of apoptosis. In a previous proteomic study, we found that calgranulin B was up-regulated in the bronchoalveolar lavage (BAL) of patients with idiopathic pulmonary fibrosis (IPF) with respect to controls and patients with other interstitial lung diseases. The aims of this study are to compare calgranulin B concentrations in BAL of patients with IPF and sarcoidosis and controls by a quantitative method, to look for correlations with clinical data, and to evaluate calgranulin B expression in lung tissue of IPF patients by immunohistochemistry. A modification of a commercial ELISA was used to determine calgranulin B concentrations in BAL of 16 patients with IPF (a group of patients in which we previously performed proteomic analysis), 17 patients with sarcoidosis, and 7 controls. The immunohistochemistry was done in a subgroup of patients with IPF and a control group of lung transplant donors. Calgranulin B concentrations were significantly higher in patients with IPF than controls (p < 0.01); they were inversely correlated with FVC and DLCO values and directly correlated with neutrophil and eosinophil percentages in BAL. Immunohistochemistry revealed a patchy distribution of calgranulin B, predominantly around areas of fibrotic remodeling. Calgranulin B may be a trigger molecule involved in the evolution and progression of IPF, being overexpressed in BAL of patients with IPF with severe functional deterioration and in the peribronchiolar area bordering zones of honeycombing.

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

Similar content being viewed by others

Abbreviations

BAL:

bronchoalveolar lavage

ILD:

interstitial lung diseases

2-DE:

two dimensional electrophoresis

IPF:

idiopathic pulmonary fibrosis

References

  1. Foell, D., H. Wittkowski, T. Vogl, and J. Roth. 2007. S100 proteins expressed in phagocytes: A novel group of damage-associated molecular pattern molecules. Journal of Leukocyte Biology 81: 28–37.

    Article  PubMed  CAS  Google Scholar 

  2. Lagasse, E., and R.C. Clerc. 1988. Cloning and expression of two human genes encoding calcium-binding proteins that are regulated during myeloid differentiation. Molecular and Cellular Biology 8: 2402–2410.

    PubMed  CAS  Google Scholar 

  3. Roth, J., S. Teigelkamp, et al. 1992. Complex pattern of myelo-monocytic differentiation antigens MRP8 and MRP14 during chronic airway inflammation. Immunobiology 186: 304–314.

    PubMed  CAS  Google Scholar 

  4. Lorenz, E., M.S. Muhlebach, P.A. Tessier, et al. 2008. Different expression ratio of S100A8/A9 and S100A12 in acute and chronic lung diseases. Respiratory Medicine 102: 567–573.

    Article  PubMed  Google Scholar 

  5. Ryckman, C., K. Vandal, P. Rouleau, et al. 2001. Proinflammatory activitiesof S100: Proteins S100A8, S100A9 and S100A8/A9 induce neutrophil chemotaxis and adhesion. Journal of Immunology 166: 4678–4688.

    Google Scholar 

  6. Gebhardt, C., J. Nemeth, P. Angel, and J. Hess. 2006. S100A8 and S100A9 in inflammation and cancer. Biochemical Pharmacology 72: 1622–1631.

    Article  PubMed  CAS  Google Scholar 

  7. Foell, D., and J. Roth. 2004. Proinflammatory S100 proteins in arthritis and autoimmune diseases. Arthritis and Rheumatism 50: 3762–3771.

    Article  PubMed  CAS  Google Scholar 

  8. Kosaki, A., T. Hagegawa, T. Kinura, et al. 2004. Increased plasma S100A12 levels in patients with type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism 89: 5423–5428.

    Article  PubMed  CAS  Google Scholar 

  9. Odink, K., N. Cerletti, J. Bruggen, et al. 1987. Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature 330: 80–82.

    Article  PubMed  CAS  Google Scholar 

  10. Haga, H.J., J. Brun, H.B. Berntzen, et al. 1993. Calprotectin in patients with SLE: Relation with clinical and laboratory parameters of disease activity. Lupus 2: 47–50.

    PubMed  CAS  Google Scholar 

  11. Schnekenburger, J., V. Schick, and B. Kruger, et al. 2008. The calcium-binding protein S100A9 is essential for pancreatic leukocyte infiltration and induces disruption of cell–cell contacts. Journal of Cellular Physiology 216: 558–567.

    Article  PubMed  CAS  Google Scholar 

  12. Yoo, B.C., Y.K. Shin, S.B. Lim, et al. 2008. Evaluation of calgranulin B in stools from the patients with colorectal cancer. Diseases of the Colon & Rectum 51: 1703–1709.

    Google Scholar 

  13. Heizmann, C.W., G.E. Ackermann, and A. Galichet. 2007. Pathologies involving S100 proteins and RAGE. Subcellular Biochemistry 45: 93–138.

    Article  PubMed  CAS  Google Scholar 

  14. Wilkinson, M.M., A. Busuttil, C. Hayward, et al. 1988. Expression pattern of related cystic fibrosis-associated calcium-binding proteins in normal and abnormal tissues. Journal of Cell Science 91: 221–230.

    PubMed  CAS  Google Scholar 

  15. Pederson, S.K., A.J. Sloane, S.S. Prasad, et al. 2005. An immunoproteomic approach for identification of clinical biomarkers formonitoring disease: Application to cystic fibrosis. Molecular & Cellular Proteomics 4: 1052–1060.

    Article  Google Scholar 

  16. Gray, R.D., G. Macgregor, D. Noble, et al. 2008. Sputum proteomics in inflammatory and suppurative respiratory diseases. American Journal of Respiratory and Critical Care Medicine 178: 444–452.

    Google Scholar 

  17. Longbottom, D., J.M. Sallenave, and V. van Heyningen. 1992. Subunit structure of calgranulin A and B obtained from sputum, plasma, granulocytes and cultured epithelial cells. Biochimica et Biophysica Acta 1120: 215–222.

    Article  PubMed  CAS  Google Scholar 

  18. Foell, D., T. Kucharzik, and M. Kraft. 2003. et al Neutrophil-derived human S100A12 is strongly expressed during chronic active inflammatory bowel disease. Gut 52: 847–853.

    Article  PubMed  CAS  Google Scholar 

  19. Magi, B., L. Bini, M.G. Perari, et al. 2002. Bronchoalveolar lavage fluid protein composition in patients with sarcoidosis and idiopathic pulmonary fibrosis: A two dimensional electrophoretic study. Electrophoresis 23: 3434–3444.

    Article  PubMed  CAS  Google Scholar 

  20. Rottoli, P., B. Magi, M.G. Perari, S. Liberatori, et al. 2005. Cytokine profile and protome analysis in broncoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiophatic pulmonary fibrosis. Proteomics 5: 1423–1430.

    Article  PubMed  CAS  Google Scholar 

  21. Bargagli E, C Olivieri, A Prasse, et al. 2008. Calgranulin B in BAL of patients with interstitial lung diseases. Inflammation 31: 351–354.

    Google Scholar 

  22. Magi, B., E. Bargagli, L. Bini, and P. Rottoli. 2006. Proteome analysis of bronchoalveolar lavage in lung diseases. Proteomics 6(23): 6354–6369.

    Article  PubMed  CAS  Google Scholar 

  23. American Thoracic Society ATS. 2002. Society, ERS. International multidisciplinary consensus classification of the idiopathic interstitial pneumonias. American Journal of Respiratory and Critical Care Medicine 165: 227–304.

    Google Scholar 

  24. Hunninghake, G.W., U. Costabel, M. Ando, et al. 1999. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases 16: 149–173.

    PubMed  CAS  Google Scholar 

  25. Ziegenhagen, M.W., M.E. Rothe, and M. Schlaak. 2003. Muller-Quernheim: BAL and serologial parameters reflecting the severity of sarcoidosis. The European Respiratory Journal 21: 407–413.

    Article  PubMed  CAS  Google Scholar 

  26. Hunninghake, G.W., S. Gilbert, R. Pueringer, et al. 1994. Outcome of the treatment of sarcoidosis. American Journal of Respiratory and Critical Care Medicine 149: 893–898.

    PubMed  CAS  Google Scholar 

  27. Bargagli, E., C. Bigliazzi, A. Leonini, N. Nikiforakis, M.G. Perari, and P. Rottoli. 2005. Tryptase concentrations in bronchoalveolar lavage from patients with chronic eosinophilic pneumonia. Clinical Science (London) 108(3): 273–276.

    Article  CAS  Google Scholar 

  28. Bargagli, E., M. Margollicci, M. Perrone, A. Luddi, N. Bianchi, L. Volterrani, M.G. Perari, S. Grosso, and P. Rottoli. 2007. Chitotriosidase levels in BAL of patients with sarcoidosis. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases 24: 59–64.

    PubMed  Google Scholar 

  29. Bradford, M.M. 1976. A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 72: 248–254.

    Article  PubMed  CAS  Google Scholar 

  30. Selman, M., T.E. King, A. Pardo, et al. 2001. Idiopathic pulmonary fibrosis: Prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Annals of Internal Medicine 134: 136–151.

    PubMed  CAS  Google Scholar 

  31. Hallgren, R., L. Bjermer, R. Lundgren, and P. Venge. 1989. The eosinophil component of the alveolitis in idiophatic pulmonary fibrosis. Signs of eosinophil activation in the lung are related to impaired lung function. The American Review of Respiratory Disease 139: 373–377.

    PubMed  CAS  Google Scholar 

  32. Kuwano, K., N. Nakashima, I. Inoshima, et al. 2003. Oxidative stress in lung epithelial cells from patients with idiopathic interstitial pneumonias. The European Respiratory Journal 21: 232–240.

    Article  PubMed  CAS  Google Scholar 

  33. Veeraraghavan, S., P.I. Latsi, A.U. Wells, et al. 2003. BAL findings in NSIP and UIP. The European Respiratory Journal 22: 239–244.

    Article  PubMed  CAS  Google Scholar 

  34. Anceriz, N., and K. Vandal. 2007. Tessier P.A. S100A9 mediates neutrophil adhesion to fibronectin to activation of beta2-integrins. Biochemical and Biophysical Research Communications 354: 84–89.

    Article  PubMed  CAS  Google Scholar 

  35. Queisser, M.A., F.M. Kouri, M. Konigshoff et al. 2008. Loss of RAGE in pulmonary fibrosis: Molecular relations to functional changes in pulmonary cell types. American Journal of Respiratory Cell and Molecular Biology. Epub.

  36. Englert, J.M., L.E. Hanford, N. Kaminski, J.M. Tobolewski, R.J. Tan, C.L. Fattman, L. Ramsgaard, T.J. Richards, I. Loutaev, P.P. Nawroth, M. Kasper, A. Bierhaus, and T.D. Oury. 2008. A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis. The American Journal of Pathology 172(3): 583–591.

    Article  PubMed  CAS  Google Scholar 

  37. He, M., H. Kubo, K. Ishizawa, A.E. Hegab, Y. Yamamoto, H. Yamamoto, and M. Yamaya. 2007. The role of the receptor for advanced glycation end-products in lung fibrosis. American Journal of Physiology. Lung Cellular and Molecular Physiology 293(6): L1427–L1436.

    Article  PubMed  CAS  Google Scholar 

  38. Morbini, P., C. Villa, I. Campo, M. Zorzetto, S. Inghilleri, and M. Luisetti. 2006. The receptor for advanced glycation end products and its ligands: A new inflammatory pathway in lung disease? Modern Pathology 19(11): 1437–1445.

    PubMed  CAS  Google Scholar 

  39. Fernández Pérez, E.R., C.E. Daniels, et al. 2009. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: A population-based study. Chest.

  40. Kottmann, R.M., C.M. Hogan, R.P. Phipps, and P.J. Sime. 2009. Determinants of initiation and progression of idiopathic pulmonary fibrosis. Respirology 14: 917–933.

    Article  PubMed  Google Scholar 

  41. Zappala, C.J., P.I. Latsi and A.G. Nicholson, et al. 2009. Marginal decline in FVC is associated with a poor outcome in IPF. European Respiratory Journal.

Download references

Acknowledgments

The authors thank Dr. Spina, Dr. Bini, and Dr. Magi for their help.

Author information

Authors and Affiliations

  1. Respiratory Diseases Section, Dept. of Clinical Medicine and Immunological Sciences, Siena University, Siena, Italy

    Elena Bargagli, Carmela Olivieri, Rosa M. Refini & Paola Rottoli

  2. Department of Human Pathology and Oncology, Siena University, Siena, Italy

    Marcella Cintorino

  3. Department of Environmental Biology, Siena University, Siena, Italy

    Nicola Bianchi

  4. Department of Pneumology, Freiburg University, Freiburg, Germany

    Antje Prasse

  5. Sezione di Malattie Respiratorie, Dipartimento di Medicina Clinica e Scienze Immunologiche, Università di Siena, Siena, Italy

    Elena Bargagli

Authors
  1. Elena Bargagli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carmela Olivieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcella Cintorino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rosa M. Refini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicola Bianchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antje Prasse
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paola Rottoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elena Bargagli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bargagli, E., Olivieri, C., Cintorino, M. et al. Calgranulin B (S100A9/MRP14): A Key Molecule in Idiopathic Pulmonary Fibrosis?. Inflammation 34, 85–91 (2011). https://doi.org/10.1007/s10753-010-9210-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-010-9210-7

KEY WORDS

Search

Navigation