Skip to main content
SpringerLink
Log in

Longitudinal study of a mouse model of chronic pulmonary inflammation using breath hold gated micro-CT

  • Experimental
  • Published:
European Radiology Aims and scope Submit manuscript

Abstract

Objectives

To evaluate the feasibility of using automatic quantitative analysis of breath hold gated micro-CT images to detect and monitor disease in a mouse model of chronic pulmonary inflammation, and to compare image-based measurements with pulmonary function tests and histomorphometry.

Material and methods

Forty-nine A/J mice were used, divided into control and inflammation groups. Chronic inflammation was induced by silica aspiration. Fourteen animals were imaged at baseline, and 4, 14, and 34 weeks after silica aspiration, using micro-CT synchronized with ventilator-induced breath holds. Lung input impedance was measured as well using forced oscillation techniques. Five additional animals from each group were killed after micro-CT for comparison with histomorphometry.

Results

At all time points, micro-CT measurements show statistically significant differences between the two groups, while first differences in functional test parameters appear at 14 weeks. Micro-CT measurements correlate well with histomorphometry and discriminate diseased and healthy groups better than functional tests.

Conclusion

Longitudinal studies using breath hold gated micro-CT are feasible on the silica-induced model of chronic pulmonary inflammation, and automatic measurements from micro-CT images correlate well with histomorphometry, being more sensitive than functional tests to detect lung damage in this model.

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
Fig. 8

Similar content being viewed by others

Abbreviations

AUC:

area under the ROC curve

C:

compliance

DAF:

damaged area fraction

DLVF:

damaged lung volume fraction

G:

tissue damping

H:

elastance

I:

inertance

micro-CT:

micro-computed X-ray tomography

MLVI:

mean lung volume intensity

R:

resistance

RRB:

radius of right mainstem bronchus

RLB:

radius of left mainstem bronchus

ROC:

receiver operating characteristic

TLC:

total lung capacity

References

  1. Shapiro SD (2000) Animal models for COPD. Chest 117:223S–227S

    Article  CAS  PubMed  Google Scholar 

  2. Thrall RS, McCormick JR, Jack RM, McReynolds RA, Ward PA (1979) Bleomycin-induced pulmonary fibrosis in the rat: inhibition by indomethacin. Am J Pathol 95:117–130

    CAS  PubMed  Google Scholar 

  3. Tuveson DA, Jacks T (1999) Modeling human lung cancer in mice: similarities and shortcomings. Oncogene 18:5318–5324. doi:10.1038/sj.onc.1203107

    Article  CAS  PubMed  Google Scholar 

  4. Zosky GR, Sly PD (2007) Animal models of asthma. Clin Exp Allergy 37:973–988. doi:10.1111/j.1365-2222.2007.02740.x

    Article  CAS  PubMed  Google Scholar 

  5. Suzuki N, Ohta K, Horiuchi T, Takizawa H, Ueda T, Kuwabara M, Shiga J, Ito K (1996) T lymphocytes and silica-induced pulmonary inflammation and fibrosis in mice. Thorax 51:1036–1042

    Article  CAS  PubMed  Google Scholar 

  6. Johnson KA (2007) Imaging techniques for small animal imaging models of pulmonary disease: micro-CT. Toxicol Pathol 35:59–64. doi:10.1080/01926230601184262

    Article  PubMed  Google Scholar 

  7. Froese AR, Ask K, Labiris R, Farncombe T, Warburton D, Inman MD, Gauldie J, Kolb M (2007) Three-dimensional computed tomography imaging in an animal model of emphysema. Eur Respir J 30:1082–1089. doi:10.1183/09031936.00000507

    Article  CAS  PubMed  Google Scholar 

  8. De Clerck NM, Meurrens K, Weiler H, Van Dyck D, Van Houtte G, Terpstra P, Postnov AA (2004) High-resolution X-ray microtomography for the detection of lung tumors in living mice. Neoplasia 6:374–379

    Article  PubMed  Google Scholar 

  9. Cavanaugh D, Travis EL, Price RE, Gladish G, White RA, Wang M, Cody DD (2006) Quantification of bleomycin-induced murine lung damage in vivo with micro-computed tomography. Acad Radiol 13:1505–1512. doi:10.1016/j.acra.2006.08.011

    Article  PubMed  Google Scholar 

  10. Ask K, Labiris R, Farkas L, Moeller A, Froese A, Farncombe T, McClelland GB, Inman M, Gauldie J, Kolb MR (2008) Comparison between conventional and “clinical” assessment of experimental lung fibrosis. J Transl Med 6:16. doi:10.1186/1479-5876-6-16

    Article  PubMed  Google Scholar 

  11. Ford NL, Nikolov HN, Norley CJ, Thornton MM, Foster PJ, Drangova M, Holdsworth DW (2005) Prospective respiratory-gated micro-CT of free breathing rodents. Med Phys 32:2888–2898

    Article  PubMed  Google Scholar 

  12. Cody DD, Nelson CL, Bradley WM, Wislez M, Juroske D, Price RE, Zhou X, Bekele BN, Kurie JM (2005) Murine lung tumor measurement using respiratory-gated micro-computed tomography. Invest Radiol 40:263–269

    Article  PubMed  Google Scholar 

  13. Ford NL, Wheatley AR, Holdsworth DW, Drangova M (2007) Optimization of a retrospective technique for respiratory-gated high speed micro-CT of free-breathing rodents. Phys Med Biol 52:5749–5769. doi:10.1088/0031-9155/52/19/002

    Article  PubMed  Google Scholar 

  14. Namati E, Chon D, Thiesse J, Hoffman EA, Jd R, Ross A, McLennan G (2006) In vivo micro-CT lung imaging via a computer-controlled intermittent iso-pressure breath hold (IIBH) technique. Phys Med Biol 51:6061–6075

    Article  CAS  PubMed  Google Scholar 

  15. Jobse BN, Johnson JR, Farncombe TH, Labiris R, Walker TD, Goncharova S, Jordana M (2009) Evaluation of allergic lung inflammation by computed tomography in a rat model in vivo. Eur Respir J 33:1437–1447. doi:10.1183/09031936.00087508

    Article  CAS  PubMed  Google Scholar 

  16. Lee HJ, Goo JM, Kim NR, Kim MA, Chung DH, Son KR, Kim HC, Lee CH, Park CM, Chun EJ, Im JG (2008) Semiquantitative measurement of murine bleomycin-induced lung fibrosis in in vivo and postmortem conditions using microcomputed tomography: Correlation with pathologic scores–initial results. Invest Radiol 43:453–460. doi:10.1097/RLI.0b013e31816900ec

    Article  PubMed  Google Scholar 

  17. Irvin CG, Bates JH (2003) Measuring the lung function in the mouse: the challenge of size. Respir Res 4:4

    Article  PubMed  Google Scholar 

  18. Bates JH, Irvin CG (2003) Measuring lung function in mice: the phenotyping uncertainty principle. J Appl Physiol 94:1297–1306. doi:10.1152/japplphysiol.00706.2002

    PubMed  Google Scholar 

  19. Hantos Z, Daroczy B, Suki B, Nagy S, Fredberg JJ (1992) Input impedance and peripheral inhomogeneity of dog lungs. J Appl Physiol 72:168–178

    Article  CAS  PubMed  Google Scholar 

  20. Lakatos HF, Burgess HA, Thatcher TH, Redonnet MR, Hernady E, Williams JP, Sime PJ (2006) Oropharyngeal aspiration of a silica suspension produces a superior model of silicosis in the mouse when compared to intratracheal instillation. Exp Lung Res 32:181–199. doi:10.1080/01902140600817465

    Article  CAS  PubMed  Google Scholar 

  21. Rivera B, Miller S, Brown E, Price R (2005) A novel method for endotracheal intubation of mice and rats used in imaging studies. Contemp Top Lab Anim Sci 44:52–55

    CAS  PubMed  Google Scholar 

  22. Allen GB, Suratt BT, Rinaldi L, Petty JM, Bates JH (2006) Choosing the frequency of deep inflation in mice: balancing recruitment against ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 291:L710–717. doi:10.1152/ajplung.00532.2005

    Article  CAS  PubMed  Google Scholar 

  23. Artaechevarria X, Pérez-Martín D, Reinhardt JM, Muñoz-Barrutia A, Ortiz de Solorzano C (2009) Automated quantitative analysis of a mouse model of chronic pulmonary inflammation using micro X-ray computed tomography. MICCAI. Available via http://www.lungworkshop.org/2009/proc2009/115.pdf. Accessed 20 April 2010

  24. Hu S, Hoffman EA, Reinhardt JM (2001) Automatic lung segmentation for accurate quantitation of volumetric X-ray CT images. IEEE Trans Med Imaging 20:490–498. doi:10.1109/42.929615

    Article  CAS  PubMed  Google Scholar 

  25. Artaechevarria X, Perez-Martín D, Ceresa M, de Biurrun G, Blanco D, Montuenga LM, van Ginneken B, Ortiz-de-Solorzano C, Munoz-Barrutia A (2009) Airway segmentation and analysis for the study of mouse models of lung disease using micro-CT. Phys Med Biol 54:7009–7024

    Article  CAS  PubMed  Google Scholar 

  26. Fawcett T (2006) An introduction to ROC analysis. Pattern Recogn Lett 27:861–874

    Article  Google Scholar 

  27. Eaton JW, Bateman D, Hauberg S (2002) GNU Octave manual. Network Theory Limited

  28. Saffiotti U, Williams A, Daniel L, Kaighn M, Mao Y, Shi X (1996) Carcinogenesis by crystalline silica: animal, cellular and molecular studies. In: Castranova V, Vallyathan V, Wallace WE (eds) Silica and silica-induced lung diseases, 1st edn. CRC, Boca Raton, pp 345–381

    Google Scholar 

  29. Ford NL, Thornton MM, Holdsworth DW (2003) Fundamental image quality limits for microcomputed tomography in small animals. Med Phys 30:2869–2877

    Article  CAS  PubMed  Google Scholar 

  30. Hu S, Hoffman EA, Reinhardt JM (2001) Automatic lung segmentation for accurate quantitation of volumetric X-ray CT images. IEEE Trans Med Imaging 20:490–498

    Article  CAS  PubMed  Google Scholar 

  31. Gietema HA, Schilham AM, van Ginneken B, van Klaveren RJ, Lammers JW, Prokop M (2007) Monitoring of smoking-induced emphysema with CT in a lung cancer screening setting: detection of real increase in extent of emphysema. Radiology 244:890–897. doi:10.1148/radiol.2443061330

    Article  PubMed  Google Scholar 

  32. Sluimer I, Prokop M, van Ginneken B (2005) Toward automated segmentation of the pathological lung in CT. IEEE Trans Med Imaging 24:1025–1038. doi:10.1109/TMI.2005.851757

    Article  PubMed  Google Scholar 

  33. Tschirren J, Hoffman EA, McLennan G, Sonka M (2005) Intrathoracic airway trees: segmentation and airway morphology analysis from low-dose CT scans. IEEE Trans Med Imaging 24:1529–1539. doi:10.1109/TMI.2005.857654

    Article  PubMed  Google Scholar 

  34. Ito S, Ingenito EP, Brewer KK, Black LD, Parameswaran H, Lutchen KR, Suki B (2005) Mechanics, nonlinearity, and failure strength of lung tissue in a mouse model of emphysema: possible role of collagen remodeling. J Appl Physiol 98:503–511. doi:10.1152/japplphysiol.00590.2004

    Article  PubMed  Google Scholar 

  35. Lutchen KR, Hantos Z, Petak F, Adamicza A, Suki B (1996) Airway inhomogeneities contribute to apparent lung tissue mechanics during constriction. J Appl Physiol 80:1841–1849

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This project was partially funded by the “UTE Project CIMA”, the Spanish Ministry of Health under grants PI070751, PI070792 and RTICC RD06/0020/0066, and the subprogram for unique strategic projects of the Spanish Science and Innovation Ministry (MCIIN PSS-010000-2008-2). Xabier Artaechevarria is funded by a pre-doctoral scholarship of the Basque Government. Carlos Ortiz de Solorzano and Arrate Muñoz-Barrutia hold a Ramón y Cajal Fellowship of the Spanish Ministry of Science and Innovation. We thank Prof. Joseph M. Reinhardt from the University of Iowa for his help with the automatic segmentation algorithms.

Author information

Authors and Affiliations

  1. Cancer Imaging Laboratory, Oncology Division, Center for Applied Medical Research, University of Navarra, 55 Pio XII, 31008, Pamplona, Spain

    Xabier Artaechevarria, Daniel Pérez-Martín, Arrate Muñoz-Barrutia & Carlos Ortiz-de-Solorzano

  2. Biomarkers Laboratory, Oncology Division, Center for Applied Medical Research, University of Navarra, 55 Pio XII, 31008, Pamplona, Spain

    David Blanco, Gabriel de Biurrun & Luis M. Montuenga

  3. Pneumology Department, Clinica Universidad de Navarra, 36 Pio XII, 31008, Pamplona, Spain

    Juan P. de Torres & Javier J. Zulueta

  4. Radiology Department, Clinica Universidad de Navarra, 36 Pio XII, 31008, Pamplona, Spain

    Gorka Bastarrika

Authors
  1. Xabier Artaechevarria
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Blanco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel Pérez-Martín
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gabriel de Biurrun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luis M. Montuenga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Juan P. de Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Javier J. Zulueta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gorka Bastarrika
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Arrate Muñoz-Barrutia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Carlos Ortiz-de-Solorzano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xabier Artaechevarria.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Artaechevarria, X., Blanco, D., Pérez-Martín, D. et al. Longitudinal study of a mouse model of chronic pulmonary inflammation using breath hold gated micro-CT. Eur Radiol 20, 2600–2608 (2010). https://doi.org/10.1007/s00330-010-1853-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00330-010-1853-0

Keywords

Search

Navigation