Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Morphological changes and proliferative activity of alveolar epithelium in mouse lungs treated with urethan


We have observed sequential cellular changes in type II pneumocytes in mouse lungs following oral administration of 0.1% urethan solution. Histologically, scatterings of swollen alveolar cells were first noticed 25 days after administration. These cells continued to swell further, after which they aggregated more compactly to form a papillary structure by day 75. After day 100, distinct tumour nodules were found with atypical large cells in some areas. Necrotic foci appeared in large tumours of more than 4 mm diameter. At day 250, nucleoli became distinct and large bizarre and multinucleated cells were intermingled with some mitotic figures. These morphologies correspond to conventional descriptions; that is, hyperplasia (day 25–75), benign neoplastic changes (day 75–100) and malignant neoplastic changes (day 100–250). The proliferating cell nuclear antigen (PCNA) and nucleolar organizer regions (AgNOR) scores in these lesions increased with time, and proliferative activities during tumour progression seemed continuous. However, proliferative activity of the cells on specific days did not differ statistically from the values on neighboring days. We speculate that the hyperplasia-like lesions seen in our mice are neoplastic in nature from their outset.

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


  1. 1.

    Bravo R, Frank R, Blundell PA, MacDonald-Bravo H (1987) Cyclin/PCNA is the auxiliary protein of DNA polymerase delta. Nature 326:515–517

  2. 2.

    Caracia RL, Coltera MD, Gown AM (1989) Analysis of proliferative embedded tissues: comparison with flow cytometric analysis. Am J Pathol 134:733–739

  3. 3.

    Ceils JE, Celis A (1985) Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: subdivision of S phase. Proc Natl Acad Sci USA 82:3262–3266

  4. 4.

    Crocker J, Ayers J, McGovern J (1987) Nucleolar organizer regions in small cell carcinoma of the bronchus. Thorax 42:972–975

  5. 5.

    Crocker J, Macartney JC, Smith PJ (1988) Correlation between DNA flow cytometry and nucleolar organizer region data in non-Hodgkin's lymphomas. J Pathol 154:151–156

  6. 6.

    Dervan PA, Gilmartin LG, Loftus BM, Camey DN (1989) Breast carcinoma kinetics: argyrophilic nucleolar organizer region counts correlate with Ki-67 scores. Am J Clin Pathol 92:401–407

  7. 7.

    Hall PA, Levison DA, Woods AL, Yu CW, Kellock DB, Watkins JA, Banes DM, Gillett CE, Camplejohn R, Dover R, Waseen NH, Lane DP (1990) Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: an index of cell proliferation with evidence of deregulated expression in some neoplasm. J Pathol 162:285–294

  8. 8.

    Monobe Y, Manabe T, Yamashita K (1994) Evaluation of atypical hyperplastic lesions of the lung by PCNA and AgNOR: comparison with hyperplastic lesions, adenoma and adenocarcinoma. (In Japanese with English abstract) Jpn J Cancer Clin 40:568–574

  9. 9.

    Ploton D, Menager M, Jeannesson P, Himber G, Pigeon F, Adenet JJ (1986) Improvement in the staining and the visualization of the argyrophilic proteins of the nucleolar or ganizer region at the optical level. Histochem J 18:5–18

  10. 10.

    Re CF, Manenti G, Borrello MG, Colombo MP, Fisher JH, Pierotti MA, Porta GD, Dragani TA (1992) Multiple molecular alterations in mouse lung tumors. Mol Carcinog 5:155–160

  11. 11.

    Svensson K (1988) Alkylation of protein and DNA in mice treated with urethan. Carcinogenesis 9:2197–2201

  12. 12.

    Weng SY, Tsuchiya E, Kasuga T, Sugano H (1992) Incidence of atypical bronchioalveolar cell hyperplasia of the lung: relation to histological subtypes of lung cancer. Virchow Arch [A] 420:563–570

Download references

Author information

Correspondence to Y. Monobe.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Monobe, Y., Manabe, T. Morphological changes and proliferative activity of alveolar epithelium in mouse lungs treated with urethan. Vichows Archiv A Pathol Anat 425, 583–588 (1995).

Download citation

Key words

  • Urethan
  • Mouse
  • Lung tumour
  • Proliferating cell nuclear antigen
  • Nucleolar organizer region