Advertisement

Lung

, Volume 161, Issue 1, pp 287–300 | Cite as

Chronic airway obstruction and bronchiectasis in the rat after intratracheal bleomycin

  • D. L. Costa
  • J. R. Lehmann
  • D. N. Slatkin
  • E. A. Popenoe
  • R. T. Drew
Original Articles

Abstract

Intratracheal instillation of bleomycin (BLM) has been used to generate rodent models of interstitial pulmonary fibrosis. In rats, we show that intratracheally instilled BLM evokes acute bronchopneumonia which persists and evolves into bronchiectasis associated with marked airflow dysfunction. Male F-344 rats, 11 weeks old, were treated once with BLM (4 or 5 units/kg body weight) and sacrificed at 2, 7, 14, 28, 56, and 154 d later for morphologic assessment. Static and dynamic pulmonary function tests were performed on the surviving rats 14 months and 2 years after treatment. The lungs from these rats were divided for histological and biochemical (elastin, hydroxyproline, DNA, protein) analyses. At both 14 months and 2 years, significantly depressed flow-volume curves and paradoxical increases in inflation pressure and residual volume were the predominant dysfunctions. Elastin and hydroxyproline levels, markedly elevated at 14 months, correlated with airflow dysfunction rather than loss of compliance. Light microscopy confirmed the presence of airway damage which comprised focal bronchiectasis and confluent peribronchial fibrosis.

Key words

Bronchiectasis Lung disease Airways Bleomycin 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Adamson IYR, Bowden DH (1974) The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am J Pathol 77:185–198PubMedGoogle Scholar
  2. 2.
    Adamson IYR, Bowden DH, Wyatt JP (1970) A pathway to pulmonary fibrosis: an ultrastructural study of mouse and rat following radiation to the whole body and hemithorax. Am J Pathol 55:481–498Google Scholar
  3. 3.
    Bedrossian CWM, Greenberg SD, Yawn DH, O’Neal RM (1977) Experimentally induced bleomycin sulfate pulmonary toxicity: histologic and ultrastructural study in the pheasant. Arch Pathol Lab Med 101:248–254PubMedGoogle Scholar
  4. 4.
    Bergman I, Loxley R (1963) Two improved and simplified methods for the spectrophometric determination of hydroxyproline. Anal Chem 35:1961–1965CrossRefGoogle Scholar
  5. 5.
    Burton K (1956) A study of the conditions and mechanisms in the diphenylamine reaction for the colorimetric determination of DNA. Biochem J 62:315–322PubMedGoogle Scholar
  6. 6.
    Collins JF, Orozio CR, McCullough B, Coalson JJ, Johanson WG (1982) Pulmonary fibrosis with small airway disease: a model in nonhuman primates. Exp Lung Res 3:91–108PubMedGoogle Scholar
  7. 7.
    Comis RL (1978) Bleomycin pulmonary toxicity. In: Bleomycin: current status and new developments. Academic Press, New York London, pp 279–291Google Scholar
  8. 8.
    Costa DL, Kutzman RS, Lehmann JR, Popenoe EA, Drew RT (1983) A subchronic multidose ozone study in rats. Adv Mod Environ Toxicol, Chapt 28:369–393Google Scholar
  9. 9.
    Fedullo AJ, Karlinsky JB, Snider GL, Goldstein RH (1980) Lung statics and connective tissue after penicillamine in bleomycin-treated hamsters. J Appl Physiol 49:1083–1090PubMedGoogle Scholar
  10. 10.
    Fischer NK, Clements JA (1969) Effects of the herbicide paraquat on the mechanical properties of rat lungs. Fed Proc 28, abstr no 1481Google Scholar
  11. 11.
    Goldiner PL, Carlon GC, Cvitkovic E, Schwizer O, Howland WS (1978) Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J 1:1664–1667PubMedCrossRefGoogle Scholar
  12. 12.
    Goldstein RH, Lucey EC, Franzblau C, Snider GL (1979) Failure of mechanical properties to parallel changes in lung connective tissue composition in bleomycin-induced fibrosis in hamsters. Am Rev Respir Dis 120:67–73PubMedGoogle Scholar
  13. 13.
    Gross P, de Treville RTP (1968) Alveolar proteinosis. Arch Pathol 86:255–261PubMedGoogle Scholar
  14. 14.
    Hartree EF (1972) Determination of protein: a modification of the Lowry method that gives a linear photometric response. Anal Biochem 48:422–427PubMedCrossRefGoogle Scholar
  15. 15.
    Hascheck WM, Witschi HP (1979) Pulmonary fibrosis — a possible mechanism. Toxicol Appl Pharmacol 51:475–487CrossRefGoogle Scholar
  16. 16.
    Hesterberg TW, Gerriets JE, Reiser KM, Jackson AC, Cross CE, Last JA (1981) Bleomycin-induced pulmonary fibrosis: correlation of biochemical, physiological, and histological changes. Toxicol Appl Pharmacol 60:360–367PubMedCrossRefGoogle Scholar
  17. 17.
    Johanson WG, Pierce AK (1973) Lung structure and function with age in normal rats and rats with papain emphysema. J Clin Invest 52:2921–2927PubMedGoogle Scholar
  18. 18.
    Keough BA, Crystal RG (1980) Clinical significance of pulmonary function tests in interstitial disease. Chest 78:856–865Google Scholar
  19. 19.
    Lehmann JR, Costa DL, Slatkin DN (1981) Diffuse interstitial pulmonary fibrosis in the rat: an approach using bleomycin in combination with oxygen. Presented at Small Animal Respiratory Function Satellite of American Thoracic Society Annual Meeting, Michigan State University, May 1981Google Scholar
  20. 20.
    McCullough B, Collins JF, Johanson WG, Grover FL (1978) Bleomycin-induced diffuse interstitial pulmonary fibrosis in baboons. J Clin Invest 61:79–88PubMedCrossRefGoogle Scholar
  21. 21.
    Naum Y, Morgan TE (1973) A microassay for elastin. Anal Biochem 53:392–396PubMedCrossRefGoogle Scholar
  22. 22.
    Pengally LD (1977) Curve fitting analysis of pressure-volume characteristics of the lungs. J Appl Physiol 42:111–116Google Scholar
  23. 23.
    Richerson HB, Seidenfeld JJ, Ratajczak HV, Richards D, Butler JE, Swanson P (1979) Models of pulmonary fibrosis, misadventures and ramifications. Chest 75S:267S-268SGoogle Scholar
  24. 24.
    Rinaldo JE, Goldstein RH, Snider GL (1980) The toxicity of oxygen in hamsters with bleomycin-induced interstitial pneumonia. Am Rev Respir Dis 121:183Google Scholar
  25. 25.
    Ryan SF (1972) Experimental fibrosing alveolitis. Am Rev Respir Dis 105:776–791PubMedGoogle Scholar
  26. 26.
    Saidel GM, Salmon RB, Chester EH (1975) Moment analysis of multibreath lung washout. J Appl Physiol 38:328–334PubMedGoogle Scholar
  27. 27.
    Snider GL, Celli BR, Goldstein RH, O’Brien JJ, Lucey EC (1978) Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Am Rev Respir Dis 117:289–297PubMedGoogle Scholar
  28. 28.
    Snider GL, Hayes JA, Korthy AL (1978) Chronic interstitial fibrosis produced in hamsters by endotracheal bleomycin. Am Rev Respir Dis 117:1099–1108PubMedGoogle Scholar
  29. 29.
    Starcher BC, Kuhn C, Overton JE (1978) Increased elastin and collagen content in the lungs of hamsters receiving an intratracheal injection of bleomycin. Am Rev Respir Dis 117:299–305PubMedGoogle Scholar
  30. 30.
    Takezawa J, Miller FJ, O’Neill JJ (1980) Single-breath diffusing capacity and lung volumes in small laboratory mammals. J Appl Physiol 48:1052–1059PubMedGoogle Scholar
  31. 31.
    Thrall RS, McCormick JR, Jack RM, McReynolds RA, Ward PA (1979) Bleomycin-induced pulmonary fibrosis in the rat. Am J Pathol 95:117–130PubMedGoogle Scholar
  32. 32.
    Tryka AF, Skornik WA, Godleski JJ, Brain JD (1982) Potentiation of bleomycin-induced lung injury by exposure to 70% oxygen: morphologic assessment. Am Rev Respir Dis 126:1074–1079PubMedGoogle Scholar
  33. 33.
    Vorwald AJ, Dinkan TM, Pratt PC (1951) Experimental studies of asbestosis. Arch Ind Hyg 3:1–43Google Scholar

Copyright information

© Springer-Verlag GmbH & Co KG 1983

Authors and Affiliations

  • D. L. Costa
    • 1
  • J. R. Lehmann
    • 1
  • D. N. Slatkin
    • 1
  • E. A. Popenoe
    • 1
  • R. T. Drew
    • 1
  1. 1.Medical DepartmentBrookhaven National LaboratoryUptonUSA

Personalised recommendations