Skip to main content
PMC home page
Thorax logoLink to Thorax
. 1987 May;42(5):374–382. doi: 10.1136/thx.42.5.374

Development of acute lung injury after the combination of intravenous bleomycin and exposure to hyperoxia in rats.

J G Hay 1, P L Haslam 1, A Dewar 1, B Addis 1, M Turner-Warwick 1, G J Laurent 1
PMCID: PMC460759  PMID: 2443992

Abstract

Pulmonary toxicity is an important adverse effect of bleomycin treatment. Very little is known of the mechanisms underlying the development of lung injury, especially after intravenous administration, or how it can be modulated. In this study acute lung injury induced by bleomycin has been examined in rats by assessment of alveolar lavage cell profiles, histological examination, and measurement of the total pulmonary extravascular albumin space. Intratracheal instillation of bleomycin 1.5 mg resulted in a severe pneumonitis with influx of inflammatory cells into the alveoli as assessed by alveolar lavage, oedema of the alveolar walls, and up to an eight fold increase in the total pulmonary extravascular albumin space, maximal at 72 hours. Intravenous bleomycin 0.15-5 mg produced no detectable injury when assessed in these ways. Exposure to hyperoxia (40-90%) after intravenous bleomycin, however, induced lung injury similar to that produced by intratracheal bleomycin. A much more severe injury followed administration of intravenous bleomycin after an exposure to hyperoxia, which itself resulted in lung injury; but lung injury was still detectable after bleomycin when the exposure to hyperoxia was insufficient to induce changes in control animals. Lung injury was not observed when the exposure to hyperoxia preceded bleomycin treatment. These results indicate the importance of oxygen in the pathways leading to acute lung injury following intravenous bleomycin. We conclude that exposure to oxygen might induce lung injury during and after bleomycin treatment, and suggest that in these circumstances oxygen therapy should be kept to a minimum.

Full text

PDF
374

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adamson I. Y., Bowden D. H. Bleomycin-induced injury and metaplasia of alveolar type 2 cells. Relationship of cellular responses to drug presence in the lung. Am J Pathol. 1979 Aug;96(2):531–544. [PMC free article] [PubMed] [Google Scholar]
  2. Alberts D. S., Chen H. S., Liu R., Himmelstein K. J., Mayersohn M., Perrier D., Gross J., Moon T., Broughton A., Salmon S. E. Bleomycin pharmacokinetics in man. I. Intravenous administration. Cancer Chemother Pharmacol. 1978;1(3):177–181. doi: 10.1007/BF00253118. [DOI] [PubMed] [Google Scholar]
  3. Bauer K. A., Skarin A. T., Balikian J. P., Garnick M. B., Rosenthal D. S., Canellos G. P. Pulmonary complications associated with combination chemotherapy programs containing bleomycin. Am J Med. 1983 Apr;74(4):557–563. doi: 10.1016/0002-9343(83)91009-4. [DOI] [PubMed] [Google Scholar]
  4. Bedrossian C. W., Luna M. A., Mackay B., Lichtiger B. Ultrastructure of pulmonary bleomycin toxicity. Cancer. 1973 Jul;32(1):44–51. doi: 10.1002/1097-0142(197307)32:1<44::aid-cncr2820320106>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  5. Berend N. The effect of bleomycin and oxygen on rat lung. Pathology. 1984 Apr;16(2):136–139. doi: 10.3109/00313028409059091. [DOI] [PubMed] [Google Scholar]
  6. Blum R. H., Carter S. K., Agre K. A clinical review of bleomycin--a new antineoplastic agent. Cancer. 1973 Apr;31(4):903–914. doi: 10.1002/1097-0142(197304)31:4<903::aid-cncr2820310422>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  7. Carson F. L., Martin J. H., Lynn J. A. Formalin fixation for electron microscopy: a re-evaluation. Am J Clin Pathol. 1973 Mar;59(3):365–373. doi: 10.1093/ajcp/59.3.365. [DOI] [PubMed] [Google Scholar]
  8. Chandler D. B., Fulmer J. D. The effect of deferoxamine on bleomycin-induced lung fibrosis in the hamster. Am Rev Respir Dis. 1985 Apr;131(4):596–598. doi: 10.1164/arrd.1985.131.4.596. [DOI] [PubMed] [Google Scholar]
  9. Chandler D. B., Hyde D. M., Giri S. N. Morphometric estimates of infiltrative cellular changes during the development of bleomycin-induced pulmonary fibrosis in hamsters. Am J Pathol. 1983 Aug;112(2):170–177. [PMC free article] [PubMed] [Google Scholar]
  10. Clark J. G., Kostal K. M., Marino B. A. Bleomycin-induced pulmonary fibrosis in hamsters. An alveolar macrophage product increases fibroblast prostaglandin E2 and cyclic adenosine monophosphate and suppresses fibroblast proliferation and collagen production. J Clin Invest. 1983 Dec;72(6):2082–2091. doi: 10.1172/JCI111173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Comis R. L., Kuppinger M. S., Ginsberg S. J., Crooke S. T., Gilbert R., Auchincloss J. H., Prestayko A. W. Role of single-breath carbon monoxide-diffusing capacity in monitoring the pulmonary effects of bleomycin in germ cell tumor patients. Cancer Res. 1979 Dec;39(12):5076–5080. [PubMed] [Google Scholar]
  12. Dalgleish A. G., Woods R. L., Levi J. A. Bleomycin pulmonary toxicity: its relationship to renal dysfunction. Med Pediatr Oncol. 1984;12(5):313–317. doi: 10.1002/mpo.2950120503. [DOI] [PubMed] [Google Scholar]
  13. Donohue J. P., Rowland R. G. Complications of retroperitoneal lymph node dissection. J Urol. 1981 Mar;125(3):338–340. doi: 10.1016/s0022-5347(17)55029-6. [DOI] [PubMed] [Google Scholar]
  14. Douglas M. J., Coppin C. M. Bleomycin and subsequent anaesthesia: a retrospective study at Vancouver General Hospital. Can Anaesth Soc J. 1980 Sep;27(5):449–452. doi: 10.1007/BF03007042. [DOI] [PubMed] [Google Scholar]
  15. Garnick M. B. Advanced testicular cancer: treatment choices in the "land of plenty". J Clin Oncol. 1985 Mar;3(3):294–297. doi: 10.1200/JCO.1985.3.3.294. [DOI] [PubMed] [Google Scholar]
  16. Goldiner P. L., Carlon G. C., Cvitkovic E., Schweizer O., Howland W. S. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J. 1978 Jun 24;1(6128):1664–1667. doi: 10.1136/bmj.1.6128.1664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hakkinen P. J., Morse C. C., Martin F. M., Dalbey W. E., Haschek W. M., Witschi H. R. Potentiating effects of oxygen in lungs damaged by methylcyclopentadienyl manganese tricarbonyl, cadmium chloride, oleic acid, and antitumor drugs. Toxicol Appl Pharmacol. 1983 Jan;67(1):55–69. doi: 10.1016/0041-008x(83)90244-2. [DOI] [PubMed] [Google Scholar]
  18. Hakkinen P. J., Whiteley J. W., Witschi H. R. Hyperoxia, but not thoracic X-irradiation, potentiates bleomycin- and cyclophosphamide-induced lung damage in mice. Am Rev Respir Dis. 1982 Aug;126(2):281–285. doi: 10.1164/arrd.1982.126.2.281. [DOI] [PubMed] [Google Scholar]
  19. Haslam P. L., Allan F., Watling A. F., Barrett C., Morris L., Turner-Warwick M. Impaired antibody-dependent cell-mediated cytotoxicity in cryptogenic fibrosing alveolitis (synonym: idiopathic pulmonary fibrosis). Clin Exp Immunol. 1982 Jul;49(1):59–66. [PMC free article] [PubMed] [Google Scholar]
  20. Haslam P. L., Turton C. W., Lukoszek A., Salsbury A. J., Dewar A., Collins J. V., Turner-Warwick M. Bronchoalveolar lavage fluid cell counts in cryptogenic fibrosing alveolitis and their relation to therapy. Thorax. 1980 May;35(5):328–339. doi: 10.1136/thx.35.5.328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jones A. W. Bleomycin lung damage: the pathology and nature of the lesion. Br J Dis Chest. 1978 Oct;72(4):321–326. [PubMed] [Google Scholar]
  22. LaMantia K. R., Glick J. H., Marshall B. E. Supplemental oxygen does not cause respiratory failure in bleomycin-treated surgical patients. Anesthesiology. 1984 Jan;60(1):65–67. doi: 10.1097/00000542-198401000-00014. [DOI] [PubMed] [Google Scholar]
  23. Laurent G. J. Biochemical pathways leading to collagen deposition in pulmonary fibrosis. Ciba Found Symp. 1985;114:222–233. doi: 10.1002/9780470720950.ch15. [DOI] [PubMed] [Google Scholar]
  24. Laurent G. J., McAnulty R. J., Corrin B., Cockerill P. Biochemical and histological changes in pulmonary fibrosis induced in rabbits with intratracheal bleomycin. Eur J Clin Invest. 1981 Dec;11(6):441–448. doi: 10.1111/j.1365-2362.1981.tb02011.x. [DOI] [PubMed] [Google Scholar]
  25. Laurent G. J., McAnulty R. J. Protein metabolism during bleomycin-induced pulmonary fibrosis in rabbits. In vivo evidence for collagen accumulation because of increased synthesis and decreased degradation of the newly synthesized collagen. Am Rev Respir Dis. 1983 Jul;128(1):82–88. doi: 10.1164/arrd.1983.128.1.82. [DOI] [PubMed] [Google Scholar]
  26. Luursema P. B., Star-Kroesen M. A., van der Mark T. W., Sleyfer D. T., Koops H. S., Peset R. Bleomycin-induced changes in the carbon monoxide transfer factor of the lungs and its components. Am Rev Respir Dis. 1983 Nov;128(5):880–883. doi: 10.1164/arrd.1983.128.5.880. [DOI] [PubMed] [Google Scholar]
  27. Mandelbaum I., Williams S. D., Einhorn L. H. Aggressive surgical management of testicular carcinoma metastatic to lungs and mediastinum. Ann Thorac Surg. 1980 Sep;30(3):224–229. doi: 10.1016/s0003-4975(10)61249-0. [DOI] [PubMed] [Google Scholar]
  28. Phan S. H., Fantone J. C. Inhibition of bleomycin-induced pulmonary fibrosis by lipopolysaccharide. Lab Invest. 1984 May;50(5):587–591. [PubMed] [Google Scholar]
  29. Phan S. H., Schrier D., McGarry B., Duque R. E. Effect of the beige mutation on bleomycin-induced pulmonary fibrosis in mice. Am Rev Respir Dis. 1983 Apr;127(4):456–459. doi: 10.1164/arrd.1983.127.4.456. [DOI] [PubMed] [Google Scholar]
  30. Phan S. H., Thrall R. S., Ward P. A. Bleomycin-induced pulmonary fibrosis in rats: biochemical demonstration of increased rate of collagen synthesis. Am Rev Respir Dis. 1980 Mar;121(3):501–506. doi: 10.1164/arrd.1980.121.3.501. [DOI] [PubMed] [Google Scholar]
  31. Phan S. H., Thrall R. S., Williams C. Bleomycin-induced pulmonary fibrosis. Effects of steroid on lung collagen metabolism. Am Rev Respir Dis. 1981 Oct;124(4):428–434. doi: 10.1164/arrd.1981.124.4.428. [DOI] [PubMed] [Google Scholar]
  32. Rinaldo J., Goldstein R. H., Snider G. L. Modification of oxygen toxicity after lung injury by bleomycin in hamsters. Am Rev Respir Dis. 1982 Dec;126(6):1030–1033. doi: 10.1164/arrd.1982.126.6.1030. [DOI] [PubMed] [Google Scholar]
  33. Schrier D. J., Phan S. H., McGarry B. M. The effects of the nude (nu/nu) mutation on bleomycin-induced pulmonary fibrosis. A biochemical evaluation. Am Rev Respir Dis. 1983 May;127(5):614–617. doi: 10.1164/arrd.1983.127.5.614. [DOI] [PubMed] [Google Scholar]
  34. Schrier D. J., Phan S. H. Modulation of bleomycin-induced pulmonary fibrosis in the BALB/c mouse by cyclophosphamide-sensitive T cells. Am J Pathol. 1984 Aug;116(2):270–278. [PMC free article] [PubMed] [Google Scholar]
  35. Slade R., Stead A. G., Graham J. A., Hatch G. E. Comparison of lung antioxidant levels in humans and laboratory animals. Am Rev Respir Dis. 1985 May;131(5):742–746. doi: 10.1164/arrd.1985.131.5.742. [DOI] [PubMed] [Google Scholar]
  36. Snider G. L., Celli B. R., Goldstein R. H., O'Brien J. J., Lucey E. C. Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Lung volumes, volume-pressure relations, carbon monoxide uptake, and arterial blood gas studied. Am Rev Respir Dis. 1978 Feb;117(2):289–297. doi: 10.1164/arrd.1978.117.2.289. [DOI] [PubMed] [Google Scholar]
  37. Thrall R. S., Barton R. W. A comparison of lymphocyte populations in lung tissue and in bronchoalveolar lavage fluid of rats at various times during the development of bleomycin-induced pulmonary fibrosis. Am Rev Respir Dis. 1984 Feb;129(2):279–283. [PubMed] [Google Scholar]
  38. Thrall R. S., Barton R. W., D'Amato D. A., Sulavik S. B. Differential cellular analysis of bronchoalveolar lavage fluid obtained at various stages during the development of bleomycin-induced pulmonary fibrosis in the rat. Am Rev Respir Dis. 1982 Sep;126(3):488–492. doi: 10.1164/arrd.1982.126.3.488. [DOI] [PubMed] [Google Scholar]
  39. Thrall R. S., McCormick J. R., Jack R. M., McReynolds R. A., Ward P. A. Bleomycin-induced pulmonary fibrosis in the rat: inhibition by indomethacin. Am J Pathol. 1979 Apr;95(1):117–130. [PMC free article] [PubMed] [Google Scholar]
  40. Tryka A. F., Godleski J. J., Brain J. D. Differences in effects of immediate and delayed hyperoxia exposure on bleomycin-induced pulmonary injury. Cancer Treat Rep. 1984 May;68(5):759–764. [PubMed] [Google Scholar]
  41. Tryka A. F., Skornik W. A., Godleski J. J., Brain J. D. Potentiation of bleomycin-induced lung injury by exposure to 70% oxygen. Morphologic assessment. Am Rev Respir Dis. 1982 Dec;126(6):1074–1079. doi: 10.1164/arrd.1982.126.6.1074. [DOI] [PubMed] [Google Scholar]
  42. Umezawa H., Maeda K., Takeuchi T., Okami Y. New antibiotics, bleomycin A and B. J Antibiot (Tokyo) 1966 Sep;19(5):200–209. [PubMed] [Google Scholar]
  43. Van Barneveld P. W., van der Mark T. W., Sleijfer D. T., Mulder N. H., Koops H. S., Sluiter H. J., Peset R. Predictive factors for bleomycin-induced pneumonitis. Am Rev Respir Dis. 1984 Dec;130(6):1078–1081. doi: 10.1164/arrd.1984.130.6.1078. [DOI] [PubMed] [Google Scholar]
  44. Wangensteen D., Yankovich R., Hoidal J., Niewoehner D. Bleomycin-induced changes in pulmonary microvascular albumin permeability and extravascular albumin space. Am Rev Respir Dis. 1983 Feb;127(2):204–208. doi: 10.1164/arrd.1983.127.2.204. [DOI] [PubMed] [Google Scholar]
  45. Wesselius L. J., Catanzaro A., Wasserman S. I. Neutrophil chemotactic activity generation by alveolar macrophages after bleomycin injury. Am Rev Respir Dis. 1984 Mar;129(3):485–490. doi: 10.1164/arrd.1984.129.3.485. [DOI] [PubMed] [Google Scholar]
  46. White D. A., Stover D. E. Severe bleomycin-induced pneumonitis. Clinical features and response to corticosteroids. Chest. 1984 Nov;86(5):723–728. doi: 10.1378/chest.86.5.723. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES