Exacerbation of bleomycin-induced injury and fibrosis by pneumonectomy in the residual lung of mice

J Surg Res. 2009 Jun 15;154(2):336-44. doi: 10.1016/j.jss.2008.06.021. Epub 2008 Jul 15.


Background: Lung resection after induction chemotherapy and/or radiotherapy for down-staging of locally advanced lung cancer can be complicated with lethal interstitial pneumonia. We studied the effects of pneumonectomy on bleomycin-induced lung injury and fibrosis in mice.

Methods: The mice underwent left pneumonectomy or a sham thoracotomy after intratracheal administration of saline or bleomycin. Lung permeability index, wet-to-dry weight ratio, histological changes, collagen contents, and concentrations of inflammatory mediators and cell counts in broncho-alveolar lavage (BAL) fluid were assessed in the residual right lung 7 d after surgery.

Results: The index of capillary permeability, lung water content, and inflammatory cell counts in BAL fluid were significantly increased by pneumonectomy. These measurements were highest in the mice with both pneumonectomy and intratracheal administration of bleomycin. Similarly, fibrotic change in lung pathology, as well as an increase in lung collagen content, was most prominent in the mice exposed to both interventions. The BAL fluid concentrations of interleukin-1beta, interleukin-6, RANTES, and high mobility group box 1 were significantly increased by pneumonectomy and enhanced by the additional administration of bleomycin.

Conclusions: The results of this study indicate that pneumonectomy alone causes noncritical lung injury, which amplifies the inflammatory response to bleomycin and promotes lung fibrosis. Several inflammatory mediators appear to be involved in the exacerbation of bleomycin-induced lung injury and fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / pathology*
  • Acute Lung Injury / surgery*
  • Animals
  • Antibiotics, Antineoplastic / toxicity
  • Bleomycin / toxicity
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • Capillary Permeability
  • Chemokine CCL2 / metabolism
  • Chemokine CCL5 / metabolism
  • Chemokine CXCL1 / metabolism
  • Collagen / metabolism
  • Extravascular Lung Water / metabolism
  • HMGB1 Protein / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pneumonectomy*
  • Postoperative Complications / immunology
  • Postoperative Complications / pathology*
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / pathology
  • Specific Pathogen-Free Organisms
  • Tumor Necrosis Factor-alpha / metabolism


  • Antibiotics, Antineoplastic
  • Ccl2 protein, mouse
  • Ccl5 protein, mouse
  • Chemokine CCL2
  • Chemokine CCL5
  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • HMGB1 Protein
  • Interleukin-1beta
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Bleomycin
  • Collagen