OBJECTIVE: Potentially fatal pulmonary toxicity is a dreaded complication of 
bleomycin. Increased use of granulocyte colony-stimulating factor in patients 
receiving chemotherapy has been paralleled by an increased incidence of 
bleomycin-induced pulmonary toxicity. We investigated whether granulocyte 
colony-stimulating factor (25 microg x kg(-1) x day(-1), 4 days) enhanced 
endotracheal bleomycin-induced (5 mg/kg) acute lung injury and fibrosis in rats.
SETTING: University laboratory.
SUBJECTS: Sprague-Dawley rats.
INTERVENTIONS: We compared the effects of alveolar instillation of bleomycin in 
rats treated with either granulocyte colony-stimulating factor or saline.
MEASUREMENTS AND MAIN RESULTS: Mortality was 25% with bleomycin only and 50% 
with bleomycin + granulocyte colony-stimulating factor. Granulocyte 
colony-stimulating factor increased alveolar neutrophil recruitment, pulmonary 
edema, and lung myeloperoxidase activity on day 4. Lung static compliance on day 
15 was severely decreased with bleomycin alone and showed a further significant 
decrease when granulocyte colony-stimulating factor was added (controls, 3.85 
+/- 0.14 mL/kPa; bleomycin, 1.44 +/- 0.06 mL/kPa; and bleomycin + granulocyte 
colony-stimulating factor, 0.65 +/- 0.09 mL/kPa; control vs. bleomycin, p 
<.0001; and bleomycin vs. bleomycin + granulocyte colony-stimulating factor, p 
=.0003). Lung morphology with bleomycin + granulocyte colony-stimulating factor 
showed, in addition to the changes observed with bleomycin alone, four patterns 
indicating more severe disease: honeycomb foci, pleural thickening with hyaline 
fibrosis, interstitial granuloma with increased number of macrophages but not 
neutrophils, and established interstitial fibrosis. Lidocaine, which prevents 
neutrophil adhesion to endothelial cells, inhibited granulocyte 
colony-stimulating factor-related exacerbation of acute lung injury 
(bronchoalveolar lavage fluid cells and pulmonary edema) and pulmonary fibrosis 
(lung static compliance and morphologic changes).
CONCLUSIONS: Granulocyte colony-stimulating factor enhances bleomycin-induced 
lung toxicity by a mechanism that probably involves neutrophils.