Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis.
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.


METHODS
University laboratory.


METHODS
Sprague-Dawley rats.


METHODS
We compared the effects of alveolar instillation of bleomycin in rats treated with either granulocyte colony-stimulating factor or saline.


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.
Azoulay
Elie
E
INSERM U 492, Faculté de Médecine-Université Paris XII, Creteil, France.
Herigault
Sabine
S
Levame
Micheline
M
Brochard
Laurent
L
Schlemmer
Benoît
B
Harf
Alain
A
Delclaux
Christophe
C
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects*; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects* / Q000502:physiology; D007322:Instillation, Drug; D008012:Lidocaine / Q000494:pharmacology / Q000627:therapeutic use; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D016179:Granulocyte Colony-Stimulating Factor; D008012:Lidocaine