Exacerbation by granulocyte colony-stimulating factor of prior acute lung injury: implication of neutrophils.
OBJECTIVE
Granulocyte colony-stimulating factor is widely prescribed to hasten recovery from cancer chemotherapy-induced neutropenia and has been reported to induce pulmonary toxicity. However, circumstances and mechanisms of this toxicity remain poorly known.


METHODS
To reproduce a routine situation in cancer patients receiving chemotherapy, we investigated the mechanisms underlying granulocyte colony-stimulating factor-induced exacerbation of alpha-naphthylthiourea-related pulmonary edema.


METHODS
Laboratory research unit.


METHODS
Male specific-pathogen-free Sprague-Dawley rats.


METHODS
The effects of granulocyte colony-stimulating factor given alone or after alpha-naphthylthiourea used to induce acute lung injury were investigated.


RESULTS
Lung injury was assessed based on neutrophil sequestration (myeloperoxidase activity in lung tissue) and influx into alveolar spaces (bronchoalveolar lavage fluid cell quantification) and on edema formation (wet/dry lung weight ratio) and alveolar protein concentration into bronchoalveolar lavage fluid. Tumor necrosis factor-alpha and interleukin-1beta were measured in serum, lung homogenates, and isolated alveolar macrophage supernatants. In control rats, granulocyte colony-stimulating factor (25 microg/kg) significantly elevated circulating neutrophil counts without producing alveolar recruitment or pulmonary edema. alpha-Naphthylthiourea significantly increased the wet/dry lung weight ratio (4.68 +/- 0.04 vs. 4.38 +/- 0.07 in controls, p=.04) and induced alveolar protein leakage. Adding granulocyte colony-stimulating factor to alpha-naphthylthiourea exacerbated pulmonary edema, causing neutrophil sequestration in pulmonary vessels, significantly increasing lung myeloperoxidase activity (12.7 +/- 2.0 mOD/min/g vs. 1.1 +/- 0.4 mOD/min/g with alpha-naphthylthiourea alone; p<.0001), and increasing proinflammatory cytokine secretion. alpha-Naphthylthiourea-related pulmonary edema was not exacerbated by granulocyte colony-stimulating factor during cyclophosphamide-induced neutropenia or after lidocaine, which antagonizes neutrophil adhesion to endothelial cells. Tumor necrosis factor-alpha and interleukin-1beta concentrations in alveolar macrophage supernatants and lung homogenates were significantly higher with alpha-naphthylthiourea + granulocyte colony-stimulating factor than with either agent alone, and anti-tumor necrosis factor-alpha antibodies abolished granulocyte colony-stimulating factor-related exacerbation of alpha-naphthylthiourea-induced pulmonary edema. In rats with cyclophosphamide-induced neutropenia, tumor necrosis factor-alpha concentrations in alveolar macrophage supernatants and lung homogenates were significantly decreased compared with rats without neutropenia.


CONCLUSIONS
Granulocyte colony-stimulating factor-related pulmonary toxicity may involve migration of neutrophils to vascular spaces, adhesion of neutrophils to previously injured endothelial cells, and potentiation of proinflammatory cytokine expression.
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004347:Drug Interactions; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced* / Q000517:prevention & control; D012378:Rodenticides / Q000633:toxicity*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000633:toxicity*
D018906:Antineoplastic Agents, Alkylating; D016207:Cytokines; D012378:Rodenticides; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; D009195:Peroxidase; D013890:Thiourea; C005277:alpha-naphthyl thiourea