Exacerbation by granulocyte colony-stimulating factor of prior acute lung injury: Implication of neutrophils

Abstract

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. To reproduce a routine situation in cancer patients receiving chemotherapy, we investigated the mechanisms underlying granulocyte colony-stimulating factor-induced exacerbation of α-naphthylthiourea-related pulmonary edema. Laboratory research unit. Male specific-pathogen-free Sprague-Dawley rats. The effects of granulocyte colony-stimulating factor given alone or after α-naphthylthiourea used to induce acute lung injury were investigated. 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-α and interleukin-1β were measured in serum, lung homogenates, and isolated alveolar macrophage supernatants. In control rats, granulocyte colony-stimulating factor (25 μg/kg) significantly elevated circulating neutrophil counts without producing alveolar recruitment or pulmonary edema. α-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 α-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 α-naphthylthiourea alone;p < .0001), and increasing proinflammatory cytokine secretion. α-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-α and interleukin-1β concentrations in alveolar macrophage supernatants and lung homogenates were significantly higher with α-naphthylthiourea + granulocyte colony-stimulating factor than with either agent alone, and anti-tumor necrosis factor-α antibodies abolished granulocyte colony-stimulating factor-related exacerbation of α-naphthylthiourea-induced pulmonary edema. In rats with cyclophosphamide-induced neutropenia, tumor necrosis factor-α concentrations in alveolar macrophage supernatants and lung homogenates were significantly decreased compared with rats without neutropenia. 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.