Cyclophosphamide stimulates lung fibroblasts to release neutrophil and monocyte chemoattractants

Cyclophosphamide is an alkylating antineoplastic agent used in several cond itions. However, little is known about the mechanism of its pulmonary toxic ity. In the present study, we determined that human lung fibroblasts releas e activity for neutrophils and monocytes in response to cyclophosphamide in a dose- and time-dependent manner. Checkerboard analysis revealed that bot h neutrophil and monocyte activities were chemotactic. The release of chemo tactic activity was inhibited by lipoxygenase inhibitors and cycloheximide. Molecular-sieve column chromatography revealed that both neutrophil (NCA) and monocyte (MCA) chemotactic activities had multiple peaks. NCA was inhib ited by a leukotriene B-4 receptor antagonist and anti-interleukin-8 and an ti-granulocyte colony-stimulating factor antibodies. MCA was attenuated by a leukotriene B-4 receptor antagonist and anti-monocyte chemoattractant pro tein-1 and anti-granulocyte-macrophage colony-stimulating factor antibodies . The concentrations of interleukin-8, granulocyte colony-stimulating facto r, monocyte chemoattractant protein-1, and granulocyte-macrophage colony-st imulating factor significantly increased in response to cyclophosphamide. T hese data suggest that lung fibroblasts may modulate inflammatory cell recr uitment into the lung by releasing NCA and MCA in response to cyclophospham ide.