Cyclophosphamide stimulates lung fibroblasts to release neutrophil and monocyte chemoattractants.
Cyclophosphamide is an alkylating antineoplastic agent used in several conditions. However, little is known about the mechanism of its pulmonary toxicity. In the present study, we determined that human lung fibroblasts release activity for neutrophils and monocytes in response to cyclophosphamide in a dose- and time-dependent manner. Checkerboard analysis revealed that both neutrophil and monocyte activities were chemotactic. The release of chemotactic 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 inhibited by a leukotriene B(4) receptor antagonist and anti-interleukin-8 and anti-granulocyte colony-stimulating factor antibodies. MCA was attenuated by a leukotriene B(4) receptor antagonist and anti-monocyte chemoattractant protein-1 and anti-granulocyte-macrophage colony-stimulating factor antibodies. The concentrations of interleukin-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, and granulocyte-macrophage colony-stimulating factor significantly increased in response to cyclophosphamide. These data suggest that lung fibroblasts may modulate inflammatory cell recruitment into the lung by releasing NCA and MCA in response to cyclophosphamide.
Koyama
S
S
Pulmonary Section, The National Chuushin Matsumoto Hospital, 811 Kotobuki Toyooka, Matsumoto 399-0021, Japan. koyama@ka3.so-net.ne.jp
Takamizawa
A
A
Sato
E
E
Masubuchi
T
T
Nagai
S
S
Izumi
T
T
D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D018946:Chemokine CCL5 / Q000032:analysis / Q000037:antagonists & inhibitors; D002630:Chemotactic Factors / Q000378:metabolism* / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D002850:Chromatography, Gel; D003520:Cyclophosphamide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D008168:Lung; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology
D000906:Antibodies; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D002630:Chemotactic Factors; D016209:Interleukin-8; D016212:Transforming Growth Factor beta; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide