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Bleomycin Stimulates Lung Fibroblasts to Release Neutrophil and Monocyte Chemotactic Activity

Akemi Takamizawa^*, Sekiya Koyama^1,*,, Etsuro Sato^*, Takeshi Masubuchi^*, Keishi Kubo^*, Morie Sekiguchi^*, Sonoko Nagai and Takateru Izumi

^* First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan; and Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

We determined whether human lung fibroblasts might release chemotactic activity for neutrophils (NCA) and monocytes (MCA) in response to bleomycin. The human lung fibroblasts supernatant fluids were evaluated for chemotactic activity by a blind well chamber technique. Human lung fibroblasts released NCA and MCA in a dose- and time-dependent manner in response to bleomycin. Checkerboard analysis of supernatant fluids revealed that both NCA and MCA were chemotactic. Partial characterization revealed that NCA was partly heat labile, trypsin sensitive, and predominantly ethyl acetate extractable. In contrast, MCA was partly trypsin sensitive and ethyl acetate extractable. The release of chemotactic activity was inhibited by lipoxygenase inhibitors and cycloheximide. Molecular sieve column chromatography revealed that both NCA and MCA had multiple chemotactic peaks. NCA was inhibited by leukotriene B₄ receptor antagonist and anti-IL-8 and G-CSF Abs. MCA was attenuated by leukotriene B₄ receptor antagonist, and monocyte chemoattractant protein-1, GM-CSF, and TGF-ß Abs. Leukotriene B₄ receptor antagonist and these Abs inhibited the corresponding m.w. chemotactic activity separated by column chromatography. The concentrations of IL-8, G-CSF, monocyte chemoattractant protein-1, GM-CSF, and TGF-ß in the supernatant fluids significantly increased in response to bleomycin. These data suggest that lung fibroblasts may modulate inflammatory cell recruitment into the lung by releasing NCA and MCA in response to bleomycin.

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