Am. J. Respir. Cell Mol. Biol., Volume 22, Number 1, January, 2000 75-84

Bradykinin Stimulates Lung Fibroblasts to Release Neutrophil and Monocyte Chemotactic Activity

Sekiya Koyama, Etsuro Sato, Hiroki Numanami, Keishi Kubo, Sonoko Nagai, and Takateru Izumi

First Department of Internal Medicine, Shinshu University School of Medicine, and National Chushin-Matsumoto Hospital, Matsumoto; and Kyoto University Chest Disease Research Institute, Kyoto, Japan

Activation of the kallikrein-kinin system in lung injury has long been recognized. However, the effects of bradykinin (BK) on human lung fibroblasts (HLF) remain to be elucidated. We determined whether BK stimulates HLF to release chemotactic activity for neutrophils and monocytes (NCA and MCA, respectively). We evaluated HLF supernatant fluids for chemotactic activity through a blind-well chamber technique. HLF released NCA and MCA in a dose- and time-dependent manner in response to BK. 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 a leukotriene (LT) B₄ receptor antagonist and by antibodies to interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF). MCA was attenuated by the LTB₄ receptor antagonist and by antibodies to monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and transforming growth factor (TGF)-. Both the LTB₄ receptor antagonist and these antibodies inhibited chemotactic activity of the molecular weights corresponding to MCP-1, GM-CSF, and TGF-, separated by column chromatography. The concentrations of IL-8, G-CSF, MCP-1, GM-CSF, and TGF- in supernatant fluids increased significantly in a time-dependent manner in response to BK. The receptors responsible for the release of NCA, MCA, and individual chemokines included both BKB₁ and BKB₂ receptors. These data suggest that BK may stimulate lung fibroblasts to release inflammatory cytokines, which may modulate lung inflammation.

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