Bradykinin stimulates lung fibroblasts to release neutrophil and monocyte chemotactic activity.
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) B(4) receptor antagonist and by antibodies to interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF). MCA was attenuated by the LTB(4) receptor antagonist and by antibodies to monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and transforming growth factor (TGF)-beta. Both the LTB(4) receptor antagonist and these antibodies inhibited chemotactic activity of the molecular weights corresponding to MCP-1, GM-CSF, and TGF-beta, separated by column chromatography. The concentrations of IL-8, G-CSF, MCP-1, GM-CSF, and TGF-beta 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 BKB(1) and BKB(2) receptors. These data suggest that BK may stimulate lung fibroblasts to release inflammatory cytokines, which may modulate lung inflammation.
Koyama
S
S
First Department of Internal Medicine, Shinshu University School of Medicine, and National Chushin-Matsumoto Hospital, Matsumoto, Japan.
Sato
E
E
Numanami
H
H
Kubo
K
K
Nagai
S
S
Izumi
T
T
D001667:Binding, Competitive; D001920:Bradykinin / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D002850:Chromatography, Gel; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D016676:Macrophages, Alveolar; D009000:Monocytes / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
D018946:Chemokine CCL5; D002630:Chemotactic Factors; D016209:Interleukin-8; D016859:Lipoxygenase Inhibitors; D011500:Protein Synthesis Inhibitors; D016212:Transforming Growth Factor beta; D016179:Granulocyte Colony-Stimulating Factor; D007975:Leukotriene B4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D001920:Bradykinin