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Serine Protease Inhibitors Modulate Smoke-Induced Chemokine Release From Human Lung Fibroblasts

Research Service, Southern Arizona Veterans Health Care System, and Arizona Respiratory Center, University of Arizona, Tucson, Arizona; First Department of Internal Medicine, and Second Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan

Address correspondence to: Richard A. Robbins, M.D., Chief, Research Service Line, Southern Arizona Veterans Health Care System, 3601 S. 6th Ave., Tucson, AZ 85723. E-mail: Richard.Robbins2{at}med.va.gov

Smoking is associated with lung inflammation and a protease–antiprotease imbalance. We previously reported that cigarette smoke extract (CSE) stimulates human lung fibroblasts to release chemotactic cytokines. We hypothesized that serine protease inhibitors might modulate lung fibroblast release of chemotactic cytokines in response to CSE. To test this hypothesis, serine protease inhibitors (FK706, 1-antitrypsin, methoxysuccinyl-Ala-Ala-Pro-Val chloromethyl ketone, or N-p-tosyl-L-lysine chloromethyl ketone) were evaluated for their capacity to attenuate the release of neutrophil chemotactic activity (NCA) and monocyte chemotactic activity (MCA) from human fetal lung fibroblasts by the blind-well chemotactic chamber. Metalloproteinases and cysteine proteinases were not examined in this study. Similarly, the release and gene expression of chemokines and nuclear factor-B (NF-B) activation were measured by means of enzyme-linked immunosorbent assay and reverse transcriptase–polymerase chain reaction. Release of NCA, MCA, chemotactic chemokines including interleukin-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, and granulocyte-macrophage colony-stimulating factor, and the expression of interleukin-8 and monocyte chemoattractant protein-1 mRNA were attenuated by FK706. Furthermore, FK706 suppressed NF-B activation. These data suggest that serine protease inhibitors attenuate the CSE-induced release of NCA and MCA from human fetal lung fibroblasts and that the inhibitory action of antiproteases might depend on NF-B signaling pathway.

Abbreviations: 1-antitrypsin, 1AT • chronic obstructive pulmonary disease, COPD • cigarette smoke extract, CSE • granulocyte colony-stimulating factor, G-CSF • granulocyte-macrophage colony-stimulating factor, GM-CSF • Hanks' balanced saline solution, HBSS • human fetal lung fibroblasts, HFL-1 • high power fields, HPF • interleukin, IL • monocyte chemotactic activity, MCA • monocyte chemoattractant protein, MCP-1 • neutrophil chemotactic activity, NCA • nuclear factor-B, NF-B • reverse transcriptase–polymerase chain reaction, RT-PCR • methoxysuccinyl-Ala-Ala-Pro-Val chloromethyl ketone, SPCK • N-p-tosyl-L-lysine chloromethyl ketone, TLCK

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