Cytokine-induced bronchoconstriction in precision-cut lung slices is dependent upon cyclooxygenase-2 and thromboxane receptor activation.
Cytokines play an essential role in the regulation of inflammatory responses. The effects of cytokines on lung functions are less well known and their study in vivo is complicated by the attraction of leukocytes to the inflamed sites. Recently the model of precision-cut lung slices was developed, where viable lung slices with an intact microanatomy are taken into culture and where bronchoconstriction can be followed by observing single airways under the microscope. We used this model to study the direct effects of cytokines on airway tonus in the absence of blood-derived leukocytes. Incubation of precision-cut lung slices with a mixture of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and interferon (IFN)-gamma resulted in contraction of airways, which was accompanied by expression of cyclooxygenase (Cox)-2 and thromboxane release into the supernatant. The thromboxane receptor antagonist SQ29548 completely prevented the cytokine-induced bronchoconstriction, whereas the 5-lipoxygenase inhibitor AA681 had no effect on cytokine-induced bronchoconstriction. Preventing the expression of Cox-2 by dexamethasone or blocking Cox-2 activity with the selective Cox-2 inhibitor NS398 attenuated both thromboxane formation and bronchoconstriction. Incubation of lung slices with each of the cytokines alone caused no bronchoconstriction; in fact, IL-1 alone rather dilated the airways. However, simultaneous incubation with TNF and IL-1beta caused a bronchoconstriction that was not further enhanced by IFN-gamma. We conclude that TNF-alpha and IL-1beta synergistically cause bronchoconstriction by induction of Cox-2 and subsequent activation of the thromboxane receptor. Our study raises the possibility that TNF and IL-1 may contribute to bronchospasm during inflammatory lung diseases.
Martin
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C
Faculty of Biology, University of Konstanz, Konstanz, Germany. cmartin@fz-borstel.de
Uhlig
S
S
Ullrich
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V
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000494:pharmacology*; D017931:DNA Primers / Q000737:chemistry; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005260:Female; D015870:Gene Expression; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D015289:Leukotrienes / Q000032:analysis; D008168:Lung / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013931:Thromboxanes / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D017931:DNA Primers; D007375:Interleukin-1; D007527:Isoenzymes; D015289:Leukotrienes; D017482:Receptors, Thromboxane; D013931:Thromboxanes; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases