Cyclooxygenase-2-dependent bronchoconstriction in perfused rat lungs exposed to endotoxin.

Abstract

BACKGROUND:

Lipopolysaccharides (LPS), widely used to study the mechanisms of gram-negative sepsis, increase airway resistance by constriction of terminal bronchioles. The role of the cyclooxygenase (COX) isoenzymes and their prostanoid metabolites in this process was studied.

MATERIALS AND METHODS:

Pulmonary resistance, the release of thromboxane (TX) and the expression of COX-2 mRNA were measured in isolated blood-free perfused rat lungs exposed to LPS.

RESULTS:

LPS induced the release of TX and caused increased airway resistance after about 30 min. Both TX formation and LPS-induced bronchoconstriction were prevented by treatment with the unspecific COX inhibitor acetyl salicylic acid, the specific COX-2 inhibitor CGP-28238, dexamethasone, actinomycin D, or cycloheximide. LPS-induced bronchoconstriction was also inhibited by the TX receptor antagonist BM-13177. The TX-mimetic compound, U-46619, increased airway resistance predominantly by constricting terminal bronchioles. COX-2-specific mRNA in lung tissue was elevated after LPS exposure, and this increase was attenuated by addition of dexamethasone or of actinomycin D. In contrast to LPS, platelet-activating factor (PAF) induced immediate TX release and bronchoconstriction that was prevented by acetyl salicylic acid, but not by CGP-28238.

CONCLUSIONS:

LPS elicits the following biochemical and functional changes in rat lungs: (i) induction of COX-2; (ii) formation of prostaglandins and TX; (iii) activation of the TX receptor on airway smooth muscle cells; (iv) constriction of terminal bronchioles; and (v) increased airway resistance. In contrast to LPS, the PAF-induced TX release is likely to depend on COX-1.

• Authors: S Uhlig, R Nüsing, A von Bethmann, R L Featherstone, T Klein, F Brasch, K M Müller, V Ullrich, A Wendel
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 2 Issue 3 Pg. 373-83 (May 1996) ISSN: 1076-1551 [Print] England
• PMID: 8784790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• DNA Primers
• Endotoxins
• Isoenzymes
• Lipopolysaccharides
• Lipoxygenase Inhibitors
• Platelet Activating Factor
• Prostaglandin Endoperoxides, Synthetic
• RNA, Messenger
• Vasoconstrictor Agents
• Thromboxane B2
• Thromboxane A2
• 6-Ketoprostaglandin F1 alpha
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• 6-Ketoprostaglandin F1 alpha (metabolism)
• Animals
• Bronchoconstriction (drug effects)
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (pharmacology)
• DNA Primers
• Endotoxins (pharmacology)
• Female
• In Vitro Techniques
• Isoenzymes (biosynthesis)
• Lipopolysaccharides (pharmacology)
• Lipoxygenase Inhibitors (pharmacology)
• Lung (drug effects, physiology, ultrastructure)
• Microscopy, Electron, Scanning
• Platelet Activating Factor (pharmacology)
• Polymerase Chain Reaction
• Prostaglandin Endoperoxides, Synthetic (pharmacology)
• Prostaglandin-Endoperoxide Synthases (biosynthesis)
• RNA, Messenger (biosynthesis)
• Rats
• Rats, Wistar
• Salmonella
• Thromboxane A2 (analogs & derivatives, pharmacology)
• Thromboxane B2 (metabolism)
• Transcription, Genetic (drug effects)
• Vasoconstrictor Agents (pharmacology)