title: 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.
  
  
  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.affiliation: Faculty of Biology, University of Konstanz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Uhlig
authors.forename: R
authors.initials: R
authors.lastname: Nüsing
authors.forename: A
authors.initials: A
authors.lastname: von Bethmann
authors.forename: R L
authors.initials: RL
authors.lastname: Featherstone
authors.forename: T
authors.initials: T
authors.lastname: Klein
authors.forename: F
authors.initials: F
authors.lastname: Brasch
authors.forename: K M
authors.initials: KM
authors.lastname: Müller
authors.forename: V
authors.initials: V
authors.lastname: Ullrich
authors.forename: A
authors.initials: A
authors.lastname: Wendel
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D017931:DNA Primers; D004731:Endotoxins / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D008855:Microscopy, Electron, Scanning; D010972:Platelet Activating Factor / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D012475:Salmonella; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D004731:Endotoxins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases