title: Cyclooxygenase and cytokine regulation in lung fibroblasts activated with viral versus bacterial pathogen associated molecular patterns.
abstract: Cyclooxygenase (COX) is required for prostanoid (e.g. prostaglandin PGE2) production. Constitutive COX-1 and inducible COX-2 are implicated in lung diseases, such as idiopathic pulmonary fibrosis (IPF). Using lung fibroblasts from humans and wild type, COX-1(-/-) and COX-2(-/-) mice, we investigated how COX activity modulates cell growth and inflammatory responses induced by activators of Toll-like receptors (TLRs) 1-8. In mouse tissue, PGE2 release from fresh lung was COX-1 driven, in lung in culture (24h) COX-1 and COX-2 driven, and from proliferating lung fibroblasts exclusively COX-2 driven. COX-2 limited proliferation in lung fibroblasts and both isoforms limited KC release induced by a range of TLR agonists. Less effect of COX was seen on TLR-induced IP-10 release. In human lung fibroblasts inhibition of COX with diclofenac was associated with increased release of IL-8 and IP-10. Our results may have implications for the treatment of IPF.
authors.affiliation: Cardiothoracic Pharmacology, Guy Scadding Building, National Heart and Lung Institute, Royal Brompton Campus, Imperial College, London SW3 6LY, UK. Electronic address: william.wright09@imperial.ac.uk.
authors.forename: William R
authors.initials: WR
authors.lastname: Wright
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.forename: Neil A
authors.initials: NA
authors.lastname: Galloway-Phillipps
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Reed
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Paul-Clark
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D004008:Diclofenac / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051193:Toll-Like Receptors; D004008:Diclofenac; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone; D011070:Poly I-C
keywords: Cyclooxygenase; IL-8; IP-10; Lung fibroblast; PGE(2); TLR