title: Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs.
abstract: The formation of neutrophil extracellular traps (NETs) is a newly described phenomenon that increases the bacteria-killing ability and the inflammatory response of neutrophils. Because NET generation occurs in an inflammatory microenvironment, we examined its regulation by anti-inflammatory drugs. Treatment of neutrophils with dexamethasone had no effect, but acetylsalicylic acid (ASA) treatment prevented NET formation. NETosis was also abrogated by the presence of BAY 11-7082 [(E)-3-[4-methylphenylsulfonyl]-2-propenenitrile] and Ro 106-9920 [6-(phenylsulfinyl)tetrazolo[1,5-b]pyridazine], two structurally unrelated nuclear factor-κB (NF-κB) inhibitors. The decrease in NET formation mediated by ASA, BAY-11-7082, and Ro 106-9920 was correlated with a significant reduction in the phosphorylation of NF-κB p65 subunit, indicating that the activation of this transcription factor is a relevant signaling pathway involved in the generation of DNA traps. The inhibitory effect of these drugs was also observed when NET generation was induced under acidic or hyperthermic conditions, two stress signals of the inflammatory microenvironment. In a mouse peritonitis model, while pretreatment of animals with ASA or BAY 11-7082 resulted in a marked suppression of NET formation along with increased bacteremia, dexamethasone had no effect. Our results show that NETs have an important role in the local control of infection and that ASA and NF-κB blockade could be useful therapies to avoid undesired effect of persistent neutrophil activation.
authors.affiliation: Laboratory of Experimental Thrombosis, Institute of Experimental Medicine, CONICET-National Academy of Medicine, Buenos Aires, Argentina.
authors.forename: María José
authors.initials: MJ
authors.lastname: Lapponi
authors.forename: Agostina
authors.initials: A
authors.lastname: Carestia
authors.forename: Verónica Inés
authors.initials: VI
authors.lastname: Landoni
authors.forename: Leonardo
authors.initials: L
authors.lastname: Rivadeneyra
authors.forename: Julia
authors.initials: J
authors.lastname: Etulain
authors.forename: Soledad
authors.initials: S
authors.lastname: Negrotto
authors.forename: Roberto Gabriel
authors.initials: RG
authors.lastname: Pozner
authors.forename: Mirta
authors.initials: M
authors.lastname: Schattner
mesh_terms: D000138:Acidosis / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology; D001424:Bacterial Infections / Q000276:immunology / Q000517:prevention & control; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D010533:Peritoneal Lavage; D013450:Sulfones / Q000494:pharmacology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D003907:Dexamethasone; D004247:DNA; D001241:Aspirin