title: Dual anti-oxidant and anti-inflammatory actions of the electrophilic cyclooxygenase-2-derived 17-oxo-DHA in lipopolysaccharide- and cigarette smoke-induced inflammation.
abstract: BACKGROUND
  17-Oxo-DHA is an endogenous electrophilic derivative of the omega-3 fatty acid docosahexaenoic acid (DHA) which is generated in activated macrophages by the action of cyclooxygenase-2.
  
  
  METHODS
  The ability of 17-oxo-DHA to control inflammation and oxidative stress was tested in human macrophages (THP-1) and bronchial epithelial cell line (16HBE) stimulated with cigarette smoke extract (CSE) and lipopolysaccharide (LPS). All data were further confirmed using primary bronchial epithelial cells, alveolar macrophages and peripheral blood mononuclear cells.
  
  
  RESULTS
  17-Oxo-DHA was a strong inducer of the anti-oxidant response promoting Nrf2 nuclear accumulation, leading to the expression of heme oxygenase 1 and more than doubling glutathione levels. This resulted in suppression of CSE-induced ROS generation in macrophages. In macrophages, 17-oxo-DHA potently suppressed TNFα release in response to LPS, CSE and IL-1β acting at transcriptional level via a mechanism independent of Nrf2. Externally supplemented 17-oxo-DHA displayed the same effects in the presence of the Cox-inhibitor indomethacin. The non-electrophilic 17-oxo-DHA precursor DHA did not show any biological actions, indicating that the electrophilic moiety was required for this compound to become bioactive.
  
  
  CONCLUSIONS
  17-Oxo-DHA promotes cytoprotective actions both in immune and structural cells. In immune cells, 17-oxo-DHA is effective in contrasting CSE- and LPS-induced oxidative damage and inflammation acting via multiple independent pathways.
  
  
  CONCLUSIONS
  Herein we provide insights on how the novel endogenous electrophilic DHA-derivative 17-oxo-DHA promotes anti-oxidant and anti-inflammatory actions. Data herein reported indicate that 17-oxo-DHA is an attractive lead compound for the development of new treatments for cigarette smoke-related airway inflammatory disorders.
authors.affiliation: Fondazione Ri.MED, Via Bandiera 11, Palermo, Italy; Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy. Electronic address: chiara.cipollina@gmail.com.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cipollina
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; Scienze e Biotecnologie Mediche e Sperimentali, Pneumologia Sperimentale e Clinica, Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Di Vincenzo
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; Dipartimento di Scienze Motorie, Università degli Studi di Palermo, Palermo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gerbino
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy.
authors.forename: Liboria
authors.initials: L
authors.lastname: Siena
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy.
authors.forename: Mark
authors.initials: M
authors.lastname: Gjomarkaj
authors.affiliation: Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pace
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000031:analogs & derivatives / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D008070:Lipopolysaccharides; D004281:Docosahexaenoic Acids; D051546:Cyclooxygenase 2
keywords: Cigarette smoke; Electrophile; Inflammation; Omega-3 fatty acid; Oxidative stress