title: Anti-inflammatory activity of a novel family of aryl ureas compounds in an endotoxin-induced airway epithelial cell injury model.
abstract: BACKGROUND
  Despite our increased understanding of the mechanisms involved in acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), there is no specific pharmacological treatment of proven benefit. We used a novel screening methodology to examine potential anti-inflammatory effects of a small structure-focused library of synthetic carbamate and urea derivatives in a well established cell model of lipopolysaccharide (LPS)-induced ALI/ARDS.
  
  
  RESULTS
  After a pilot study to develop an in vitro LPS-induced airway epithelial cell injury model, a library of synthetic carbamate and urea derivates was screened against representative panels of human solid tumor cell lines and bacterial and fungal strains. Molecules that were non-cytotoxic and were inactive in terms of antiproliferative and antimicrobial activities were selected to study the effects on LPS-induced inflammatory response in an in vitro cell culture model using A549 human alveolar and BEAS-2B human bronchial cells. These cells were exposed for 18 h to LPS obtained from Escherichia coli, either alone or in combination with the test compounds. The LPS antagonists rhein and emodin were used as reference compounds. The most active compound (CKT0103) was selected as the lead compound and the impact of CKT0103 on pro-inflammatory IL-6 and IL-8 cytokine levels, expression of toll-like receptor-4 (TLR4) and nuclear factor kappa B inhibitor alpha (IκBα) was measured. CKT0103 significantly inhibited the synthesis and release of IL-6 and IL-8 induced by LPS. This suppression was associated with inhibition of TLR4 up-regulation and IκBα down-regulation. Immunocytochemical staining for TLR4 and IκBα supported these findings.
  
  
  CONCLUSIONS
  Using a novel screening methodology, we identified a compound - CKT0103 - with potent anti-inflammatory effects. These findings suggest that CKT0103 is a potential target for the treatment of the acute phase of sepsis and sepsis-induced ALI/ARDS.
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Nuria E
authors.initials: NE
authors.lastname: Cabrera-Benitez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pérez-Roth
authors.forename: Milena
authors.initials: M
authors.lastname: Casula
authors.forename: Angela
authors.initials: A
authors.lastname: Ramos-Nuez
authors.forename: Carla
authors.initials: C
authors.lastname: Ríos-Luci
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodríguez-Gallego
authors.forename: Ithaisa
authors.initials: I
authors.lastname: Sologuren
authors.forename: Virginija
authors.initials: V
authors.lastname: Jakubkiene
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: José M
authors.initials: JM
authors.lastname: Padrón
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology*; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014508:Urea / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004731:Endotoxins; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C000606204:NFKBIA protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha; D014508:Urea