title: Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is frequently observed in patients with acute respiratory distress syndrome (ARDS) and it is associated with an increased risk of mortality. Both acid sphingomyelinase (aSMase) activity and interleukin 6 (IL-6) levels are increased in patients with sepsis and correlate with worst outcomes, but their role in pulmonary vascular dysfunction pathogenesis has not yet been elucidated. Therefore, the aim of this study was to determine the potential contribution of aSMase and IL-6 in the pulmonary vascular dysfunction induced by lipopolysaccharide (LPS).
  
  
  METHODS
  Rat or human pulmonary arteries (PAs) or their cultured smooth muscle cells (SMCs) were exposed to LPS, SMase or IL-6 in the absence or presence of a range of pharmacological inhibitors. The effects of aSMase inhibition in vivo with D609 on pulmonary arterial pressure and inflammation were assessed following intratracheal administration of LPS.
  
  
  RESULTS
  LPS increased ceramide and IL-6 production in rat pulmonary artery smooth muscle cells (PASMCs) and inhibited pulmonary vasoconstriction induced by phenylephrine or hypoxia (HPV), induced endothelial dysfunction and potentiated the contractile responses to serotonin. Exogenous SMase and IL-6 mimicked the effects of LPS on endothelial dysfunction, HPV failure and hyperresponsiveness to serotonin in PA; whereas blockade of aSMase or IL-6 prevented LPS-induced effects. Finally, administration of the aSMase inhibitor D609 limited the development of endotoxin-induced PH and ventilation-perfusion mismatch. The protective effects of D609 were validated in isolated human PAs.
  
  
  CONCLUSIONS
  Our data indicate that aSMase and IL-6 are not simply biomarkers of poor outcomes but pathogenic mediators of pulmonary vascular dysfunction in ARDS secondary to Gram-negative infections.
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.|Gregorio Marañón Biomedical Research Institution (IiSGM), Madrid, Spain.
authors.forename: Rachele
authors.initials: R
authors.lastname: Pandolfi
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.|Gregorio Marañón Biomedical Research Institution (IiSGM), Madrid, Spain.
authors.forename: Bianca
authors.initials: B
authors.lastname: Barreira
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.|Gregorio Marañón Biomedical Research Institution (IiSGM), Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Lara-Acedo
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.|Gregorio Marañón Biomedical Research Institution (IiSGM), Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morales-Cano
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.|Gregorio Marañón Biomedical Research Institution (IiSGM), Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Martínez-Ramas
authors.affiliation: Department of Thoracic Surgery, Hospital Universitario de Getafe, Getafe, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Olaiz Navarro
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Herrero
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain.|Universidad Europea, Madrid, Spain.
authors.forename: José Ángel
authors.initials: JÁ
authors.lastname: Lorente
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.|Gregorio Marañón Biomedical Research Institution (IiSGM), Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Cogolludo
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.|Gregorio Marañón Biomedical Research Institution (IiSGM), Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.affiliation: Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.|Gregorio Marañón Biomedical Research Institution (IiSGM), Madrid, Spain.
authors.forename: Laura
authors.identifier: http://orcid.org/0000-0001-9028-2299
authors.initials: L
authors.lastname: Moreno
mesh_terms: D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D055572:Ceramidases / Q000378:metabolism; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009636:Norbornanes; D011651:Pulmonary Artery / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism* / Q000494:pharmacology*; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D001952:Bridged-Ring Compounds; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009636:Norbornanes; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate; D013108:Sphingomyelin Phosphodiesterase; D055572:Ceramidases
keywords: ARDS; Bacterial Infection; Cytokine Biology; Innate Immunity