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Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction
  1. Rachele Pandolfi1,2,3,
  2. Bianca Barreira1,2,3,
  3. Enrique Moreno1,2,3,
  4. Victor Lara-Acedo2,
  5. Daniel Morales-Cano1,2,3,
  6. Andrea Martínez-Ramas1,2,3,
  7. Beatriz de Olaiz Navarro4,
  8. Raquel Herrero1,5,
  9. José Ángel Lorente1,5,6,
  10. Ángel Cogolludo1,2,3,
  11. Francisco Pérez-Vizcaíno1,2,3,
  12. Laura Moreno1,2,3
  1. 1Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain
  2. 2Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
  3. 3Gregorio Marañón Biomedical Research Institution (IiSGM), Madrid, Spain
  4. 4Department of Thoracic Surgery, Hospital Universitario de Getafe, Getafe, Spain
  5. 5Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain
  6. 6Universidad Europea, Madrid, Spain
  1. Correspondence to Dr Laura Moreno, Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain; lmorenog{at}med.ucm.es

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.

  • ARDS
  • Bacterial Infection
  • Cytokine Biology
  • Innate Immunity

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