TY - JOUR 
A1 - Pandolfi, Rachele
AU - Barreira, Bianca
AU - Moreno González, Enrique
AU - Lara Acedo, Víctor
AU - Morales Cano, Daniel
AU - Martínez Ramas, Andrea
AU - Oláiz Navarro, Beatriz de
AU - Herrero, Raquel
AU - Lorente Balanza, José Ángel
AU - Moreno, Laura
AU - Et al.
T1 - Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction
Y1 - 2017
SN - 1468-3296

UR - http://hdl.handle.net/11268/9801
AB - 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.
KW - Síndrome respiratorio agudo grave
KW - Infecciones bacterianas y micosis
KW - Aparato respiratorio
KW - Enfermedad transmisible
KW - Bacteria
LA - eng
ER -