Publication: Papel de los esfingolípidos en las alteraciones vasculares asociadas al daño pulmonar agudo
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2016-07-11
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Universidad Complutense de Madrid
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Abstract
El síndrome de distrés respiratorio agudo (SDRA) se caracteriza por edema pulmonar y colapso alveolar que conduce a hipoxemia arterial grave. Las causas más frecuentes de SDRA son la sepsis y los traumatismos. Aunque las estrategias protectoras de soporte ventilatorio y hemodinámico han permitido mejorar el pronóstico, la mortalidad asociada se mantiene intolerablemente elevada por lo que el descubrimiento de nuevos tratamientos efectivos tendría un gran impacto en la supervivencia de los pacientes. Además, la existencia de disfunción vascular pulmonar es un factor independiente asociado a un peor pronóstico en estos pacientes. Los esfingolípidos son componentes estructurales de las membranas, que regulan la dinámica de éstas y forman parte de los microdominios de membrana denominados balsas lipídicas de membrana (“lipid rafts”). Los esfingolípidos actúan también como segundos mensajeros intracelulares implicados en la regulación de procesos celulares clave como la diferenciación, el crecimiento, la apoptosis o la inmunidad innata y adquirida. Estudios previos sugieren que la ceramida producida por la esfingomielinasa (SMasa) neutra (nSMasa) está implicada en la regulación del tono vascular pulmonar. Además, la esfingomielinasa ácida (aSMasa) se encuentra elevada en pacientes en estado crítico. Las evidencias acumuladas durante los últimos años sugieren que los esfingolípidos podrían desempeñar un papel en el SDRA. La imipramina o su análogo desipramina y el D609 son compuestos no relacionados químicamente que tienen en común su capacidad de inhibir la esfingomielinasa ácida...
The acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and alveolar collapse leading to severe arterial hypoxemia. The most common causes of ARDS are sepsis and trauma. Although the strategies of protective mechanical ventilation and hemodynamic support have improved patient outcome, mortality remains unacceptably high, so the discovery of new effective treatments could have a major impact on patient survival. Moreover, the existence of pulmonary vascular dysfunction is independently associated with a worse prognosis in these patients. Sphingolipids are structural components of membranes that regulate its dynamics and form membrane microdomains called lipid rafts. Sphingolipids also act as intracellular second messengers involved in the regulation of key processes such as cell differentiation, growth, apoptosis or innate and acquired immunity. Some evidence has accumulated in recent years regarding the possible role of sphingolipids in lung diseases, including ARDS. Previous studies suggest that ceramide produced by neutral sphingomyelinase (nSMase) is involved in the regulation of pulmonary vascular tone. In addition, acid sphingomyelinase (aSMase) is elevated in critically ill patients. Imipramine or its analogue desipramine and D609 are not chemically related compounds, which inhibit acid sphingomyelinase. Quercetin and other related flavonoids are compounds present in fruits and vegetables. It is proposed that through its antioxidant and anti-inflammatory action and its ability to modulate a large number of enzymes and receptors, its consumption within the diet can reduce the risk of cardiovascular disease, diabetes or neurodegenerative diseases. Recent studies suggest that quercetin, probably through the inhibition of the release of high-mobility group box 1 nuclear proteins (HMGB1), attenuates the systemic inflammation and reduces mortality in a rat model of endotoxemia...
The acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and alveolar collapse leading to severe arterial hypoxemia. The most common causes of ARDS are sepsis and trauma. Although the strategies of protective mechanical ventilation and hemodynamic support have improved patient outcome, mortality remains unacceptably high, so the discovery of new effective treatments could have a major impact on patient survival. Moreover, the existence of pulmonary vascular dysfunction is independently associated with a worse prognosis in these patients. Sphingolipids are structural components of membranes that regulate its dynamics and form membrane microdomains called lipid rafts. Sphingolipids also act as intracellular second messengers involved in the regulation of key processes such as cell differentiation, growth, apoptosis or innate and acquired immunity. Some evidence has accumulated in recent years regarding the possible role of sphingolipids in lung diseases, including ARDS. Previous studies suggest that ceramide produced by neutral sphingomyelinase (nSMase) is involved in the regulation of pulmonary vascular tone. In addition, acid sphingomyelinase (aSMase) is elevated in critically ill patients. Imipramine or its analogue desipramine and D609 are not chemically related compounds, which inhibit acid sphingomyelinase. Quercetin and other related flavonoids are compounds present in fruits and vegetables. It is proposed that through its antioxidant and anti-inflammatory action and its ability to modulate a large number of enzymes and receptors, its consumption within the diet can reduce the risk of cardiovascular disease, diabetes or neurodegenerative diseases. Recent studies suggest that quercetin, probably through the inhibition of the release of high-mobility group box 1 nuclear proteins (HMGB1), attenuates the systemic inflammation and reduces mortality in a rat model of endotoxemia...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Farmacología, leída el 11/09/2015