Publication: Inactivación y reactivación del surfactante pulmonar: mecanismos moleculares e implicación en patologías respiratorias
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2013-06-04
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Universidad Complutense de Madrid
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Abstract
La inactivación del surfactante pulmonar se encuentra asociada a muchas patologías respiratorias, como el síndrome de aspiración de meconio (MAS), síndrome del distrés respiratorio agudo (ARDS) o fibrosis pulmonar idiopática (IPF), que da lugar tensiones superficiales elevadas en la interfase alveolar. Las causas de la inactivación del surfactante son diferentes en origen y en su mecanismo molecular. Así, muchos agentes inactivadores llegan a los pulmones, como el meconio, durante el MAS, o suero debido al daño en la barrera epitelial. Por otro lado, deficiencias en las proteínas del surfactante también influye en la actividad del surfactante, como es el caso de IPF. El estudio de los mecanismos moleculares de la inactivación, así como la optimización de métodos permite el desarrollo de nuevas preparaciones de surfactante para su uso clínico en el tratamiento de patologías respiratorias. La adición de polímeros como el ácido hialurónico (HA) a las preparaciones de surfactante resulta en el aumento de la resistencia a la inactivación, de manera independiente del mecanismo de inactivación. Fuerzas entrópicas, como la presión osmótica y las fuerzas de exclusión (depletion forces), actúan en el surfactante de forma irreversible dando lugar a una preparación de surfactante pre-‐activada que muestra alta resistencia a inactivación. Además, la caracterización biofísica de muestras clínicamente relevantes permite la combinación de datos clínicos y biofísicos, que pone de manifiesto la implicación de la inactivación del surfactante pulmonar en el desarrollo y resultados de las patologías respiratorias estudiadas, como el ARDS. Correlaciones significantes entre la elevada tensión superficial y parámetros clínicos como PaO2/FiO2 (índice de oxigenación), CRS (distensibilidad del sistema respiratorio), PRISM (riesgo pediátrico de mortalidad) y el índice de Murray (severidad del daño pulmonar), demuestra la importancia de la inactivación del surfactante pulmonar en ARDS. Desarrollo de preparaciones de surfactante resistentes a la inactivación puede ser la clave para el tratamiento de estas patologías. Finalmente, la completa caracterización de modelos animales clínicamente relevantes permite la combinación de datos moleculares, celulares y biofísicos. La caracterización del modelo de ratones deficientes en napsina A permite determinar niveles de proteínas no solo en el surfactante sino también en el tejido pulmonar. Resultados de la caracterización de este modelo apuntan a la inducción de daño en neumocitos tipo II que podría dar lugar al desarrollo de fibrosis. Este modelo supondría una herramienta de estudio del desarrollo de tejido fibrótico y su tratamiento. Combinación de datos moleculares, celulares, clínicos y biofísicos supone una buena herramienta para entender patologías respiratorias y desarrollar tratamientos eficientes.
Pulmonary surfactant inactivation curses with many respiratory pathologies such as meconium aspiration syndrome (MAS), acute respiratory distress syndrome (ARDS) or idiopathic pulmonary fibrosis (IPF), resulting in abnormally high surface tension. Causes of inactivation of surfactant are different in origin and molecular mechanism. On the one hand, many inactivating agents reach the alveolar interface such as meconium, during MAS, or serum, due to leakage of fluid through the damaged epithelial barrier. On the other hand, deficiency in surfactant proteins may also influence the activity of surfactant, as in IPF. Studying molecular mechanisms of inactivation as well as optimizing new standardized methods allows the development of new surfactant preparations for clinical use in the treatment of respiratory pathologies. Addition of polymers such as hyaluronic acid (HA) to surfactant preparations results in an increase resistance to inactivation, independently of the inactivating mechanism. Entropic forces, such as osmotic pressure and depletion forces, act on surfactant in a non-‐reversible way resulting in a pre-‐activated surfactant preparation that shows enhanced resistance to inactivation. Moreover, the biophysical characterization of clinically relevant samples allow the combination of clinical and biophysical data that highlights the implication of surfactant inactivation in the development and outcome of the studied respiratory pathologies, such as ARDS. Significant correlation between high surface tension and clinical parameters such as PaO2/FiO2 (oxygenation index), CRS (compliance of the respiratory system), PRISM (paediatric mortality risk) and Murray score (lung injury severity), demonstrate the importance of surfactant inactivation in ARDS. Developing of inactivation-‐resistant surfactant preparations could be the key for the treatment of such pathologies. Finally the complete characterization of clinically relevant animal models allows the combination of molecular, cellular, biophysical and clinical data. Characterization of a Napsin A KO mouse model allows us to determine levels of protein not only in surfactant but also in lung tissue. Results from these mice seem to resemble type II cell injury that would result in development of fibrosis. This mouse model would be a tool for the study of fibrosis development and its treatment. Combination of molecular, cellular, clinical and biophysical data is a powerful tool for understanding respiratory pathologies and developing effective treatments.
Pulmonary surfactant inactivation curses with many respiratory pathologies such as meconium aspiration syndrome (MAS), acute respiratory distress syndrome (ARDS) or idiopathic pulmonary fibrosis (IPF), resulting in abnormally high surface tension. Causes of inactivation of surfactant are different in origin and molecular mechanism. On the one hand, many inactivating agents reach the alveolar interface such as meconium, during MAS, or serum, due to leakage of fluid through the damaged epithelial barrier. On the other hand, deficiency in surfactant proteins may also influence the activity of surfactant, as in IPF. Studying molecular mechanisms of inactivation as well as optimizing new standardized methods allows the development of new surfactant preparations for clinical use in the treatment of respiratory pathologies. Addition of polymers such as hyaluronic acid (HA) to surfactant preparations results in an increase resistance to inactivation, independently of the inactivating mechanism. Entropic forces, such as osmotic pressure and depletion forces, act on surfactant in a non-‐reversible way resulting in a pre-‐activated surfactant preparation that shows enhanced resistance to inactivation. Moreover, the biophysical characterization of clinically relevant samples allow the combination of clinical and biophysical data that highlights the implication of surfactant inactivation in the development and outcome of the studied respiratory pathologies, such as ARDS. Significant correlation between high surface tension and clinical parameters such as PaO2/FiO2 (oxygenation index), CRS (compliance of the respiratory system), PRISM (paediatric mortality risk) and Murray score (lung injury severity), demonstrate the importance of surfactant inactivation in ARDS. Developing of inactivation-‐resistant surfactant preparations could be the key for the treatment of such pathologies. Finally the complete characterization of clinically relevant animal models allows the combination of molecular, cellular, biophysical and clinical data. Characterization of a Napsin A KO mouse model allows us to determine levels of protein not only in surfactant but also in lung tissue. Results from these mice seem to resemble type II cell injury that would result in development of fibrosis. This mouse model would be a tool for the study of fibrosis development and its treatment. Combination of molecular, cellular, clinical and biophysical data is a powerful tool for understanding respiratory pathologies and developing effective treatments.
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular, leída el 17/12/2012