Publication: Relaciones estructura-función de la proteína SP-C del surfactante pulmonar: efectos sobre la estructura de membranas y papel del colesterol
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2017-12-04
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Universidad Complutense de Madrid
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Abstract
La función respiratoria depende del establecimiento de una interfase aire-líquido que tiene lugar en los alveolos pulmonares. La estabilización de dicha interfase requiere la presencia de un complejo lipoproteico que es sintetizado y secretado por las células epiteliales alveolares de tipo II, también llamadas neumocitos tipo II. Este material se denomina surfactante pulmonar y sus funciones principales implican la estabilización de los alveolos a lo largo de los ciclos respiratorios, así como la regulación de la respuesta inmunológica innata frente a partículas y microorganismos exógenos que acceden al organismo por vía pulmonar. Una vez secretado, el surfactante pulmonar se adsorbe rápidamente a la interfase aire-líquido respiratoria, donde da lugar a una película interfacial continua e insoluble responsable de reducir la tensión superficial de manera proporcional a la reducción de área. De esta forma, el surfactante pulmonar previene la atelectasis (o colapso alveolar), minimizando la energía requerida para abrir la superficie respiratoria durante la inspiración. El surfactante pulmonar tiene una composición optimizada para llevar a cabo las funciones descritas anteriormente, y en su mayoría está constituido por fosfolípidos. La dipalmitoil fosfatifil colina (DPPC), un lípido poco frecuente en membranas biológicas, representa el 40% en peso del surfactante. Este lípido insaturado es capaz de soportar altos grados de empaquetamiento, por lo que es el principal responsable de los bajos valores de tensión superficial que se adoptan durante la espiración. Otros componentes del surfactante, como fosfolípidos insaturados tales como especies moleculares de fosfatidil colina (PC) y fosfatidil glicerol (PG), y lípidos neutros, mayoritariamente colesterol, proporcionan al surfactante una fluidez y viscosidad apropiadas. Sin embargo, aunque los lípidos constituyen el 90% en peso del surfactante, para una correcta función tensioactiva depende de la presencia de proteínas asociadas (SP). La SP-A y SP-D son proteínas de gran tamaño e hidrófilas relacionadas con la función inmunológica del surfactante...
The respiratory function is supported by a lipid-protein complex produced and secreted by alveolar type II cells. This material is termed lung surfactant, and their main functions include the alveolar stabilization along the respiratory cycles and the regulation of the innate immune response against foreign particles and microorganisms entering the lung. Upon secretion, lung surfactant is rapidly adsorbed into the alveolar air-liquid interface, where it constitutes a continuum non-soluble film in charge of reducing surface tension in a proportional way to area reduction. Doing so it prevents atelectasis (alveolar collapse), and optimizes the amount of energy required to open the respiratory surface when inhalation takes place. Lung surfactant is compositionally optimized to fulfil the functions described above, being phospholipids its main constituents. A lipid rarely found in most biological membranes, dipalmitoyl phosphatidyl choline (DPPC), accounts for 40 wt% of lung surfactant. This disaturated phospholipid can attain highly packed structures upon area reduction, becoming the main responsible for the extremely low surface tensions reached during exhalation. Other surfactant components, such as unsaturated phospholipids including phosphatidyl choline (PC) and phosphatidylglycerol (PG) species, and neutral lipids, mainly cholesterol, confer surfactant membranes and films optimal properties in terms of fluidity and viscosity. Nevertheless, although surfactant is 90 wt% lipids, it requires the presence of surfactant associated proteins (SP) to perform its specific associated activities. Surfactant protein A and D (SP-A and SP-D), are large hydrophilic proteins principally involved in the innate immune response in the lung. Both proteins belong to the collagenous calcium-dependent lectin (collectin) family, and exhibit different functions depending on their oligomeric state. Surfactant protein B and C (SP-B and SP-C), on the contrary, are small hydrophobic proteins that strongly associate to surfactant membranes. These two proteins are essential for surfactant to achieve a proper biophysical function, and they are responsible for the structural rearrangements of surfactant lipid assemblies involved in a fast lipid adsorption into the air-liquid interface, and the efficient re-spreading of surfactant material along the interface during area expansion (inhalation). The re-spreading ability of surfactant films is associated with 3D structures promoted by the proteins, which lead to the generation of multilayer structures that serve to store lipid material excluded from the interfacial film during compression, and newly secreted surfactant complexes. Thus, the action of SP-B and SP-C support the generation of an intricate meshwork of lipid structures connecting different surfactant extracellular forms, from secreted lamellar bodies to the interfacial film. All these structures contribute to provide active surfactant-forms to the interfacial film, which once exhausted, are recycled or degraded by lung homeostatic mechanisms involving type II alveolar cells and alveolar macrophages...
The respiratory function is supported by a lipid-protein complex produced and secreted by alveolar type II cells. This material is termed lung surfactant, and their main functions include the alveolar stabilization along the respiratory cycles and the regulation of the innate immune response against foreign particles and microorganisms entering the lung. Upon secretion, lung surfactant is rapidly adsorbed into the alveolar air-liquid interface, where it constitutes a continuum non-soluble film in charge of reducing surface tension in a proportional way to area reduction. Doing so it prevents atelectasis (alveolar collapse), and optimizes the amount of energy required to open the respiratory surface when inhalation takes place. Lung surfactant is compositionally optimized to fulfil the functions described above, being phospholipids its main constituents. A lipid rarely found in most biological membranes, dipalmitoyl phosphatidyl choline (DPPC), accounts for 40 wt% of lung surfactant. This disaturated phospholipid can attain highly packed structures upon area reduction, becoming the main responsible for the extremely low surface tensions reached during exhalation. Other surfactant components, such as unsaturated phospholipids including phosphatidyl choline (PC) and phosphatidylglycerol (PG) species, and neutral lipids, mainly cholesterol, confer surfactant membranes and films optimal properties in terms of fluidity and viscosity. Nevertheless, although surfactant is 90 wt% lipids, it requires the presence of surfactant associated proteins (SP) to perform its specific associated activities. Surfactant protein A and D (SP-A and SP-D), are large hydrophilic proteins principally involved in the innate immune response in the lung. Both proteins belong to the collagenous calcium-dependent lectin (collectin) family, and exhibit different functions depending on their oligomeric state. Surfactant protein B and C (SP-B and SP-C), on the contrary, are small hydrophobic proteins that strongly associate to surfactant membranes. These two proteins are essential for surfactant to achieve a proper biophysical function, and they are responsible for the structural rearrangements of surfactant lipid assemblies involved in a fast lipid adsorption into the air-liquid interface, and the efficient re-spreading of surfactant material along the interface during area expansion (inhalation). The re-spreading ability of surfactant films is associated with 3D structures promoted by the proteins, which lead to the generation of multilayer structures that serve to store lipid material excluded from the interfacial film during compression, and newly secreted surfactant complexes. Thus, the action of SP-B and SP-C support the generation of an intricate meshwork of lipid structures connecting different surfactant extracellular forms, from secreted lamellar bodies to the interfacial film. All these structures contribute to provide active surfactant-forms to the interfacial film, which once exhausted, are recycled or degraded by lung homeostatic mechanisms involving type II alveolar cells and alveolar macrophages...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, Departamento de Bioquímica y Biología Molecular I, leída el 11-05-2017