Lung surfactant adsorption and inhibition

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a molecular-level understanding of lung surfactant inhibition by blood serum proteins, to see if this understanding can be generalized to include other inhibitors such as lysolipids and meconium, and to provide simple rules for choosing an optimal polymer and determining its concentration to reverse inhibition. Inhibition, the impediment of lung surfactant adsorption from the alveolar fluid to the air-water interface, prevents the low surface tensions necessary for proper lung function. This is an important effect in diseases associated with a lack of lung surfactant including neonatal respiratory distress syndrome (NRDS), often due to premature delivery, and acute respiratory distress syndrome (ARDS). The common features of inhibitors are (1) they are not normally present in the alveolar fluid; (2) they are water soluble, and (3) they are surface active. We hypothesize that small, soluble inhibitors (such as albumin, lysolipids, etc.) adsorb faster to an interface than the larger surfactant aggregates; hence the surfactant has to displace inhibitor from the interface in order to adsorb. This leads to an energy barrier to surfactant adsorption, and hence, less surfactant at the interface. As a result, the interface must be compressed further to reach the low surface tensions necessary for lung function. Adding hydrophilic polymers to the surfactant solution has recently been shown in animal models to reverse inhibition; however, the mechanism and method of determining the optimal polymer concentration, molecular weight and chemistry is still unknown. We have proposed that the inhibition reversal is due to the "depletion effect", caused by the increase in free volume of the solution when the surfactant is forced to the interface, which increases the polymer entropy. The depletion force helps overcome the barrier to surfactant adsorption and the theory makes specific predictions regarding polymer molecular weight, chemistry and molecular weight which will be tested under this proposal.