Inhibition of Pulmonary Surfactant Adsorption by Serum and the Mechanisms of Reversal by Hydrophilic Polymers: Theory

Abstract

A theory based on the Smolukowski analysis of colloid stability shows that the presence of charged, surface-active serum proteins at the alveolar air-liquid interface can severely reduce or eliminate the adsorption of lung surfactant from the subphase to the interface, consistent with the observations reported in the companion article (pages 1769-1779). Adding nonadsorbing, hydrophilic polymers to the subphase provides a depletion attraction between the surfactant aggregates and the interface, which can overcome the steric and electrostatic resistance to adsorption induced by serum. The depletion force increases with polymer concentration as well as with polymer molecular weight. Increasing the surfactant concentration has a much smaller effect than adding polymer, as is observed. Natural hydrophilic polymers, like the SP-A present in native surfactant, or hyaluronan, normally present in the alveolar fluids, can enhance adsorption in the presence of serum to eliminate inactivation.

Chitosan Enhances the In Vitro Surface Activity of Dilute Lung Surfactant Preparations and Resists Albumin-Induced Inactivation

“…However, the underlying mechanism of chitosan to enhance surface activity of lung surfactant may differ from that of nonionic polymers. Both experimental (5,6) and theoretical (28) studies support the notion that the nonionic polymers improve the surface activity of lipid extract surfactant by a depletion-attraction mechanism. It has been demonstrated that in a pure phospholipid vesicle system, PEG at certain molecular weights and concentrations can induce a depletion-attraction force that promotes the formation of large phospholipid aggregates (30).…”

“…1) supports the notion that that the water-soluble serum proteins, such as albumin, inactivate lung surfactant due to a competitive adsorption mechanism, i.e. by rapidly adsorbing to the air-water interface and hence creating a steric and/or electrostatic barrier for surfactant adsorption (6,28). To resist or reverse the inactivation, the phospholipid components of lung surfactant must overcome these barriers by adsorbing more rapidly than albumin and/or effectively replacing the albumin molecules at the interface.…”

“…Low polymer concentrations would also help to minimize the osmotic stress in vivo, which minimizes the possibility of polymer-induced imbalance in lung water, i.e. it is a desirable effect in the treatment of ARDS (28,29). The cytotoxicity tests support this hypothesis.…”

“…Large aggregates are known to be more surface active than their smaller counterpart both in vitro (31) and in vivo (32). Theoretical study has established that the depletion attraction force is proportional to the aggregate radius (28). Thus, larger aggregates would experience a larger push to the interface and also deliver more surfactant to the interface.…”

Transient Exposure of Pulmonary Surfactant to Hyaluronan Promotes Structural and Compositional Transformations into a Highly Active State

“…Previous work by us and others (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) has shown that a range of polymers can enhance surfactant activity, among them hyaluronan (HA). 2 HA is a naturally occurring linear polysaccharide with repeating disaccharide units of glucuronic acid and N-acetylglucosamine, linked via alternating ␤ 1-4 and ␤ 1-3 glycosidic bonds.…”