The potential role of bioactive plasmalogens in lung surfactant

Zhuo R, Rong P, Wang J, Parvin R, and Deng Y. (2021) The potential role of bioactive plasmalogens in lung surfactant. Frontier in Cell and Developmental Biology

Lung surfactant is a stabilizer for the respiratory surface of the mammalian lung. The main purpose for this membrane layer is to minimize surface tension at the area where alveolus (small air containing compartment in the lungs where respiratory gases are exchanged with the pulmonary capillaries) meet air and liquid, optimizing the mechanics of breathing, and helping to avoid alveolar collapse. The initial discovery of lung surfactant occurred in patients with neonatal respiratory distress syndrome (NRDS) where surfactant is late appearing or deficient. Two membrane proteins, SP-B and SP-C, are thought to be important for the absorption and spread of surfactant film. To date it has not been possible to make an effective artificial surfactant treatment due to the size and complexity of SP-B and the hydrophobicity and instability of SP-C. Research into the composition and physical properties of surfactant has shown that plasmalogens, a class of lipids that contain a vinyl-ether bond, is a critical component of lung surfactant. Zhuo et al review the roles and properties of plasmalogens in general and as a component of lung surfactant.

Plasmalogens make up 15-20% of the phospholipids in cell membranes and are most abundant in the brain, leukocytes, heart, and skeletal muscle. They contain a glycerol backbone with a vinyl-ether bond at sn-1, an ester bond at sn-2 and a polar headgroup, often ethanolamine, at sn-3. The vinyl-ether bond in plasmalogens provides these lipids with unique and beneficial characteristics. The double bond in plasmalogens causes their structure to be more compact and organized, essential for myelin and secretory membranes including areas of vesicular fusion and lung surfactant. Changes in plasmalogen levels is also associated with lipid raft stability and involvement in cell signaling, which may allow plasmalogens to modify lung surfactant membrane structure. The vinyl bond also scavenges reactive oxygen species (ROS), providing these lipids with antioxidant properties.

The antioxidant properties may be one of the largest benefits that plasmalogens provide to lung surfactant. When rodent lung surfactant was analyzed, 38% of the phospholipid species present were found to be plasmalogens. As the lung is known to be a target for ROS, plasmalogens may provide protection against respiratory diseases simply by acting as antioxidants. It has been shown many times that increasing plasmalogens levels protects against oxidative stress, and in line with the previous findings, premature infants treated with surfactant replacements that contained higher levels of plasmalogens showed far better respiratory outcomes.

Work with surfactant-like mixtures that contain plasmalogens has suggested a role for these lipids in maintaining surface tension and viscosity of surfactant. Mixtures with different concentrations of plasmalogens were analyzed, with higher concentrations associated with a decrease in surface tension. As low as 2% total phospholipid content being plasmalogens was able to greatly reduce the surface tension and encouraged respiration. In addition, it is thought that plasmalogens promote and stabilize non-lamellar membrane phase structure, which encourages membrane fusion.

The data summarized by Zhuo et al suggests that an effective lung surfactant treatment would have to contain adequate levels of plasmalogens. They propose that their antioxidant properties protect the lungs from ROS damage and their ability to promote non-lamellar structures increases the distribution of the lung surfactant lipid mixture.  A disorder that results from plasmalogen deficiency called rhizomelic chondrodysplasia punctata (RCDP) causes a severe form of dwarfism and cognitive disability. Recurrent respiratory infections and trouble clearing respiratory secretions are also commonly observed clinical manifestations of RCDP. The importance  of plasmalogens in lung surfactant suggests an additional effect of plasmalogen deficiency in RCDP and could explain the respiratory issues experienced in these patients.