The airspaces are lined with a lipoprotein complex called pulmonary surfactant, named for its ability to maintain normal respiratory mechanics by reducing surface tension at the air/liquid interface, preventing the lungs from collapsing at the end of expiration.

Lack of pulmonary surfactant, whether caused by premature birth, lung injury, or mutations in genes critical to surfactant production or function, causes respiratory failure.

Pulmonary surfactant consists of a complicated network of extracellular membranes that overlies the alveolar epithelium and alveolar macrophages.

Its functions are:

• Protection against collapse
• Defense against inhaled pathogens, and
• Protection against injury, acting as an anti-inflammatory and antioxidant.

Surfactant membranes contain about 2 wt % of two hydrophobic lipoproteins (SP-B and SP-C), 3-5 wt % of a surfactant lipoprotein (SP-A) peripherally associated to the membranes, 0.5 wt % of surfactant protein D (SP-D) and approximately 90 wt % of lipids which consist of equimolar amounts of saturated and unsaturated phospholipid species and cholesterol.

Surfactant proteins B and C are small and very hydrophobic proteins, mainly involved in surface activity. SP-B is essential for breathing. Full-term infants unable to produce SP-B develop lethal neonatal respiratory distress. However, SP-B deficient infants lack not only SP-B but also mature SP-C. SP-C knockout mice can breathe normally, thus SP-C is not essential for breathing. However, recent studies indicate that children with selective deficiency of SP-C develop acute and chronic lung disease in infancy.

Nevertheless, SP-C mutations have more severe consequences than the absence of expression of SP-C gene. SP-C mutations seems to be conformational diseases that occur as a consequence of misfolded pro-SP-C but not to lack of SP-C.

The other two proteins associated with surfactant are SP-A and SP-D. These proteins have an enormous size, are relatively hydrophilic, and belong to the collectin family, so named because all of them contain a collagen-like domain, and lectin domains. Lung collectins have supratrimeric assembly in the native state. It is important to understand the consequences of incomplete oligomerization on their function since the extent of oligomerization of SP-A and SP-D may be altered in various diseases and can vary among individuals.

SP-A and SP-D are primarily involved in innate host defense in the alveolus. Host defense in the alveolar interface is extremely demanding since even moderate degrees of inflammation and exudation compromise gas exchange. Surfactant proteins A and D bind and agglutinate pathogens, facilitating phagocytosis and the killing of pathogens by alveolar macrophages. In addition, SP-A and SP-D possess antiviral properties, although the mechanisms involved in this activity are not understood. Lung collectins not only limit alveolar infection by binding to pathogens and/or phagocytic cells, but also regulate alveolar inflammation by binding to receptors on epithelial and immune cells.

Unlike SP-D, SP-A is closely associated with surfactant membranes, which contain the hydrophobic surfactant peptides, SP-B, and SP-C. SP-A aggregates these membranes and improves surface activity of surfactant, protecting the lung against alveolar collapse. In addition, SP-A prevents surfactant inactivation by several transudatedserum proteins.

Surfactant is synthesized by type II epithelial cells and stored in characteristic intracellular inclusions called lamellar bodies (LB). After regulated secretion by exocytosis, lamellar bodies unravel spontaneously in the alveolar fluid to form multilamellar vesicles and highly organized membranes, termed “tubular myelin”.

These large extracellular membranes, called large aggregates (LA), have high surface activity. They adsorb very rapid to the air-liquid interface. The surface film at the alveolar air/liquid interface consists of a phospholipid monolayer with bilayer structures attached to it. With surface compression and expansion, small vesicles are generated. These vesicles are named smal aggregates and have poor surface activity. These small aggregates are taken up and degraded by alveolar macrophages and/or re-uptaken by type II cells.

Cristina Casals,Ph.D.
Department of Biochemistry and Molecular Biology
Complutnese University of Madrid

 

The particular composition of surfactant membranes results in the coexistence of two distinct micrometer-sized fluid phases (liquid ordered and liquid disordered) at physiological temperatures.

The image below corresponds to a giant unilamellar vesicle formed from surfactant membranes and labeled with DiIC18 (red) and Bodipy-PC (green). The rounded green areas in the image correspond to liquid disordered regions, enriched in unsaturated phospholipids and surfactant hydrophobic peptides (SP-B and SP-C).

The red background corresponds to liquid ordered phase, enriched in high Tm phospholipids (such as dipalmitoylphosphatidylcholine and sphingomyelin) and cholesterol.

Pulmonary surfactant is one of the membranous systems where phase coexistence of specialized micrometer-sized membrane domains is required for its function.

There are multiple disorders that may have elements of surfactant deficiency, dysfunction or inactivation.

Premature babies with surfactant deficiency develop a respiratory distress. Premature infants have benefited from recent advances in the development of artificial surfactant therapy. However, among the survivors treated with currently available surfactants (which do not contain SP-A or SP-D) there is a significant percentage of infants who grow up with recurrent pulmonary infection and chronic inflammation. Given that preterm infants are particularly poor at mounting an antibody response, the mechanisms of innate immunity, in this group of patients, may be especially important. Thus, there is a need to develop better surfactant therapies.

There are other disorders in infants and adults in which surfactant activity is inhibited and/or surfactant production adversely affected:

 

Surfactant dysfunction in some respiratory diseases is still not fully understood, but it is believed that it occurs due to the leakage of a variety of inhibitory plasma proteins in the alveoli such as albumin, fibrinogen, and C-reactive protein. In addition, inhaled airborne particles containing bacterial lipopolysaccharide that incorporate into the surfactant monolayer might alter surfactant function.

A better understanding of the biophysical properties of lung surfactant and its susceptibility to inhibition is important for the development of new surfactant formulations to treat lung diseases.

Recommended Reviews

Lung surfactant in health and disease

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• Fessler MB, Summer RS. Surfactant Lipids at the Host-Environment Interface. Metabolic Sensors, suppressors, and Effectors of Inflammatory Lung Disease. Am J Respir Cell Mol Biol. 2016, 54:624-635. doi: 10.1165/rcmb.2016-0011PS.

• Griese M. Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J. 1999. 13:1455-76. doi:10.1034/j.1399-3003.1999.13f36.x

• Kumar A, Abdelmalak B, Inoue Y, Culver DA. Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach. Lancet Respir Med. 2018, 6:554-565. doi: 10.1016/S2213-2600(18)30043-2.
• Trapnell BC, Nakata K, Bonella F, Campo I, Griese M, Hamilton J, Wang T, Morgan C, Cottin V, McCarthy C. Pulmonary alveolar proteinosis. Nat Rev Dis Primers. 2019, 5:16. doi: 10.1038/s41572-019-0066-3.
• Whitsett JA, Wert SE, Weaver TE. Diseases of pulmonary surfactant homeostasis. Annu Rev Pathol. 2015, 10:371-393. doi: 10.1146/annurev-pathol-012513-104644.

• Zuo YY, Veldhuizen RA, Neumann AW, Petersen NO, Possmayer F. Current perspectives in pulmonary surfactant‐‐ inhibition, enhancement and evaluation. Biochim Biophys Acta. 2008, 1778(10):1947‐77.

Surfactant Collectins SP-A & SP-D

• Casals C, Campanero-Rhodes MA, García-Fojeda B, Solís D. The Role of  Collectins and Galectins in Lung Innate Immune Defense. Front Immunol. 2018, 9:1998. doi: 10.3389/fimmu.2018.01998.

   

• Casals C, García-Fojeda B, Minutti CM. Soluble defense collagens: Sweeping up immune threats. Mol Immunol. 2019, 112:291-304. doi: 10.1016/j.molimm.2019.06.007.

   

• McCormack FX, Whitsett JA. The pulmonary collectins, SP‐A and SP‐D, orchestrate innate immunity in the lung. J Clin Invest. 2002, 109:707‐712. doi: 10.1172/JCI15293

• Sorensen GL. Surfactant protein D in respiratory and non-respiratory diseases. Front Med. 2018, 5:18. doi: 10.3389/fmed.2018.00018

   

• Watson A, Madsen J, Clark HW. SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties. Front Immunol. 2021, 11:622598. doi: 10.3389/fimmu.2020.622598.

• Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005, 5:58‐68. doi: 10.1038/nri1528.

   

Surfactant hydrophobic proteins SP-B & SP-C

• Hawgood S, Derrick M, Poulain F. Structure and properties of surfactant protein B. Biochim Biophys Acta. 1998, 1408:150-160. doi: 10.1016/s0925-4439(98)00064-7.

• Johansson J. Structure and properties of surfactant protein C. Biochim Biophys Acta. 1998, 1408:161-172. doi: 10.1016/s0925-4439(98)00065-9.

• Johansson J. Molecular determinants for amyloid fibril formation: lessons from lung surfactant protein C. Swiss Med Wkly. 2003, 133:275-82. doi: 10.4414/smw.2003.09987.

   

• Nogee LM. Alterations in SP‐B and SP‐C expression in neonatal lung disease. Annu Rev Physiol. 2004, 66:601‐23. doi: 10.1146/annurev.physiol.66.032102.134711.

   

• Serrano AG, Pérez‐Gil J. Protein‐lipid interactions, and surface activity in the pulmonary surfactant system. Chem Phys Lipids. 2006, 141(1‐2):105‐18.

   

• Whitsett JA, Weaver TE. Hydrophobic surfactant proteins in lung function and disease. N Engl J Med. 2002, 347(26):2141‐8. doi: 10.1056/NEJMra022387.

Surfactant synthesis and degradation

• Whitsett JA, Alenghat. T  2015. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat Immunol, 16:27-35. doi: 10.1038/ni.3045.
• Lopez-Rodriguez E, Gay-Jordi G, Mucci A, Lachmann N, Serrano-Mollar A. Lung surfactant metabolism: early in life, early in disease and target in cell therapy. Cell Tissue Res. 2017, 367:721-735. doi: 10.1007/s00441-016-2520-9.

 Surfactant replacement therapy

• Hentschel R, Bohlin K, van Kaam A, Fuchs H, Danhaive O. Surfactant replacement therapy: from biological basis to current clinical practice. Pediatr Res. 2020, 88:176-183. doi: 10.1038/s41390-020-0750-8

• Johansson J, Curstedt T. Synthetic surfactants with SP-B and SP-C analogues to enable worldwide treatment of neonatal respiratory distress syndrome and other lung diseases. J Intern Med. 2019, 285:165-186. doi: 10.1111/joim.12845

   

• Sardesai S, Biniwale M, Wertheimer F, Garingo A, Ramanathan R. Evolution of surfactant therapy for respiratory distress syndrome: past, present, and future. Pediatr Res. 2017, 81:240-248. doi: 10.1038/pr.2016.203.