Production and components of surfactant
Surfactant is a product of the alveolar type 2 cells. This complex mixture of lipids and proteins starts being secreted into the alveoli form 24 weeks gestational age[13]. Following synthesis in the endoplasmic reticulum and Golgi apparatus, [14]surfactant is packaged in lamellar bodies[15] before exocytosis. The Adenosine Triphosphate Binding Cassette 3 (ABCA3) protein that is located on the limiting membrane of the lamellar body facilitates transport of phospholipids into the lamellar bodies[16]. After exocytosis into the alveolar surface, hydrophobic proteins become essential in the formation of the lipid monolayer at the air-liquid interface. This mixture forms a film that is made up of a lipid bilayer and a monolayer enriched with dipalmitoylphosphatidylcholine that is mostly responsible to lower surface tension in the air fluid interface of the alveoli[17].
Surfactant is made up of 90% phospholipids and 10% protein. The major component of phospholipid is phospatidylcholine which in about 80% exists in the dipalmitoylphosphatidylcholine form[18]. The next component of phospholipids is phospatidylglycerol that may play a secondary role in reducing surface tension. It has been demonstratedin vitro that mixtures with dipalmitoylphosphatidylcholine: phospatidylglycerol has better lipid adsorption when compared to mixtures with dipalmitoylphosphatidylcholine alone[19, 20]. Additionally, studies have demonstrated that phospatidylglycerol plays a part in the innate immune pathway and regulates both viral and bacterial infections[21-23]. The remainder of phospholipid components are made up of phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, sphingomyelin and neutral lipids (cholesterol and diacylglycerol), the exact function of these components remains unclear[24].
The protein component of surfactant is comprised of 4 protein types namely surfactant protein A (SP-A), Surfactant protein B (SP-B), Surfactant protein C (SP-C) and surfactant protein D (SP-D)[25]. These proteins can be divided into two groups based on their chemical properties, SP-B and SP-C are two small hydrophobic proteins, while SP-A and SP-D are hydrophilic. In addition toABCA3 , Thyroid transcription factor-1 (TTF-1) is also an important protein required for the normal structure and functioning of pulmonary surfactant [26].
SP-A was the first protein to be discovered as a component of surfactant[27]. SP-A and SP-D function as part of the innate immune system[11, 28] as opsonins that act against pathogens by increasing membrane permeability or facilitating the attachment of phagocytes[29]. SP-A deficient animal models are more susceptible to infections but at the same time able to maintain normal oxygenation, suggesting that SP-A does not influence the normal functioning of surfactant[23].
SP-B and SP-C are of particular interest in congenital surfactant protein deficiencies. SP-B and SP-C molecules are first synthesised as larger precursor molecules that are further cleaved into their mature forms. This process occurs in the lamellar body and it is here that ABCA3 enables phospholipid translocation and organelle development. ABCA3 (ATP-binding cassette, subfamily A, member 3) is an intracellular lipid transporter that is localized within the outer membrane of lamellar bodies in which transports phospholipids and cholesterol into the lamellar body lumen[30]. Lamellar bodies function as a production and storage organelle for surfactant before secretion into the alveolar space[31].
The production of these molecules is under the control of TTF1 or NKX2.1 which is a nuclear transcription factor that also is expressed in the basal ganglia and thyroid gland[32, 33].