The hydrophilic proteins SP-A and SP-D play a major role in host defense by inhibiting bacterial growth, facilitating bacterial uptake by host cells, and aggregating and opsonizing pathogens ( 65 ). These surfactant proteins can bind to both gram-negative and gram-positive bacteria. SP-A and/or SP-B interact with LPS derived from K. pneumoniae ( 30 , 66 ), E. coli ( 30 , 67 ), P. aeruginosa ( 68 &#; 70 ), and Legionella pneumophila ( 71 ), which consequently result in agglutination, enhancement of pathogen uptake, and growth inhibition. These surfactant proteins also bind with peptidoglycan, a cell wall component of gram-positive bacteria derived from Staphylococcus aureus ( 72 ) and Streptococcus pneumoniae ( 26 , 27 ), as well as Mycobacterium avium, Mycobacterium tuberculosis, and Mycoplasma pneumoniae to enhance uptake by phagocytes and inhibit their growth ( 73 &#; 78 ).
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Both SP-A and SP-D are able to bind to a variety of fungi, mostly opportunistic pathogens, to facilitate agglutination and phagocytosis by host cells. Animal studies demonstrate that pulmonary collectins (SP-A and SP-D) increase the permeability of the cell membrane of H. capsulatum, inhibiting its growth directly ( 31 ). They also bind to A. fumigatus ( 79 ), Blastomyces dermatitidis ( 80 ), Coccidioides posadasii ( 81 ), Cryptococcus neoformans ( 82 , 83 ), and Pneumocystis jiroveci (carinii) ( 84 , 85 ), which results in agglutination and enhanced uptake. Interestingly, this effect appears to be microbe specific, as the binding of pulmonary collectins to Candida albicans inhibits phagocytosis by alveolar macrophages while still inhibiting the fungal growth ( 86 , 87 ).
Pulmonary collectins (SP-A and SP-D) bind to viruses to facilitate pathogen removal. Viruses are unique compared with many microorganisms in that they require entrance into host cells to replicate. As SP-A and SP-D are present in the mucus layer and alveolar surface, they are well positioned to prevent infection of epithelial cells through viral neutralization, agglutination, and enhanced phagocytosis. SP-A and/or SP-D bind to hemagglutinin and neuraminidase of influenza A virus to inhibit their activity ( 88 &#; 90 ). Interestingly, the hemagglutinin of pandemic influenza viruses has a low binding activity for surfactant protein D compared with that of a seasonal influenza strain ( 91 ). Pulmonary collectins also bind to glycoproteins of viruses, including HIV ( 92 , 93 ), RSV ( 94 ), and severe acute respiratory syndrome coronavirus ( 95 ). Recent studies indicate that, in addition to pulmonary collectins, the surfactant lipid components also inhibit RSV infection ( 96 ).
The primary indication for surfactant replacement therapy is RDS in preterm infants. Several human observational studies and RCTs demonstrate reduced mortality and morbidity, including interstitial emphysema and pneumothorax, when exogenous surfactant is administered to preterm infants born at less than 30 weeks&#; gestation who are at high risk for RDS (97&#;99). Both synthetic and natural types of surfactant are effective, but natural preparations that retain surfactant protein B and C analogs have been shown to be superior in terms of decreasing mortality and lowering the rate of RDS complications in preterm infants (100, 101). Currently the American Academy of Pediatrics guidelines recommend initial nasal continuous positive airway pressure immediately after birth for all preterm infants and subsequent intubation with prophylactic or early surfactant administration in select patients (102). Endotracheal instillation remains a widely accepted technique of surfactant administration (103). However, this technique may be complicated by episodes of severe airway obstruction (104). Noninvasive or less-invasive techniques, including aerosolized surfactant, laryngeal mask airway-aided delivery, pharyngeal instillation, and the use of thin intratracheal catheters, are being evaluated (105&#;109).
For adult patients, both synthetic and natural animal surfactants have been tried for the treatment of ARDS, via either intratracheal instillation or aerosolized delivery. However, studies did not demonstrate a significant mortality benefit or a consistent improvement in oxygenation with this approach (42, 110&#;114). Initially it was believed that exogenous surfactant could be beneficial to patients with ARDS because they have decreased surfactant levels and persistent atelectasis contributing to gas exchange abnormalities. Patients with ARDS also have altered composition and function of surfactant, which is compounded further by mechanical ventilation (40, 41, 115). Despite the theoretical soundness of exogenous surfactant administration in patients with ARDS, this therapeutic option has limited justification at this time. Given the fact that neonates start surfactant therapy early in the course of the disease before RDS becomes severe, it may be worthwhile to consider studying an approach with early surfactant administration, but this depends on the development of effective biomarkers that can identify or predict patients with ARDS early in the course of disease. Contrary to RDS, ARDS is a heterogeneous syndrome with various degrees of inflammation and tissue remodeling depending on the individual patient, which may explain differential responses to surfactant therapy. Alternatively, the utility of novel proteolytically stable surfactant preparations as replacement therapies might be an area of future study.
Exogenous surfactant also has been examined in a variety of lung diseases such as asthma and pneumonia (116). Although a pilot study for aerosolized natural surfactant showed improved lung function during an acute asthma exacerbation (117), it did not show clinical benefit in patients with stable asthma (118). One case report demonstrated oxygenation improvement with intrabronchial instillation of surfactant in an adult patient with gram-negative lobar pneumonia (119). Other case reports demonstrate similar oxygen improvements in HIV-infected infants with P. carinii pneumonia (120, 121) or RSV pneumonia (122). One RCT of a 2-week treatment course with aerosolized synthetic surfactant showed improved pulmonary function in adult patients with stable chronic bronchitis (123). These observations need to be confirmed with larger well-controlled studies in subjects with respiratory illness.
One potential therapeutic implication of surfactant replacement therapy is immunosuppression. Animal studies and limited human data show that exogenous surfactant decreases cytokine release (124), DNA synthesis of inflammatory mediators (125, 126), lymphocyte proliferation (127), immunoglobulin production (128), and expression of adhesion molecules (129). Intratracheal administration of a surfactant&#;amikacin mixture to rats with Pseudomonas pneumonia showed improved antiinflammatory effects compared with amikacin alone (130). These observations suggest the possibility that surfactant may be used to modulate immune responses during inflammatory lung disease, but further studies are necessary.
Outside of exogenous surfactant therapy, there is also evidence that certain pharmacologic agents may enhance endogenous surfactant levels, although the current data are limited. Corticosteroids have been widely used in women at risk for preterm delivery, as they reduce neonatal morbidity and mortality from RDS. Antenatal steroids accelerate development of type 2 pneumocytes and thus increase the production of surfactant proteins and enzymes necessary for phospholipid synthesis. Corticosteroids also induce pulmonary β-receptors, which play a role in surfactant release and alveolar fluid absorption when stimulated (131). Thyroid hormone also has a synergistic effect on phospholipid synthesis with corticosteroids in animal models (132, 133). Ambroxol may also act to increase surfactant release and is under investigation for use in RDS (134). Hydroxychloroquine has been anecdotally reported to successfully treat children with SP-C deficiency with or without corticosteroid use (135&#;137). The mechanism of action is unclear, but it may be related to hydroxychloroquine&#;s inhibition of the intracellular processing of SP-C precursors leading to late accumulation of SP-C (138). Other agents such as keratinocyte growth factor have been shown to increase surfactant secretion or its synthesis (139).
Surfactants are produced on a global, industrial scale, mostly by major international companies. The starting point for production can be either a synthetic or natural raw material called a feedstock.
Synthetic or petrochemical feedstocks are produced by oil, gas and chemical processing. The resulting chemicals, synthetic alcohols, can be further processed or reacted (including through alkylation, ethoxylation or sulphation) to produce a range of different types of surfactant molecules.
Because of their synthetic make-up, the molecular structure can be controlled during manufacturing to produce closely defined physical and performance characteristics. They are also chemically flexible, making them compatible with a wide range of other chemicals and substances.
This means they can be mixed with different components, including other surfactants, to produce a finished formulation with properties tailored to specific application requirements.
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Naturally occurring surfactants play an important role in human metabolism. They facilitate the exchange of gases (oxygen and carbon dioxide) via the lungs into the blood and vice versa - without them our bodies would not be able to perform such an important function as breathing.
Natural (also known as bio-based or oleo), surfactant feedstocks are derived from plant oils, mainly coconut and palm kernel. These feedstocks are renewable, coming from large tropical plantations typically providing a yield for over 25 years before replanting is required.
The plant oils are chemically processed (including through esterification, hydrogenation and distillation) to produce a fatty alcohol. Although their origin may be quite different, these alcohols are similar to their synthetic counterparts and hence go through the same kind of further chemical processing steps to produce the final surfactant.
Natural feedstocks could be perceived to be more environmentally sustainable although further criteria need to be recognised when assessing sustainability and all aspects of the surfactant life-cycle considered.
See also Surfactants and sustainability
The biggest technical difference between the two feedstock types is that synthetic feedstocks have greater molecular functionality (called branching) that can provide additional formulation flexibility and enhanced performance for technically demanding surfactant applications.
From a surfactant manufacturing perspective, however, the two types of feedstocks are not mutually exclusive, with producers able to utilise both, either separately or in combination, depending on economics, availability, market demand and performance requirements. As a result, surfactants containing at least one constituent derived from renewable natural raw materials now have about 50 per cent share of the total surfactant market in Europe.
Regardless of the origin of the feedstock, most surfactant production takes place in large industrial facilities under carefully controlled conditions.
The final surfactants are supplied to converters and formulators in a range of downstream industry sectors, the largest being detergent producers or &#;soapers&#;, where they are turned into finished products for both consumers and industrial customers. Today, surfactant chemistry is one of the best researched and scientifically developed fields. This enables the safe and responsible production of a vast range of different kinds of surfactants, each with its own performance characteristics and suitability for an equally diverse range of applications, many of which enhance our everyday lives.
See also Surfactant applications
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