Metrics details. Pulmonary surfactant is a unique mixture of lipids and surfactant-specific proteins that covers the entire alveolar surface of the lungs. Surfactant is not restricted to the alveolar compartment; it also reaches terminal conducting airways and is present in upper airway secretions.
While the role of surfactant in the alveolar compartment has been intensively elucidated both in health and disease states, the possible role of surfactant in the airways requires further research. This review summarizes the current knowledge on surfactant functions regarding the airway compartment and highlights the impact of various surfactant components on allergic inflammation in asthma. Pulmonary surfactant reduces the surface tension at the air-liquid interface throughout the lung by forming a lining layer between the aqueous airway liquid and the inspired air.
The major component of surfactant, dipalmitoyl-phosphatidylcholine DPPC , is an amphiphatic phospholipid. Its polar head region is associated with the aqueous hypophase lining the airways whereas the hydrophobic fatty acid chains face the luminal air.
Surfactant-specific proteins facilitate the arrangement of phospholipids in the lining layer, thereby optimizing surface-tension-reducing capacity. This important function prevents alveolar and airway collapse at end-expiration and thus allows cyclic ventilation of the lungs. After the discovery of the basic functional principle of pulmonary surfactant more than 70 years ago, the pulmonary surfactant system has been intensively investigated and more than publications have revealed numerous aspects of surfactant synthesis, secretion, metabolism and various functions in the alveolar compartment.
The pathogenetic relevance of surfactant was initially recognized in infant respiratory distress syndrome as a quantitative surfactant deficiency [ 1 ], but today biochemical and biophysical surfactant abnormalities are reported in various lung diseases, such as acute respiratory distress syndrome, pneumonia, and cardiogenic lung edema [ 2 ].
The precise composition of surfactant in health and disease is known down to the genetic code of its specific proteins. While surfactant was initially thought to be a key player in the biophysical behavior of the lung, today its immunomodulatory properties make surfactant a fascinating compound in innate and adaptive immunity of the lung. Surfactant proteins act as a first-line defense against invading microorganisms.
Moreover, they possess binding capacity for aeroallergens, highlighting the possible role of the pulmonary surfactant system in allergic diseases such as asthma. The possible involvement of pulmonary surfactant in the pathophysiology of respiratory diseases with a predominant disturbance in the conducting airways, such as asthma, has only recently been addressed [ 3 ].
Asthma is characterized by chronic inflammation of the airways with eosinophils and T helper lymphocytes associated with bronchial hyper-responsiveness, which causes a reversible form of airway obstruction after inhalation of a variety of stimuli. Airway obstruction with increased airway resistance in asthma, which is commonly thought to be caused by smooth muscle constriction, mucosal edema and secretion of fluid into the airway lumen, may partly be due to a poor function of pulmonary surfactant.
In the past decade, direct and indirect evidence has emerged for surfactant as a factor in the regulation of airway calibers and a modulator of allergic inflammation. The following sections review the potential role of surfactant in asthma. The majority of surfactant is synthesized and secreted by alveolar type II cells.
During expiration, alveolar surfactant becomes extruded into the adjacent conducting airways. Electron microscopy has revealed that surfactant material forming monolayers and multilayers can be found at the air-liquid interface of the airway lumen.
In addition, multi-lamellar vesicles and lattice-like tubular myelin can be found within the hypophase of the epithelial lining fluid covering the airways [ 4 ]. Immunohistochemistry and in situ hybridization studies demonstrated that surfactant protein and mRNA expression are not restricted to alveolar type II cells.
Whitsett and coworkers [ 5 ] have shown that during lung development, the hydrophobic surfactant protein SP -B and SP-C mRNAs are first expressed in bronchi and bronchioles. Expression in epithelial cells of the bronchiolo-alveolar portals and in type II cells increased with gestational age [ 5 ]. In the fetal and adult human lung, SP-B and SP-C are expressed primarily in distal conducting and terminal airway epithelium [ 5 ]. Surfactant-protein synthesis has been shown in Clara cells [ 6 , 7 ] and SP-A and SP-D were also found in more proximal parts of the respiratory tract [ 8 , 9 , 10 ].
In addition to the spatial distribution of surfactant proteins, local synthesis and release of phospholipids in tracheal epithelial cells have been demonstrated [ 11 ]. Clara cells do not, however, secrete or synthesize lamellar bodies or DPPC. To conclude, local synthesis of surfactant components in the airways might indicate the possibility of adaptation and regulation of the airway surfactant system.
Studying the composition of airway surfactant still has major limitations, as there is no method for selective sampling of surfactant from the conducting airways. It has been demonstrated that airway secretions from tracheal aspirates contain significant amounts of surfactant with a phospholipid composition similar to alveolar surfactant [ 12 , 13 ].
In contrast, the concentrations of surfactant proteins have been found to be decreased in tracheal aspirates from porcine lungs [ 12 ]. Van de Graaf et al.
In contrast, Cheng and co-workers [ 16 ] found increased levels of SP-A and SP-D in bronchial and alveolar lavages in mild, stable asthmatics compared with controls.
The discrepancy of these findings might be due to different time points and methods of sampling of the lavage fluids, and requires further clarification. Airway surfactant reduces surface tension at the air-liquid interface of conducting airways. This decreases the tendency of airway liquid to form bridges in the more narrow airway lumen film collapse.
In addition, a low surface tension minimizes the amount of negative pressure in the airway wall and its adjacent liquid layer, which in turn decreases the tendency for airway wall 'compliant' collapse.
This causes transmural pressures of less than 1 cmH 2 O whereby the patency of airways is maintained. By preventing both film collapse and compliant collapse, airway surfactant secures airway architecture and its openness.
A simple method to estimate surfactant function, as it applies to the cylindrical surface of a narrow conducting airway, is the capillary surfactometer. This instrument simulates the morphology and function of a terminal conducting airway with a glass capillary that in a short section is particularly narrow with an inner diameter of 0.
It utilizes a very small volume 0. By raising the pressure, the liquid is extruded from the narrow section. Pressure is zero if the capillary is open for free airflow, but there is an increase in pressure when the liquid returns to block the narrow section. Liu et al. The ability of surfactant to maintain free airflow was lost with the addition of albumin or fibrinogen two potent surfactant inhibitors.
In a recent study, we demonstrated that surfactant dysfunction by proteins was further disturbed by cooling [ 21 ]. This may explain the finding of increased airway resistance in patients with exercise-induced asthma where airway surfactant with sufficient surface activity becomes seriously inactivated due to cooling during exercise with hyperventilation of cold air. The principal findings of surfactant function and dysfunction in the rigid airway model using the capillary surfactometer have been confirmed using an elegant approach to study conducting airway function in excised isolated rat lungs [ 22 ].
Surfactant also contributes to the regulation of airway fluid balance, improves bronchial clearance and sets up a barrier to inhaled agents. Firstly, the high surface pressure low surface tension of surfactant counteracts fluid influx into the airway lumen. Loss of surface activity would result in additional inward forces that cause fluid accumulation in the airway lumen.
The influence of surfactant on airway liquid balance also includes prevention of desiccation. Secondly, surfactant improves bronchial clearance by optimizing transport of particles and bacteria from the peripheral to the more central airways. Moreover, surfactant has been shown to enhance mucociliary clearance [ 23 ], partly by increasing ciliary beat frequency [ 24 ]. Thirdly, several studies have suggested that surfactant sets up a barrier to the diffusion of inhaled agents, including bacteria, allergens and drugs [ 25 , 26 ].
For example, depletion of the surfactant layer by lung lavage leads to augmented responses to drugs and allergens [ 27 , 28 ]. Interestingly, exogenous surfactant treatment lessens the airway response to inhaled, but not systemically given, bronchoconstrictor stimuli in rats, suggesting an airway barrier to drug diffusion [ 29 ]. In addition, it has recently been shown that treatment of rats with exogenous phospholipids suppresses the neural activity of bronchial irritant receptors [ 30 ].
This may support the view of a possible link between airway hyper-responsiveness and airway surfactant balance. Besides the important biophysical properties of pulmonary surfactant, its role in immunomodulation has attracted increasing interest in asthma.
They are members of the collectins, a family of oligomeric molecules containing a collagen-like domain and a calcium-dependent lectin domain, known as a carbohydrate recognition domain.
The ability of lung collectins to regulate immune cells has been shown to be affected by the presence of lipids [ 31 ]. In asthma, the important immune cells in the allergic inflammatory response are dendritic cells, T-helper lymphocytes, IgE-producing B lymphocytes plasma cells , mast cells and eosinophils.
Of course, airway inflammation in asthma is a more complex scenario that also includes epithelial cells, smooth muscle cells and parenchymal cells; however, available data on the effect of surfactant components on these cells are rare. Of the various aspects of modulation of immune cell functions by surfactant components, the important findings relevant to asthma are summarized in the following section and illustrated in Fig.
Interaction of surfactant with airway inflammation in asthma. After uptake through the airway surfactant barrier right side of figure , allergens are presented by dendritic cells DC to T cells T that release IL-2, proliferate, and differentiate into T helper 2 lymphocytes Th2. IgE is bound to mast cells MC that, upon stimulation with allergen, release mediators such as histamine inducing acute asthma attacks. SP-A and SP-D are shown in bold to emphasize the importance of these surfactant molecules as immunomodulators in asthma.
A very early step in the induction of allergic inflammation is allergen uptake by dendritic cells, antigen processing and subsequent antigen presentation to T lymphocytes. SP-A has been shown to bind to pollen grains [ 32 ]. In addition, it has been demonstrated that both SP-A and SP-D interact with mite allergens in a carbohydrate-specific and calcium-dependent manner [ 33 ].
These data may suggest that lung collectins inhibit the induction of allergic reactions by direct allergen binding. This in turn would be beneficial in preventing acute asthma attacks by inhibition of the allergen-specific IgE binding and possibly also by inhibition of allergen processing by dendritic cells. However, further research is required to answer questions on possible interactions of dendritic cells with surfactant components.
T lymphocyte proliferation and cytokine release is an important step in the further activation of the adaptive immune system in asthma. This T-cell response can induce B lymphocyte differentiation into specific IgE antibody secreting plasma cells. Characteristics and details of pulmonary surfactant proteins and surfactant lipids. In anticipation of birth during gestation period, the alveoli start producing PS in 24th week and reaches to the peak production in 34th week.
The endogenous cortisol stimulates the production of PS during gestation. Premature infants, especially those born before 34th weeks, have immature lungs and are deficient in p S. Pregnant women who are at the risk of premature delivery are given betamethasone for 48 h before delivery to improve the lung maturity and reduce the risk of developing NRDS. AT-II epithelial cells are reported to be the primary site of influenza virus replication.
Mice infected with influenza virus have shown lower amounts of phosphatidylcholine and alters the metabolism of PS, which are attributed to the development of ARDS Woods et al. The effects of SP deficiencies or dysfunctions is paramount in the pathogenesis of neonatal respiratory diseases Verlato et al. It was also substantiated that there is a significant lack of surfactant protein found in preterm newborns with RDS or had experienced failure in extubation than that of newborns with normal functioning lungs Ballard et al.
It is also known that polymorphisms of SP-A, B and D showed association with idiopathic pulmonary fibrosis and various other pulmonary diseases. Chang et al. The beneficial use of surfactant protein as a treatment in neonates with RDS has been a breakthrough and has been studied in-depth for neonatal medicine in the past 3 decades Speer et al. Thus, it is logical to hypothesize that restoration of PS does improve the lung function Echaide et al.
The primary application of pulmonary surfactants is in the treatment of NRDS in premature infants. However, the studies did not demonstrate significant benefit of pulmonary surfactants in ARDS. Meta-analysis of randomized controlled trials for the effect of surfactant in adult patients with ARDS Ballard et al. Marcel Filoche et al. However, this approach requires the identification of patients who are at the stage of developing ARDS. The clinical efficacy of PS is also being actively investigated in other pulmonary diseases such as asthma and pneumonia Choi et al.
One study reported that PS improved lung function in an acute asthma exacerbation but not in stable asthma Tepper et al. Another study reported that PS improved the pulmonary function in adult patient with stable chronic bronchitis Agudelo et al.
In addition, PS is reported to decrease the cytokine release, synthesis of inflammatory mediators, lymphocyte proliferation, immunoglobulin production, and expression of adhesion molecules. Another study reported PS improves the anti-inflammatory effect of amikacin. All the above observations suggest the possible role of surfactants in modulating the immune responses in pulmonary diseases. There are two types of therapeutic PS: natural and synthetic. The natural therapeutic PS are being sourced from bovine, porcine, and human amniotic fluid.
Currently the use of human amniotic fluid for sourcing therapeutic PS are halted mainly because of non-availability and cost. The advantage of natural surfactants is that they contain surfactant-associated proteins and thus results in better spreading and lung defense properties.
Due to the difficulties in sourcing animal derived surfactant, well-defined synthetic surfactants were developed.
It was also reported that synthetic surfactant containing only one protein has not found success Johansson and Curstedt, Both synthetic and natural surfactants are found to be effective in RDS with natural surfactants containing SP-B and SP-C are found to be superior in clinical efficacy. To date, the list of natural surfactants, and synthetic surfactants developed for the treatment of respiratory infections are shown in Table 2.
However, the first-generation surfactants do not contain either SP-B or SP-C peptide mimics, thus limiting their clinical efficacy. The second-generation of synthetic surfactants are found to be clinically effective, suggesting the presence of SP-B and SP-C in surfactants are essential. TABLE 2. Colfosceril palmitate is a first generation commercially available artificial surfactant Law et al. At present, it is under the state of cancellation in the post-marketing stage because of adverse effects.
In addition to being useful in RDS, it has also shown to significantly reduce the risk of pneumothoraces, pulmonary interstitial emphysema and mortality, bronchopulmonary dysplasia, intraventricular hemorrhage and patent ductus arteriosus. It is administered as its aqueous dispersion with the phospholipids. Beractant is another natural pulmonary surfactant from bovine lungs containing phosphotidylcholine, triglycerides, fatty acids, SP-B and SP-C.
Portactant alfa is another natural pulmonary surfactant from porcine lungs containing phosphatidylcholine, dipaImitoylphosphatidylcholine, SP-B and SP-C. Decreased surfactant production causes atelectasis and reduced the pulmonary compliance.
Mirastschijski et al. Preliminary observations from lung autopsies of COVID patients found that pulmonary surfactant increased blood oxygenation, reduced pulmonary edema, and ameliorated the excessive inflammatory reaction Mirastschijski et al. Oxygen in the alveolus is exchanged with carbon dioxide in the capillaries. Type I cells enables gas exchange.
Type II cells secrete pulmonary surfactant PS. PS lines the alveolus and prevent it from collapsing B In a moderately infected lung, Alveolar Type II cells are inflamed resulting in reduced pulmonary surfactant. Surface tension and pressure increase inside the alveolus affecting the gas exchange. Vasodilation of the capillary occurs resulting in the release of inflammatory cytokines and accumulation of protein-rich fluid inside the alveolus C In severely infected lung, the alveolar type II cells become more inflamed thereby resulting in complete loss of pulmonary surfactant.
Scar tissue on the alveolar surface began to form. The release of inflammatory cytokines is increased, and more protein-rich fluid accumulate inside the alveolus. Gattinoni et al. Gene expression studies on lung biopsy cells in COVID patients have confirmed the downregulation of pulmonary surfactant proteins and their metabolism which has provided a scientific base to advocate further studies on investigating the usefulness of surfactant therapy in COVID patients Islam and Khan, Peter et al.
Schousboe et al. Lung surfactant therapy is a standard, safe and effective therapy for the treatment of ARDS in neonates, however clinical trials on recombinant SP-C based surfactant was found to be ineffective in the treatment of ARDS in adults Spragg et al. The natural surfactants, compared to synthetic surfactants, are reported to be superior in improving the blood oxygenation and shortening the ventilation time in infants Ainsworth et al. These observations suggest that early administration of natural surfactant to COVID patients might be beneficial to improve the pulmonary function Mirastschijski et al.
A recent review article by Francesco et al. Cattel et al. Kumar et al. Kumar, has proposed an innovative hypothesis that co-aerosolized exogenous pulmonary surfactant and ambroxol can be a potential therapeutic option for the treatment of COVID ARDS. The hypothesis was made based on reported evidences on beneficial effects of exogenous surfactants Davidson et al.
However, this hypothesis is yet to be tested. Abbas et al. Abbasi et al. Thus, in an opinion article by Abbs et al. However, contradicting to this study, another clinical study Kerget et al. The contradictory results from these two studies may be due to differences in the population demographics, and objectives of the study.
In a case study of a year-old-male non-smoker COVID patient with comorbidities of hyperlipidemia and prediabetes Heching et al. The recombinant fragment of human lung surfactant protein D rfhSP-D is reported to be more potent than remdesivir, an antiviral, in inhibiting the replication and infectivity of SARS-CoV-2 and the activity is found to mediated through down regulation of RdRp gene expression Hsieh et al. Computational fluid dynamics simulation studies Kitaoka et al. Hideyuki has put forward a hypothesis Takano, based on cumulative scientific evidences that pulmonary surfactants or synthetic surfactants or surfactant production stimulants may be effective for either prophylaxis or treatment for COVID However, this hypothesis is yet to be tested and validated in clinic.
There are two trials that are underway on poractant alfa using two different routes of administration: bronchial fibroscopy and endotracheal intubation.
Another two trials are underway on BLSE using two different routes of administration: endotracheal intubation and inhalation. The lipid-protein interaction is very important for the structural organization of surfactant monolayer and its functioning.
Alterations in surfactant homeostasis or biophysical properties can result in surfactant insufficiency which may be responsible for diseases like respiratory distress syndrome, lung proteinosis, interstitial lung diseases and chronic lung diseases.
The biochemical, physiological, developmental and clinical aspects of pulmonary surfactant are presented in this article to understand the pathophysiological mechanisms of these diseases. Abstract Surfactant is an agent that decreases the surface tension between two media.
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