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Atelectasis due to decreased surfactant in lungs

Atelectasis due to decreased surfactant in lungs


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Surfactant is a protein lipid mixture produced by alveolar pneumocytes composed of Dipalmitoyl Phosphatidyl Choline lipid, apoproteins and calcium ions. This surface lines the alveolar epithelium thereby reducing surface tension preventing lungs from collapse. Atelectasis is collapse of lung mainly due to lack of surfactant. Moreover it may also be due to obstruction of the airway tract.

My question is why is this surfactant found to be lowered in patients who have undergone cardiac surgery under pump oxygentor? Why does long term exposure to 100% Oxygen affect the surfactant. Is it due to its chemical composition or is it something to do with pulmonary circulation?

This Wikipedia article states alveolar collapse due to Oxygen Toxicity http://en.m.wikipedia.org/wiki/Oxygen_toxicity


Long-term exposure to excessive oxygen will lead to damage in pulmonary tissue. This damage resembles the same damage which is seen in patients with Acute Respiratory Distress Syndrome (ARDS). In these patients surfactant specific proteins are damaged by proteolysis. This proteolysis is caused by the neutrophil elastase enzyme, after a massive influx of activated neutrophils.

The damage done by exposure to excessive oxygen is thought to be done by Reactive Oxygen Species (ROS).

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. ROS are formed as a natural byproduct of the normal metabolism of oxygen…

These ROS can cause oxidative damage to DNA, RNA and proteins. They can form covalent bonds between molecules in the surfactant, thus inactivating them. Damaging of molecules can lead to cellular damage, causing ROS-mediated necrosis or apoptosis. Therefore there will be less surfactant production possible.

Also interestingly:

An important feature of pulmonary oxygen toxicity is that it is almost impossible to distinguish from damage caused by other lung injury processes. Consequently, it is unclear whether deterioration of lung function during high concentration oxygen therapy is due to worsening of the primary disease process or to oxygen-free radical-induced damage; the administration of high concentration oxygen may be perpetuating lung injury in some patients.

So in patients who undergo long-term 100% oxygen exposure, for example due to lung problems, the problems could be perpetuated or even worsened due to oxygen therapy and the oxidative stress caused by it.


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    Etiology

    The mechanism by which atelectasis occurs is due to one of three processes: compression of lung tissue (compressive atelectasis), absorption of alveolar air (resorptive atelectasis), or impaired pulmonary surfactant production or function.[2]

    Atelectasis can categorize into obstructive, non-obstructive, postoperative, and rounded atelectasis. 

    Nonobstructive atelectasis can further classify into compression, adhesive, cicatrization, relaxation, and replacement atelectasis.  Compression atelectasis is secondary to increased pressure exerted on the lung causing the alveoli to collapse. In other words, there is a򠷬reased transmural pressure gradient (transmural pressure gradient = alveolar pressure - intrapleural pressure) across the alveolus resulting in alveolar collapse. In an awake, spontaneously-ventilating patient, caudad excursion of the diaphragm during contraction causes a subsequent decrease in intrapleural pressure and alveolar pressure. The decrease in pressure allows for passive movement of air into the lungs. This process is inhibited by general anesthesia due to diaphragm relaxation. Patients lying supine have cephalad displacement of the diaphragm further decreasing the transmural pressure gradient and increasing the likelihood of atelectasis.ꂭhesive atelectasis is often the result of a surfactant deficiency or dysfunction as seen in ARDS or RDS in premature neonates. Surfactant functions to decrease alveolar surface tension and prevent alveolar collapse therefore, any alterations to surfactant production and function often manifest as an increase in the surface tension of the alveoli leading to instability and collapse.  Cicatrization atelectasis is often the result of parenchymal scarring of the lung, leading to contraction of the lung. Processes that lead to cicatrization atelectasis include tuberculosis, fibrosis, and other chronic destructive lung processes. Relaxation atelectasis involves the loss of contact between parietal and visceral tissue as seen in pneumothoraces and pleural effusions. Replacement atelectasis is one of the most severe forms and occurs when all of the alveoli in an entire lobe are replaced by tumor. This is typically seen in bronchioalveolar carcinoma and results in complete lung collapse. 

    Obstructive atelectasis is often referred to as resorptiveਊtelectasis and occurs when alveolar air gets absorbed distal to an obstructive lesion. The obstruction either partially or completely inhibits ventilation to the area. Perfusion to the area is maintained however, so gas uptake into the blood continues. Eventually, all of the gas in that segment will be absorbed and, without return of ventilation, the airway will collapse. Resorption atelectasis can be secondary to numerous pathologic processes, including intrathoracic tumors, mucous plugs, and foreign bodies in the airway. Children are especially susceptible to resorption atelectasis in the presence of an aspirated foreign body because they have poorly developed collateral pathways for ventilation.

    In contrast, adults with COPD have extensive collateral ventilation secondary to airway destruction and thus are less likely to develop resorption atelectasis in the presence of an obstructing lesion (i.e., intrathoracic tumor). The use of high inspiratory oxygen concentration (high FiO2) during induction and maintenance of general anesthesia also contributes to atelectasis via absorption atelectasis. Room air is 79% nitrogen nitrogen is slowly absorbed into the blood and therefore helps maintain alveolar patency. In contrast, oxygen is rapidly absorbed into the blood. 

    Postoperative atelectasis typically occurs within 72 hours of general anesthesia and is a well-known postoperative complication. 

    Rounded atelectasis is less common and often seen in asbestosis.  The pathophysiology involves theਏolding of the atelectatic lung tissue to the pleura.

    While all of the mechanisms mentioned above may contribute to the formation of perioperative atelectasis, absorption and compression mechanisms are the two most commonly implicated.[3]

    Middle lobe syndrome involves recurrent or fixed atelectasis of the right middle lobe and lingula. Extraluminal and intraluminal bronchial obstruction can result in middle lobe syndrome. Nonobstructive causes include inflammatory processes, defects in bronchial anatomy, and collateral ventilation. Fiberoptic bronchoscopy and bronchoalveolar lavage are the treatment of choice for this syndrome. Long term consequences of chronic atelectasis include bronchiectasis. Sjogren syndrome has associations with middle lobe syndrome and treatment with glucocorticoids has been favorable.


    Pulmonary Disorders Related to Surfactant Dysfunction or Deficiency

    Abnormalities in surfactant production or function are associated with several pulmonary diseases, and, at the same time, pulmonary infections alter surfactant metabolism. The most well-known disorder of surfactant deficiency is RDS in preterm infants. As discussed earlier, preterm neonates who are born before they produce enough surfactant develop RDS, which can be treated with exogenous surfactant. There are several genetic disorders that cause surfactant dysfunction. The mode of their inheritance is either autosomal dominant (involving the gene encoding SP-C or thyroid transcription factor 1) or autosomal recessive (involving the gene encoding SP-B or the gene encoding ATP-binding cassette protein member A3) (39). Most neonates with these genetic disorders do not survive without lung transplantation. For adults, several human observational studies show that subjects with acute respiratory distress syndrome (ARDS) have altered composition and function of surfactant (40, 41). Unfortunately, exogenous surfactant did not show a mortality benefit in randomized controlled trials (RCTs) (42).

    Although the disorders mentioned above are related to inadequate or dysfunctional surfactant, an overabundance of surfactant can also cause clinical disease. Pulmonary alveolar proteinosis, a rare disease caused by gene mutations leading to dysfunction of the granulocyte-macrophage colony-stimulating factor receptor or development of granulocyte-macrophage colony-stimulating factor antibodies, results in accumulation of surfactant within the alveoli and the terminal airways and can cause impairment of gas exchange. Varying levels of SP-A and SP-D from bronchoalveolar lavage in different pulmonary disorders are summarized in Table 1 . It was previously believed that surfactant components existed only in the lungs. Animal models and human observation studies have shown, however, that surfactant proteins leak into the vascular space when alveolocapillary membranes are injured (43�). Importantly, circulating surfactant protein levels may have clinical usefulness. One study demonstrated that surfactant protein levels can be used as an indicator of lung injury and poor outcomes in H1N1 viral infections (47), and another showed that SP-A and SP-D levels are elevated in those with pulmonary fibrosis compared with healthy volunteers (48).

    Table 1.

    Levels of SP-A and SP-D from bronchoalveolar lavage in pulmonary disease

     SP-A LevelsSP-D LevelsLipid LevelsReferences
    RDS in neonatesN/A140�
    PAP144�
    ARDSN/A40, 147
    IPF=145, 148�
    Sarcoidosis==145, 149, 151, 152
    Bacterial pneumoniaN/A153, 154
    Smokers=155, 156
    AsthmaN/A=157

    Definition of abbreviations: ARDS =�ute respiratory distress syndrome IPF = idiopathic pulmonary fibrosis N/A = not available PAP = pulmonary alveolar proteinosis RDS = respiratory distress syndrome.

    ↓ indicates decrease ↑ indicates increase = indicates unchanged.

    Genetic polymorphisms of surfactant proteins are known to be associated with a higher prevalence of idiopathic pulmonary fibrosis (49, 50) but also a reduced prevalence of interstitial lung disease in systemic sclerosis (51). Additionally, several studies also describe the association between genetic polymorphisms for surfactant proteins and high-altitude pulmonary edema (52), ARDS (53), lung carcinoma (54), and bronchopulmonary dysplasia (55). A rare missense mutation in SFTPA2, the gene encoding SP-A2, is associated with development of familial idiopathic pulmonary fibrosis and lung cancer (56).

    On the other hand, numerous respiratory infections have been shown to modify surfactant composition. For example, P. aeruginosa inhibits surfactant biosynthesis (57, 58), decreases its host defense and biophysical function (59), and secretes elastase to degrade surfactant proteins A and D (60, 61). Also, LPS, a major cell wall component of gram-negative bacteria, inhibits phospholipid synthesis and secretion (57, 58). Surfactant inhibition by bacteria seems to be associated with host cell cytokines such as tumor necrosis factor-α, which leads to degradation of surfactant biosynthetic enzymes. Human adenovirus disrupts the trafficking of surfactant phosphatidylcholine (62), whereas A. fumigatus down-regulates SP-B and SP-C protein and mRNA expression in mice (63). Respiratory syncytial virus (RSV)-infected bronchial epithelial cells have decreased SP-A protein levels through reduced mRNA translation efficiency (64).


    Is Atelectasis Life Threatening?

    Atelectasis is the condition characterized by the collapse of the lungs. However, it is different from the condition known as pneumothorax in which the air leaves the lungs and finds its way in the area between the lungs and the chest wall. In the atelectasis, the severity of the condition and the risk to life depends upon two important factors:

    Severity of Lung Collapse: The life-threatening risk of the atelectasis depends upon the severity of lung collapse. Atelectasis may relate to partial or full collapse of the lungs. Thus, if the atelectasis is full which means that there is no oxygen supply to the blood, then it becomes life-threatening. The condition may also become serious when major part of lungs gets affected.

    Underlying Cause: The life-threatening risk also takes in to account the reason due to which atelectasis happens. There are certain conditions which are not so serious such as post-operative atelectasis. However, certain underlying diseases, which if not treated quickly, may lead to fatal consequences. These diseases may include chest tumor or pneumonia. Further, it may also aggravate the underlying respiratory conditions such as asthma which may further complicate the situation.

    Thus, life-threatening capability of atelectasis depends upon the area of lungs which is collapsed and the underlying cause of the lung collapse. Generally, the atelectasis is not life threatening but is also a condition which requires quick medical intervention.


    Etiology and Pathogenesis of Atelectasis

    Three sets of mechanisms have been proposed that may cause or contribute to the development of atelectasis,4including compression of lung tissue, absorption of alveolar air, and impairment of surfactant function. This section describes these three underlying “physiologic” causes of atelectasis clinical factors that can modulate the development of atelectasis are described in a subsequent section.

    Compression Atelectasis

    Compression atelectasis occurs when the transmural pressure distending the alveolus is reduced to a level that allows the alveolus to collapse. The diaphragm normally separates the intrathoracic and abdominal cavities and, when stimulated, permits differential pressures in the abdomen and chest. After induction of anesthesia, the diaphragm is relaxed and displaced cephalad and is therefore less effective in maintaining distinct pressures in the two cavities. Specifically, the pleural pressure increases to the greatest extent in the dependent lung regions (fig. 1) and can compress the adjacent lung tissue. This is termed compression atelectasis .5

    Fig. 1. ( Aand B) In normal lungs ( A), the alveolar inflation and vascular perfusion are associated with low stress and are not injurious. Two separate barriers form the alveolar–capillary barrier, the microvascular endothelium, and the alveolar epithelium. In contrast, with atelectasis ( B), alveolar inflation and deflation may be heterogeneous, and the resulting airway stress causes epithelial injury. Because the blood vessels are compressed, perfusion may be traumatic because of flow-induced disruption of the microvascular endothelium. Both epithelial and endothelial injury may initiate or propagate lung injury. This figure depicts the advanced stage of lung injury caused by atelectasis. The initial injury is simple collapse of alveoli. However, with time, this leads to an inflammatory reaction. As the derecruited lungs cause epithelial injury and loss of epithelial integrity, both type I and type II alveolar cells are damaged. Injury to type II cells disrupts normal epithelial fluid transport, impairing the removal of edema fluid from the alveolar space. In addition to collapse, derecruited lungs also become fluid filled. Neutrophils adhere to the injured capillary endothelium and migrate through the interstitium into the alveolar airspace. In the airspace, alveolar macrophages secrete cytokines, interleukin (IL)-1, -6, -8, and -10, and tumor necrosis factor (TNF)-α, which act locally to stimulate chemotaxis and activate neutrophils. IL-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). MIF = macrophage inhibitory factor.

    Fig. 1. ( Aand B) In normal lungs ( A), the alveolar inflation and vascular perfusion are associated with low stress and are not injurious. Two separate barriers form the alveolar–capillary barrier, the microvascular endothelium, and the alveolar epithelium. In contrast, with atelectasis ( B), alveolar inflation and deflation may be heterogeneous, and the resulting airway stress causes epithelial injury. Because the blood vessels are compressed, perfusion may be traumatic because of flow-induced disruption of the microvascular endothelium. Both epithelial and endothelial injury may initiate or propagate lung injury. This figure depicts the advanced stage of lung injury caused by atelectasis. The initial injury is simple collapse of alveoli. However, with time, this leads to an inflammatory reaction. As the derecruited lungs cause epithelial injury and loss of epithelial integrity, both type I and type II alveolar cells are damaged. Injury to type II cells disrupts normal epithelial fluid transport, impairing the removal of edema fluid from the alveolar space. In addition to collapse, derecruited lungs also become fluid filled. Neutrophils adhere to the injured capillary endothelium and migrate through the interstitium into the alveolar airspace. In the airspace, alveolar macrophages secrete cytokines, interleukin (IL)-1, -6, -8, and -10, and tumor necrosis factor (TNF)-α, which act locally to stimulate chemotaxis and activate neutrophils. IL-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). MIF = macrophage inhibitory factor.

    Several lines of evidence support a role of the diaphragm in this setting. Froese and Bryan6used cineradiography to demonstrate a cephalad shift of the diaphragm during anesthesia and spontaneous breathing, which did not progress after muscle relaxation. However, a difference in the pattern of diaphragmatic movement was noted. In supine patients, during spontaneous breathing, the lower, dependent portion of the diaphragm moved the most, whereas with muscle paralysis, the upper, nondependent part showed the largest displacement. Two distinctly different patterns of diaphragmatic displacement were seen from the same new functional residual capacity (FRC) position. In an anesthetized patient breathing spontaneously, the active tension in the diaphragm is capable of overcoming the weight of the abdominal contents, and the diaphragm moves the most in the lower, dependent portion (because the lower or posterior diaphragm is stretched higher into the chest, it has the smallest radius of curvature and therefore contracts most effectively). In addition, the diaphragm is thicker posteriorly than anteriorly, and this may account for the disproportionate movement.7During paralysis and positive-pressure ventilation, the passive diaphragm is displaced by the positive pressure preferentially in the upper, nondependent portion (where there is least impedance to diaphragmatic movement). Subsequent studies confirmed these findings and, in addition, documented a reduction in the transverse area of the chest.8Using an advanced computed tomography (CT) scanner, Krayer et al. 9demonstrated a reduced thoracic cross-sectional area in anesthetized subjects but had more variable results regarding shape and position of the diaphragm some subjects showed a cranial shift of the diaphragm, but in other subjects, part of the diaphragm was unaffected or even moved caudally. Other investigators have also shown results inconsistent with the classic model of regional ventilation10 nevertheless, it can be concluded that FRC is reduced in the anesthetized subject, whether caused by loss of traction of the chest wall or compression of the lung. Loss of intercostal muscle function may also contribute to reduced FRC during anesthesia. Inhalation agents decrease intercostal muscle activity, particularly in children.11

    Hedenstierna et al. 8also noted an additional source of lung compression in that there was a net shift of central blood volume from the thorax, which seemed to pool in the abdomen, resulting in additional dependent pressure arising from the abdomen and acting on the diaphragm. Finally, the displacement of the diaphragm has been studied under dynamic conditions, whereby increases in diaphragm tension through phrenic nerve stimulation have been shown to reduce the amount of atelectasis at isovolumic conditions in anesthetized patients.12

    Therefore, compression atelectasis occurs during general anesthesia and is caused by chest geometry, overall cephalad diaphragm displacement, differential regional diaphragmatic changes, shift of thoracic central vascular blood into the abdomen, and altered diaphragmatic dynamics.

    Gas Resorption

    Resorption atelectasis—sometimes called gas atelectasis 4—can occur by two mechanisms. After complete airway occlusion, a pocket of trapped gas is created in the lung unit distal to the obstruction. Because gas uptake by the blood continues and gas inflow is prevented by blocked airways, the gas pocket collapses.13Under these conditions, the rate of absorption of gas from an unventilated lung area increases with elevation of the fraction of inspired oxygen (Fio 2 ).14

    A somewhat different mechanism explains absorption atelectasis in the absence of airway occlusion. In this context, lung zones that have low ventilation relative to perfusion (low ventilation/perfusion [V A /Q] ratio) have a low partial pressure of alveolar oxygen (Pao 2 ) when air is breathed. When the Fio 2 is increased, Pao 2 increases, causing the rate at which oxygen moves from the alveolar gas to the capillary blood to increase greatly. The oxygen flux may increase so much that the net flow of gas into the blood exceeds the inspired flow of gas, and the lung unit becomes progressively smaller. Collapse is most likely to occur when the Fio 2 (and duration of exposure) is high or where the V A /Q ratio (and mixed venous oxygen content) is low.15,16

    Surfactant Impairment

    Pulmonary surfactant that covers the large alveolar surface is composed of phospholipids (mostly phosphatidylcholine), neutral lipids, and surfactant-specific apoproteins (termed surfactant proteins A , B , C , and D ). By reducing alveolar surface tension, pulmonary surfactant stabilizes the alveoli and prevents alveolar collapse. This stabilizing function of surfactant may be depressed by anesthesia, and such an effect has been confirmed in vitro by Woo et al. 17The authors evaluated the effect of anesthetic agents on surfactant function using deflation pressure–volume curves in excised dog lungs. They found that the reduction in percent maximum lung volume was proportional to the concentration of both chloroform and halothane.17Wollmer et al. 18also used pulmonary clearance of technetium-labeled diethylenetriamine pentaacetic acid to demonstrate that halothane anesthesia, in combination with high oxygen concentration, caused increased permeability of the alveolar–capillary barrier in rabbit lungs. The authors postulated that the increased rate of pulmonary clearance of technetium-labeled diethylenetriamine pentaacetic acid during anesthesia with halothane was likely to be caused by combined effects on the pulmonary surfactant or the alveolar epithelium or both.18In addition, it is known that the content of alveolar surfactant in isolated lungs is modified by mechanical factors. Hyperventilation by increased tidal volume,19sequential air inflations to total lung capacity,20or even a single cycle of increased tidal volume19all cause release of surfactant in isolated animal lungs. In rabbits, maintained increases in tidal volume increased the amount of total phospholipids recovered from bronchoalveolar lavages.21,22Supporting this is the report that the spontaneous occurrence of large gasping respirations increases the proportion of active forms of alveolar surfactant (phospholipids). Oyarzun et al. 23examined the ventilatory variables of cats breathing spontaneously during anesthesia for 4 h. They found that the frequency of large gasps is directly correlated with the concentration of phospholipids in bronchoalveolar lavage fluid.23

    All three mechanisms—compression, gas resorption, and surfactant impairment—may contribute to atelectasis formation during general anesthesia (fig. 2). However, given the surfactant reserve and the 14-h surfactant turnover time, it may be that primary changes in surface forces are less important it is not known whether a collapsed alveolus can denature surfactant, and so the 14-h turnover time may not be relevant. Nonetheless, absorption and compression are considered to be the two mechanisms most implicated in perioperative atelectasis formation.24


    The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections

    Pulmonary surfactant is essential for life as it lines the alveoli to lower surface tension, thereby preventing atelectasis during breathing. Surfactant is enriched with a relatively unique phospholipid, termed dipalmitoylphosphatidylcholine, and four surfactant-associated proteins, SP-A, SP-B, SP-C, and SP-D. The hydrophobic proteins, SP-B and SP-C, together with dipalmitoylphosphatidylcholine, confer surface tension–lowering properties to the material. The more hydrophilic surfactant components, SP-A and SP-D, participate in pulmonary host defense and modify immune responses. Specifically, SP-A and SP-D bind and partake in the clearance of a variety of bacterial, fungal, and viral pathogens and can dampen antigen-induced immune function of effector cells. Emerging data also show immunosuppressive actions of some surfactant-associated lipids, such as phosphatidylglycerol. Conversely, microbial pathogens in preclinical models impair surfactant synthesis and secretion, and microbial proteinases degrade surfactant-associated proteins. Deficiencies of surfactant components are classically observed in the neonatal respiratory distress syndrome, where surfactant replacement therapies have been the mainstay of treatment. However, functional or compositional deficiencies of surfactant are also observed in a variety of acute and chronic lung disorders. Increased surfactant is seen in pulmonary alveolar proteinosis, a disorder characterized by a functional deficiency of the granulocyte-macrophage colony-stimulating factor receptor or development of granulocyte-macrophage colony-stimulating factor antibodies. Genetic polymorphisms of some surfactant proteins such as SP-C are linked to interstitial pulmonary fibrosis. Here, we briefly review the composition, antimicrobial properties, and relevance of pulmonary surfactant to lung disorders and present its therapeutic implications.

    It is established that pulmonary surfactant reduces surface tension at the air–water interface in the alveoli, thereby preventing collapse of these structures at end-expiration. In this manner, surfactant reduces the work associated with breathing. Although surfactant and its surface active properties were discovered relatively early in the 1920s (1), its components and mechanism of action only began to be elucidated in the 1950s by Pattle (2) and Clements (3). The breakthrough by Avery and Said helped identify a fundamental discovery linking pulmonary surfactant deficiency to infants who died of respiratory distress syndrome (RDS) (4). Indeed, these critical findings helped propel surfactant replacement therapy as an approach that has revolutionized treatment of RDS. However, during the 1990s, investigators uncovered several additional important biological properties of this surface-active material in the area of host immunity against microbial infection and immunomodulatory activity.

    Pulmonary surfactant is composed primarily of phospholipids and key proteins (5). Lipids compose 80 to 90% of its molecular weight, of which the most abundant species are phosphatidylcholine, phosphatidylglycerol, and phosphatidylinositol ( Figure 1 ) specifically, phosphatidylcholine constitutes approximately 70% of the lipid portion of surfactant, and it exists as a relatively unique form, known as dipalmitoylphosphatidylcholine (DPPC). Together with surfactant proteins, DPPC provides the surface activity of surfactant (6–8). The remaining types of lipid, including phosphatidylserine, phosphatidylethanolamine, and sphingomyelin, appear to be present in relatively small amounts. This lipid composition is well conserved among vertebrates (7).

    Figure 1. The composition and function of surfactant. Surfactant is composed of 90% lipid and 10% protein. The lipid content contains primarily phospholipid, specifically dipalmitoylphosphatidylcholine, which is responsible for the biophysical function of surfactant. The large hydrophilic proteins, surfactant protein (SP)-A and SP-D, play an important role in host defense and immune modulation, whereas SP-B and SP-C primarily partake in modulating biophysical properties.

    Surfactant contains four associated proteins, surfactant protein (SP)-A, SP-B, SP-C, and SP-D. Two of these proteins, SP-A and SP-D, are hydrophilic, and the others are hydrophobic (9). SP-A and SP-D are members of a family of innate immune proteins, termed collectins (10, 11). These proteins have in common an NH2-terminal collagen-like region and a C-terminal lectin domain that binds carbohydrates in a calcium-dependent manner. Binding sites for these lectin domains are found on bacterial and viral surfaces (12), and this in part is responsible for the role collectins play in innate and adaptive immunity.

    The hydrophobic surfactant proteins, SP-B and SP-C, are stored and secreted along with surfactant phospholipids (13, 14). SP-B is an indispensable protein that plays a role in enhancing the surface tension–reducing properties of surfactant (14) and also appears to have some antimicrobial activity (15–17). The role of SP-C, one of the most hydrophobic peptides known, is uncertain, but its high degree of conservation among species suggests an integral function (17).

    Surfactant components are synthesized primarily by the alveolar type II cell, which produces surfactant lipids and surfactant proteins (5, 18), and the airway club cell, which synthesizes surfactant proteins SP-A, SP-B, and SP-D (19–21) ( Figure 2 ).

    Figure 2. Surfactant life cycle—synthesis, secretion, and recycling. Alveolar type II cells, which cover about 7% of alveolar epithelial surface, are mainly responsible for surfactant production using dietary substrates (1). Surfactant is synthesized in the endoplasmic reticulum (ER) (2) of alveolar type II cells, and transported to the Golgi (3) for further modification. Most of the surfactant components are stored in the lamellar bodies (4) until they are secreted into liquid hypophase on the alveoli by exocytosis (5). Surfactant forms a lattice-like structure, called tubular myelin (6), which is transported to the air–liquid interface to form a monolayer of surfactant film (7). The phospholipids are either internalized and degraded by macrophages (8) or recycled back to the type II cells for reuse (8′). Note that surfactant protein (SP)-A, SP-B, and SP-D are also synthesized in club cells in terminal bronchioles.

    The main functions of surfactant are as follows: (1) lowering surface tension at the air–liquid interface and thus preventing alveolar collapse at end-expiration, (2) interacting with and subsequent killing of pathogens or preventing their dissemination, and (3) modulating immune responses.

    The drastic change in surface area of alveoli throughout the respiratory cycle dictates that alveolar surface tension needs to be less than 2 mN/m at end-expiration to prevent alveolar collapse (22). This critical function of surfactant is achieved through its maintenance of a film highly enriched in DPPC, which produces extremely low surface tension (<1 mN/m) on compression (17). These biophysical properties have led to modified exogenous surfactant replacement therapies that have impacted outcomes of neonatal RDS in many studies (23, 24).

    Surfactant also plays a vital role in host defense against infection. The collectins SP-A and SP-D enhance bacterial and viral clearance. As previously mentioned, the C-terminal lectin domains of these proteins preferentially bind nonhost oligosaccharides found on viruses and bacteria. The most well-described function of the collectins is their ability to opsonize pathogens and facilitate their phagocytosis by cells of the innate immune system, such as macrophages and monocytes, as well as regulate the production of cell-derived mediators (11, 25). Studies have shown that mice deficient in SP-A exhibit impaired clearance against various bacterial and viral infections, including group B Streptococcus (26, 27), Pseudomonas aeruginosa (28), and respiratory syncytial virus (29). More recently, SP-A and SP-D have also been demonstrated to have direct antibacterial activity against Escherichia coli, Klebsiella pneumoniae, and Enterobacter aerogenes (30), as well as antifungal activity against Histoplasma capsulatum (31), through increasing membrane permeability of the microbes. In humans there exist two genes, SP-A1 and SP-A2, that encode for SP-A1 and SP-A2 proteins, respectively (32). This suggests a possibility that there may be human subpopulations with differential vulnerabilities to microbial infection based on these SP-A isoforms.

    In addition to facilitating and activating the immune system, the lung collectins also act as immunomodulators. SP-A can inhibit dendritic cell maturation (33) and inhibit eosinophil release of IL-8 (34). Studies have shown that SP-A and SP-D inhibit allergen-induced lymphocyte proliferation via multiple mechanisms and that this effect is blunted in activated lymphocytes from children with asthma (35). SP-A and SP-D also bind directly to allergens and particles such as pollen grains (36), house dust mite allergen (37), and Aspergillus fumigatus allergen (38), inhibiting specific IgE binding to allergens and subsequently decreasing allergen-induced histamine release.

    Abnormalities in surfactant production or function are associated with several pulmonary diseases, and, at the same time, pulmonary infections alter surfactant metabolism. The most well-known disorder of surfactant deficiency is RDS in preterm infants. As discussed earlier, preterm neonates who are born before they produce enough surfactant develop RDS, which can be treated with exogenous surfactant. There are several genetic disorders that cause surfactant dysfunction. The mode of their inheritance is either autosomal dominant (involving the gene encoding SP-C or thyroid transcription factor 1) or autosomal recessive (involving the gene encoding SP-B or the gene encoding ATP-binding cassette protein member A3) (39). Most neonates with these genetic disorders do not survive without lung transplantation. For adults, several human observational studies show that subjects with acute respiratory distress syndrome (ARDS) have altered composition and function of surfactant (40, 41). Unfortunately, exogenous surfactant did not show a mortality benefit in randomized controlled trials (RCTs) (42).

    Although the disorders mentioned above are related to inadequate or dysfunctional surfactant, an overabundance of surfactant can also cause clinical disease. Pulmonary alveolar proteinosis, a rare disease caused by gene mutations leading to dysfunction of the granulocyte-macrophage colony-stimulating factor receptor or development of granulocyte-macrophage colony-stimulating factor antibodies, results in accumulation of surfactant within the alveoli and the terminal airways and can cause impairment of gas exchange. Varying levels of SP-A and SP-D from bronchoalveolar lavage in different pulmonary disorders are summarized in Table 1. It was previously believed that surfactant components existed only in the lungs. Animal models and human observation studies have shown, however, that surfactant proteins leak into the vascular space when alveolocapillary membranes are injured (43–46). Importantly, circulating surfactant protein levels may have clinical usefulness. One study demonstrated that surfactant protein levels can be used as an indicator of lung injury and poor outcomes in H1N1 viral infections (47), and another showed that SP-A and SP-D levels are elevated in those with pulmonary fibrosis compared with healthy volunteers (48).

    Table 1. Levels of SP-A and SP-D from bronchoalveolar lavage in pulmonary disease

    Definition of abbreviations: ARDS = acute respiratory distress syndrome IPF = idiopathic pulmonary fibrosis N/A = not available PAP = pulmonary alveolar proteinosis RDS = respiratory distress syndrome.

    ↓ indicates decrease ↑ indicates increase = indicates unchanged.

    Genetic polymorphisms of surfactant proteins are known to be associated with a higher prevalence of idiopathic pulmonary fibrosis (49, 50) but also a reduced prevalence of interstitial lung disease in systemic sclerosis (51). Additionally, several studies also describe the association between genetic polymorphisms for surfactant proteins and high-altitude pulmonary edema (52), ARDS (53), lung carcinoma (54), and bronchopulmonary dysplasia (55). A rare missense mutation in SFTPA2, the gene encoding SP-A2, is associated with development of familial idiopathic pulmonary fibrosis and lung cancer (56).

    On the other hand, numerous respiratory infections have been shown to modify surfactant composition. For example, P. aeruginosa inhibits surfactant biosynthesis (57, 58), decreases its host defense and biophysical function (59), and secretes elastase to degrade surfactant proteins A and D (60, 61). Also, LPS, a major cell wall component of gram-negative bacteria, inhibits phospholipid synthesis and secretion (57, 58). Surfactant inhibition by bacteria seems to be associated with host cell cytokines such as tumor necrosis factor-α, which leads to degradation of surfactant biosynthetic enzymes. Human adenovirus disrupts the trafficking of surfactant phosphatidylcholine (62), whereas A. fumigatus down-regulates SP-B and SP-C protein and mRNA expression in mice (63). Respiratory syncytial virus (RSV)-infected bronchial epithelial cells have decreased SP-A protein levels through reduced mRNA translation efficiency (64).

    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).

    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 2014 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).

    In summary, pulmonary surfactant has important functions beyond reducing surface tension and altering mechanical properties that lead to decreased work of breathing. As the lung epithelium is in constant exposure to the environment, surfactant provides a crucial first line of defense against infection by enhancing the removal of pathogens, modulating the response of inflammatory cells, and optimizing lung biophysical activity. Hydrophilic proteins, which constitute a small portion of surfactant, play a major role in antimicrobial activity. Although surfactant is an established treatment for RDS in preterm infants, there has been no compelling clinical benefit for use of exogenous surfactant in adult patients with ARDS thus far. Further studies need to be performed to explore the possibility of surfactants as an immune modulating therapy or designing small molecules that modulate availability of surfactant components in respiratory illness.

    Surfactant has many biological functions, including its tension-reducing property at the air–water interface, antimicrobial activity, and immunomodulation.

    Although surfactant is an established treatment for RDS in preterm infants, no clinical benefit has been shown in adult patients with ARDS.

    Animal studies and limited anecdotal reports suggest surfactant could be used to treat infectious and inflammatory lung disease however, further preclinical and clinical studies are necessary.


    Terminology

    Atelectasis may be used synonymously with collapse, but some authors reserve the term “atelectasis” for partial collapse, not inclusive of total atelectasis of the affected part of lung or of whole lung collapse.

    Classification

    Atelectasis is a radiopathological sign which can be classified in many ways. The aim of each classification approach is to help identify possible underlying causes together with other accompanying radiological and clinical findings.

    Atelectasis can be subcategorised based on underlying mechanism, as follows:

    • resorptive (obstructive) atelectasis
      • occurs as a result of complete obstruction of an airway
      • no new air can enter the portion of the lung distal to the obstruction and any air that is already there is eventually absorbed into the pulmonary capillary system, leaving a collapsed section of the affected lung
      • because the visceral and parietal pleura do not separate in resorptive atelectasis, traction is created, and if the loss of volume is considerable, mobile thoracic structures may be pulled toward the side of volume loss ("mediastinal shift")
      • potential causes of resorptive atelectasis include obstructing neoplasms, mucus plugging in asthmatics or critically ill patients and foreign body aspiration
      • resorptive atelectasis of an entire lung ("collapsed lung") can result from complete obstruction of the right or left main bronchus
      • occurs when contact between the parietal and visceral pleura is disrupted
      • the three most common specific aetiologies of passive atelectasis are pleural effusion, pneumothorax and diaphragmatic abnormality
      • occurs as a result of any thoracic space-occupying lesion compressing the lung and forcing air out of the alveoli
      • occurs as a result of scarring or fibrosis that reduces lung expansion
      • common aetiologies include granulomatous disease, necrotising pneumonia and radiation fibrosis
      • ​occurs from surfactant deficiency 2
      • depending on aetiology, this deficiency may either be diffuse throughout the lungs or localised
      • in the most dependant portions of the lungs due to the weight of the lungs

      Atelectasis can also be subcategorised by morphology:

      • linear (a.k.a. plate, band, discoid) atelectasis: a minimal degree of collapse as seen in patients who are not taking deep breaths ("splinting"), such as postoperative patients or patients with rib fracture or pleuritic chest pain this is very common
      • round atelectasis: classically associated with asbestos exposure

      or by anatomical extent:

      • lung atelectasis: complete collapse of one lung
      • lobar atelectasis: collapse of one or more lobes of a lung.
      • segmental atelectasis: collapse of one or more individual pulmonary segments

      Radiographic features

      Vary depending on the underlying mechanism and type of atelectasis

      Plain radiograph / CT
      Direct signs of atelectasis
      • displacement of interlobar fissures
      • crowding together of pulmonary vessels
      • crowded air bronchograms (does not apply to all types of atelectasis can be seen in subsegmental atelectasis due to small peripheral bronchi obstruction, usually by secretions if the cause of the atelectasis is central bronchial obstruction, there will usually be no air bronchograms)
      Indirect signs of atelectasis
      • pulmonary opacification
      • shifting granuloma (or any other previously documented lesion, used as a reference for comparison)
      • compensatory hyperexpansion of the surrounding or contralateral lung
      • displacement of the heart, mediastinum, trachea, hilum
      • propinquity of the ribs
      Resorptive (obstructive) atelectasis
      • increased density (opacity) of the atelectatic portion of lung
      • displacement of the fissures toward the area of atelectasis
      • upward displacement of hemidiaphragm ipsilateral to the side of atelectasis
      • crowding of pulmonary vessels and bronchi in region of atelectasis
      • +/- compensatory overinflation of unaffected lung
      • +/- displacement of thoracic structures (if atelectasis is substantial)
      Linear (plate, discoid, subsegmental) atelectasis
      • relatively thin, linear densities in the lung bases orientated parallel to the diaphragm (known as Fleischner lines)
      Ultrasound

      The sonographic morphology of atelectatic lung may resemble hepatic parenchyma, often referred to as "tissue-like" or "hepatized" in appearance. Distinguishing features of atelectasis by aetiology may appear as follows:

      • compressive atelectasis is most often visualised in the costophrenic recess bordered by a disproportionately large pleural effusion
        • low-level, homogenous echogenicity with few to no air bronchograms
        • margins are usually regular with a triangular shape 10
        • a shred sign may be present at the transition to aerated lung
        • early static air bronchograms due to distal air trapping
        • as the air is resorbed, bronchi may fill with fluid resulting in anechoic, tubular structures known as fluid bronchograms 11
        • may be differentiated from blood vessels with colour flow Doppler

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        History and etymology

        Atelectasis comes from the Greek words 'ateles' and 'ektasis' translating to 'incomplete stretching or expansion'.


        Atelectasis

        a collapsed or airless state of the lung, which may be acute or chronic, and may involve all or part of the lung. The primary cause is obstruction of the bronchus serving the affected area. adj., adj atelectat´ic. ƒ

        In congenital atelectasis of the fetus or newborn, the lungs fail to expand normally at birth. This may be due to any of a variety of causes, including prematurity (often accompanying hyaline membrane disease ) diminished nervous stimulus to breathing and crying fetal hypoxia from any cause, including oversedation of the mother during labor and delivery or obstruction of the bronchus by a mucous plug.

        In older individuals atelectasis may be the result of airway obstruction, as by secretions or a tumor (called obstructive, absorption, or acquired atelectasis) or it may be from a failure to deep breathe, such as postoperatively or because of neuromuscular disease. It occurs most commonly as a complication in the postoperative period, when deep breathing and incentive spirometry are often used to prevent or treat it.

        Symptoms . In acute atelectasis in which there is sudden obstruction of the bronchus, there may be dyspnea and cyanosis, elevation of temperature, a drop in blood pressure, or shock. In the chronic form, the patient may experience no symptoms other than gradually developing dyspnea and weakness.

        X-ray examination may show a shadow in the area of collapse. If an entire lobe is collapsed, the x-ray will show the trachea, heart, and mediastinum deviated toward the collapsed area, with the diaphragm elevated on that side.

        Treatment . Atelectasis in the newborn is treated by suctioning the trachea to establish an open airway, positive-pressure breathing, and administration of oxygen. High concentrations of oxygen given over a prolonged period tend to promote atelectasis and may lead to the development of retrolental fibroplasia in premature infants.

        Acute atelectasis is treated by removing the cause whenever possible. To accomplish this, coughing, suctioning, and bronchoscopy may be employed. In atelectasis due to airway obstruction with secretions, chest physiotherapy is often useful. Chronic atelectasis usually requires surgical removal of the affected segment or lobe of lung. Antibiotics are given to combat the infection that almost always accompanies secondary atelectasis.


        Effect of lung collapse on alveolar surfactant in rabbits subjected to unilateral pneumothorax

        To determine whether atelectasis might modify lung surfactant, we injected N2 into the right pleural space of adult rabbits. Daily, under sedation, pleural gas volume and pressure were measured and adjusted to 20 ml/kg and 0 to +2 cm H2O with N2. On the sixth day, pHa, PaCO2, PaO2, and FRC were measured. Pressure-volume diagrams or bronchoalveolar lavages (BAL) were performed separately on right and left lungs. Surfactant subfractions were obtained from BAL fluid, and total protein, LDH, and cell counts were determined. Phospholipid (PL) was assayed in lung homogenate, BAL fluid, and subfractions, and PL composition was determined on the largest BAL subfraction (P4). On the sixth day the pleural gas volume was 19.7 +/- 2.7 (SD) ml/kg, and PaO2 and FRC were significantly decreased. Air volume in excised right lungs at 30 cm H2O was 13.1 +/- 2.8 (SE) ml/kg with pneumothorax (PN) and 22.8 +/- 1.9 (SE) ml/kg in controls. Total PL was decreased 43% in BAL and 59% in P4 of collapsed lungs. Phosphatidylglycerol to phosphatidylinositol (PI) plus phosphatidylserine (PS) ratio of P4 was substantially decreased in both lungs of PN animals. Cell counts, LDH, and protein in BAL did not suggest inflammation or epithelial damage. We conclude that pneumothorax decreases the quantity of alveolar surfactant in the collapsed lung and alters its phospholipid composition toward the fetal pattern in both lungs, possibly due in part to the proliferative response of the lungs to pneumothorax.


        Watch the video: Video πλευριτική συλλογή ατελεκτασία πνεύμονα (February 2023).