key: cord-0037749-voem0l5o
authors: Willson, Douglas F.; Chess, Patricia R.; Wang, Zhengdong; Notter, Robert H.
title: Pulmonary Surfactant: Biology and Therapy
date: 2008-11-15
journal: The Respiratory Tract in Pediatric Critical Illness and Injury
DOI: 10.1007/978-1-84800-925-7_10
sha: 9ea6951c5a4626267dd65e3fe6315060c62a0552
doc_id: 37749
cord_uid: voem0l5o

nan

Pulmonary surfactant is the evolutionary solution to the problem of surface tension and air breathing. Without surfactant, each breath would require inordinate energy expenditure to expose the huge intrapulmonary surface (approximately the size of a badminton court) to inspired air, and life on land, at least as we know it, would be virtually impossible. One of the fi rst insights into the existence of surface tension forces in the lungs came from the study of von Neergaard in 1929 [1] . Von Neergaard observed that it took nearly twice as much pressure to infl ate excised animal lungs with air as it did with fl uid. He speculated that because infl ating the lungs with an aqueous solution eliminated the air-liquid interface in the alveoli, the additional work required to infl ate the lungs with air must be incurred in overcoming surface tension forces at that interface. Von Neergaard's work was supported several decades later in studies by Gruenwald [2] and Mead et al. [3] , which further documented the importance of surface tension forces in respiration. Moreover, additional studies indicated that surface tension forces were moderated in the normal lungs by the action of surfaceactive agents (i.e., surfactants). Work by Pattle [4] in 1955 suggested that the stability of bubbles in the foam expressed from the lungs was related to surfactants that acted to abolish the tension of the alveolar surface. Clements [5] , Brown [6] , and Pattle [7] subsequently confi rmed the existence of surfactants in the lungs by further surface tension and biochemical studies.

The crucial physiologic importance of lung surfactant in respiration was shown by the early fi nding that a lack of this material in premature infants contributed to the development of hyaline membrane disease (HMD; later called the neonatal respiratory distress syndrome or RDS) [7, 8] . This fi nding stimulated the interest of physicians, spurring further research into the function and composition of surfactant. However, clinical interest was signifi cantly interface involves a water-based fl uid layer contacting air, as occurs in the alveoli of mammals. In the absence of lung surfactant, surface tension at the alveolar interface would be quite high-on the order of 50 dynes/cm for tissue fl uid that contains nonspecifi c soluble proteins and other endogenous solutes [12] . The surface tension of aqueous fl uids is high because water is a strongly polar substance with signifi cant intermolecular attractive forces. Liquid (water) molecules at the interface have a strong attraction toward the bulk of the liquid with no equivalent attractive forces above the surface because molecules in the gas (air) are so dilute. These unbalanced forces cause the surface to minimize its area, giving rise to surface tension ( Figure 10 .1). In a construct such as a spherical bubble, surface tension forces necessitate a pressure drop to maintain the interface at equilibrium against collapse. As described by Laplace in the 18th century for a spherical bubble, this pressure drop (ΔP) is directly proportional to the surface tension (γ) and inversely proportional to the radius of curvature (R), that is, ΔP = 2γ/R. Surfactants are molecules that have an energetic preference for the interface. Molecules that are surface active at an air-water interface all share the characteristic of being amphipathic, that is, possessing both polar and nonpolar regions in their structure. Pulmonary surfactant is largely composed of phospholipids that are molecules with polar phosphate head groups and nonpolar fatty chains or tails. This structure gives phospholipids an energetic preference for the interface in that they can orient with the polar head group in the aqueous hypophase and the nonpolar hydrocarbon moieties in the air. Lung surfactant also contains proteins that have regions of polar and nonpolar structure, and these proteins interdigitate with phospholipid molecules in the interfacial fi lm and in bilayers/lamellae in the aqueous phase. A surfactant fi lm at an air-water interface acts to lower surface tension because the attractive forces between surfactant molecules and water molecules are less than those of water molecules for each other (if this were not true, and the surfactant molecules had a stronger attraction for water, they would necessarily go into solution rather than being at the interface). The presence of a surfactant fi lm thus reduces the net unbalanced attractive force between interfacial region and bulk liquid molecules, lowering surface tension as a function of surfactant concentration. In the lungs, the surfactant fi lm at the alveolar interface has powerful consequences for pressure-volume (PV) mechanics and respiratory function.

Pulmonary surfactant exists in the alveolar hypophase in a complex microstructure of phospholipid-rich aggregates with incorporated apoproteins. Surfactant molecules in the hypophase adsorb to the air-water interface, which is energetically preferred as described above. The resulting surface fi lm is compressed and expanded during breathing and lowers and varies surface tension in a dynamic fashion. As alveolar size decreases during exhalation, the surfactant fi lm is compressed and surface tension reaches very low values (<1 mN/m compared with 70 mN/m for pure water at 37°C). As alveolar size increases with inspiration, the surfactant fi lm is expanded, and surface tension proportionately increases. This dynamic variation of surface tension with area allows alveoli of different sizes to coexist stably at fi xed pressure during respiration ( Figure 10 .2). Small alveoli resist collapse at end expiration because their surface tension is low, and alveolar infl ation is better distributed during inhalation because the ratio of surface tension to area is more uniform in different-sized alveoli. Moreover, by reducing surface tension throughout the lungs, surfactant decreases the pressures (work) needed for pulmonary infl ation. There is a direct connection between the surface activity of lung surfactant and pulmonary PV mechanics. The physiologic consequences of surfactant defi ciency or dysfunction are profound, as seen in the diffuse atelectasis, uneven infl ation, and severe ventilation/ Liquid Gas 2 1 FIGURE 10.1. Molecular forces leading to surface tension at a liquid-gas interface. Attractive forces from nearest neighbors are illustrated for an idealized bulk liquid molecule (1) and an interfacial region molecule (2) contacting a gas. Because the gas is much more dilute, gas molecules exert a negligible attraction on interfacial molecules compared with the liquid. This leads to an unbalanced inward attractive force that causes the surface to minimize its area, generating surface tension. (From Notter [12] When alveolar radius is large RESULT: The ratio of surface tension to radius is more uniform in each alveolus and throughout the lung, stabilizing P-V behavior from Laplace's law. to maintain alveoli at equilibrium is proportional to surface tension (γ) and inversely proportional to radius (r), i.e., ΔP = 2γ/r (Laplace's law for a sphere). By lowering and varying surface tension as a function of alveolar size (radius), lung surfactant acts to stabilize pulmonary P-V mechanics as shown schematically. Surfactant also greatly decreases the overall work of breathing by a generalized lowering of surface tension throughout the alveolar network. See text for discussion.

perfusion mismatching present in the lungs of preterm infants with RDS. The physiologic roles of lung surfactant, and the surface properties that generate them as described earlier, are summarized in Table 10 .1.

The surface behavior of lung surfactant results from molecular interactions between its lipid and protein components. An overall mass composition of lung surfactant is given in . Lung surfactant also contains fl uid unsaturated PCs, plus a range of other phospholipid classes with a mix of saturated and unsaturated compounds. Fluid phospholipids increase the respreading of lung surfactant fi lms so that material ejected from the interface during compression reenters the fi lm during expansion and remains available for subsequent respiratory cycles. Neutral lipids in lung surfactant also may help increase fi lm respreading. Surfac-tant proteins have crucial biophysical actions in facilitating the adsorption of phospholipids into the air-water interface, and SP-B and SP-C also act within the surface fi lm itself to refi ne its composition, increase respreading, and optimize surface tension, lowering during dynamic cycling. A summary of the molecular characteristics and activities of the four lung surfactant proteins is given in Table 10 .3. The two small hydrophobic surfactant proteins (SP-B and SP-C) are found in approximately equal amounts in endogenous surfactant (totaling about 1.5% by weight relative to phospholipid) and are vital to surface activity. Surfactant protein B, which is the most active of the two in increasing adsorption and overall dynamic surface activity [12, [14] [15] [16] [17] [18] , is a particularly important component of functional surfactant. The presence or absence of hydrophobic Aggregates and orders phospholipids (Ca 2+ dependent) Necessary for tubular myelin formation (along with SP-B, Ca 2+ ) Enhances ability of lung surfactant to resist biophysical inhibition Helps regulate reuptake/recycling in addition to aiding host defense SP-B Molecular weight 8.5-9 kD (monomer), 79 amino acids in humans (active peptide) Hydrophobic, with 2-3 amphipathic helices plus β-sheet structural regions Forms dimers and other oligomers of probable functional significance Has 10 positive Arg/Lys and 2 negative Glu/Asp residues at neutral pH Interacts biophysically with both head groups and chains of phospholipids Necessary for tubular myelin formation (along with SP-A, Ca 2+ ) Disrupts and fuses lipid bilayers and promotes lipid insertion/mixing in surface films Enhances the adsorption, film spreading, and dynamic surface activity of lipids Most active SP in increasing overall adsorption and dynamic surface activity SP-C Molecular weight 4.2 kD (monomer), 35 amino acids in humans (active peptide) Most hydrophobic SP, with only 2 charged Arg/Lys residues Contains two palmitoylated cysteine residues in humans Can form dimers and other oligomers Primarily α-helical in structure, with a length that spans a lipid bilayer Interacts biophysically primarily with hydrophobic phospholipid chains Disrupts and fuses lipid bilayers Enhances the adsorption, film spreading, and dynamic surface activity of lipids SP-D Molecular weight 39-46 kD (monomer), 355 amino acids in humans Has significant structural similarity to SP-A Oligomerizes to a dodecamer (four triplet monomers) C-type lectin and member of the collectin family of host defense proteins Not implicated in lung surfactant biophysics Important in host defense and may also participate in surfactant metabolism Source: Adapted from Notter [12] and Notter et al. [61] .

apoproteins in exogenous lung surfactants is a crucial factor in their effi cacy as pharmaceutical agents as described later. Genetic defi ciency of SP-B is associated with fatal respiratory distress in infancy [19] [20] [21] [22] , and mutations in SP-C have now been associated with diffuse interstitial pneumonitis and the early development of emphysema [23] .

Pulmonary surfactant is also important in innate (nonadaptive) pulmonary host defense. The epithelial lining of the lungs is critically positioned to participate in the neutralization and clearance of inhaled microorganisms or other particles. Two of the surfactant proteins (SP-A and SP-D) are members of a family of proteins called collectins that play a vital role in innate host defense [24] [25] [26] [27] . Other collectins include complement, mannan binding lectin (MBL), and conglutinin. Surfactant proteins A and D are synthesized and secreted by alveolar type II cells and also by nonciliated bronchiolar cells (Clara cells) in the airways [24, 25] . As a class, collectins are large multimeric proteins composed of an N-terminal cysteine-rich region, a collagen-like region, an αhelical coiled neck region, and a carbohydrate recognition domain (CRD) [24] [25] [26] . The basic collectin structure is a trimer of the polypeptide chain, but different collectins have different degrees of higher order oligomerization [26] . Surfactant protein A forms octadecamers (6 trimers), whereas SP-D preferentially accumulates as dodecamers (4 trimers). The C-terminal domains of SP-A and SP-D are responsible for their lectin (carbohydrate binding) activity, and trimeric clusters of the peptide chains are required for high-affi nity binding to multivalent ligands. Both proteins bind to the mannose or glucose sugars present in most microbial ligands, although SP-A preferentially binds to the di-mannose repeating unit in Grampositive capsular polysaccharides and SP-D to the glucose-containing core oligosaccharides of Gram-negative lipopolysaccharide (LPS) [24] . Both can also interact with lipids, SP-A with phospholipids and the lipid A domain of Gram-negative LPS and SP-D with the lipid and inositol moieties of phosphatidylinositol.

Surfactant proteins A and D can bind, agglutinate, and opsonize a variety of pathogens as well as induce chemotaxis, phagocytosis, and provoke killing by phagocytic cells. Table 10 .4 lists organisms bound by SP-A and/or SP-D. Although no specifi c diseases associ-ated with defi ciencies of these proteins in humans have been described, murine knockout models have elucidated their role in host defense. Surfactant protein-A-defi cient mice have normal surfactant homeostasis and respiratory function but enhanced susceptibility to a number of different bacteria, viruses, and parasites [24, 28, 29] . The phenotype of SP-D-defi cient mice is somewhat confusing in that these animals develop a lipoproteinosis-like disease that makes effects on innate immunity diffi cult to separate from changes in surfactant function [30] . Nonetheless, SP-D can be shown to similarly bind, agglutinate, and opsonize a variety of pathogens [24, 31, 32] .

A good deal of information is now available about the complex metabolism of pulmonary surfactant [e.g., 12, [33] [34] [35] [36] [37] [38] [39] [40] [41] . Lung surfactant is synthesized, packaged, stored, secreted, and recycled in type II epithelial cells in the alveolar lining (shown schematically in Figure 10 .3). The phospholipid components are synthesized in the endoplasmic reticulum and transported through the Golgi apparatus to the lamellar bodies, whereas surfactant proteins are translated in the usual fashion and then undergo extensive posttranslational processing. Surfactant proteins A, B, and C [42] [43] [44] [45] [46] , but not SP-D [47, 48] , are found in lamellar bodies.

Lamellar bodies are subcellular organelles, and their contents are composed of tightly packed membrane-like structures that are effectively identical in composition to surfactant obtained from the alveolar space. Lamellar bodies make their way to the cell surface where their contents are extruded into the alveolar hypophase and unwind into a lattice-like construction called tubular myelin [49] [50] [51] (Figure 10.4) . Tubular myelin is a regularly spaced lattice of phospholipid bilayers studded with regularly spaced particles thought to be SP-A. Surfactant protein B and calcium are also required for tubular myelin formation [51, 52] and are present in its lattice structure. In addition to tubular myelin, a variety of other size-distributed surfactant aggregate forms (lamellar, vesicular, and nonspecifi c) exist in the alveolar hypophase [12] . Lung surfactant adsorbs from tubular myelin and other active aggregates to form a complex mixed lipid-protein fi lm at the alveolar hypophase-air interface as described earlier.

Lung surfactant has a fi nite life span in the alveoli and then is cleared from the alveolar space. As much as 90% of the surfactant cleared from the alveolar space is taken up and recycled by type II pneumocytes, with the highest uptake percentages found in newborn compared with adult or premature animals [12, 33, 53, 54] . Alveolar macrophages are responsible for only about 10%-15% of surfactant clearance, and a smaller percentage (<5%) is cleared via the airways. Studies using labeled surfactant introduced into the airways have demonstrated direct uptake by type II pneumocytes, repackaging in lamellar bodies, and eventual resecretion [55] . The half-life for turnover of human surfactant is variable and has been reported to range from 1 to 24 hr in animals [12, 33, 53] . Surfactant protein A has been shown to enhance the uptake of surfactant phospholipids into type II pneumocytes [56] [57] [58] , and SP-B/C may also infl uence phospholipid uptake in type II cells [59, 60] . The uptake of exogenously administered surfactants as substrate is thought to be an important factor in the indirect (nonsurfaceactive) benefi ts of surfactant therapy, particularly for relatively inactive preparations with a high DPPC content such as Exosurf® and ALEC® (pharmaceutical surfactants are described in more detail later).

The pathophysiology of acute pulmonary injury (ALI/ARDS) is multifactorial and includes infl ammation, surfactant dysfunction, vascular dysfunction, edema, oxidant injury, ventilation/perfusion mismatching, and injury to alveolar, capillary, and other pulmonary cells. A common aspect of acute pulmonary injury is damage to the cells of the alveolar-capillary membrane (type I and type II alveolar epithelial cells and capillary endothelial cells) with a loss of barrier integrity leading to interstitial and alveolar edema. Another common feature is infl ammation. The innate pulmonary infl ammatory response is complex, involving the recruitment and activation of circulating leukocytes as well as participation by resident lung cells. A large number of infl ammatory mediators and transduction and regulatory pathways are involved in acute pulmonary infl ammation and injury (for comprehensive reviews on lung injury and infl ammation, see Notter et al. [61] ).

In infants, although not generally labeled ALI/ARDS, common causes of respiratory failure include meconium aspiration, sepsis, and pulmonary infection. Although acute respiratory failure in preterm neonates is typically initiated by surfactant defi ciency (i.e., RDS), secondary lung injury and surfactant dysfunction can arise in association with hyperoxia, mechanical ventilation, infection, edema from patent ductus arteriosus, and other factors. In addition to acute respiratory failure, ALI/ARDS can also progress to a fi broproliferative phase that leads to chronic lung injury with tissue remodeling and the initiation of fi brosis. However, surfactant dysfunction is most prominent in the acute phase of ALI/ARDS.

In their original descriptions of ARDS, Ashbaugh, Petty, and colleagues [62, 63] commented on its similarity to infantile RDS, and Petty et al. [64] subsequently reported abnormalities in surfactant function. However, respiratory failure in RDS is initiated by a quantitative defi ciency in surfactant that leads to progressive atelectasis and overdistension with decreased lung compliance. Although an element of surfactant defi ciency can be present in ALI/ARDS, surfactant dysfunction (inhibition and/or inactivation) as a consequence of infl ammatory injury and edema is generally much more prominent. Extensive basic research over the past two decades has identifi ed many of the mechanisms contributing to surfactant dysfunction in lung injury (detailed reviews of lung surfactant inhibition and mechanisms of dysfunction are available [12, 17, 65] ). Irrespective of whether the initiating event is direct injury from the alveolar side or indirect pulmonary injury from the vascular side, surfactant dysfunction may arise by multiple pathways that include the following (Table 10 .5):

1. Physicochemical interactions with inhibitory or reactive substances: A prevalent cause of surfactant dysfunction in lung injury is through biophysical or chemical interactions with substances that gain access to the alveolar space following damage to the alveolar-capillary membrane. Albumin, hemoglobin, fi brin, fi brinogen, and other blood or serum proteins have been shown in vitro to diminish the surface tension lowering of lung surfactant by competing with the adsorption of its active components into the airwater interface, thus compromising fi lm formation [66, 67] . Other biophysical inhibitors include cell membrane lipids, lysophospholipids, or fatty acids that mix into the interfacial fi lm itself to impair surface tension lowering during dynamic compression [67] [68] [69] [70] [71] [72] . Additional biophysical inhibitors are listed in Table 10 .6, which also notes chemically acting inhibitors such as phospholipases or proteases that can degrade essential surfactant lipids or proteins to impair surface activity [71] [72] [73] . Lung surfactant can also be chemically altered by interactions with reactive oxygen and nitrogen species [65] . Fortunately, although surfactant can be inhibited by these physicochemical processes, it has been well-documented, at least in vitro, that dysfunction can be overcome by increasing the concentration of active surfactant even if inhibitors are still present [12, 65] .

2. Altered surfactant aggregates and metabolism: Another pathway by which surfactant activity can be reduced during lung injury is by depletion or alteration of active large aggregates. As noted earlier, surfactant exists in the alveolar hypophase in a sizedistributed microstructure of aggregates, the largest of which typically have the greatest surface activity and the highest apoprotein content [74] [75] [76] [77] [78] [79] [80] [81] . The percentage of large aggregates and their content of SP-A and SP-B are reduced in bronchoalveolar lavage from patients with ARDS [82] [83] [84] . Surfactant phospholipid composition can also be altered in patients with ALI/ARDS [84, 85] . Animal models of ALI/ARDS show that large surfactant aggregates can be depleted or reduced in activity by interactions with inhibitors or by changes in surfactant metabolism [77, [86] [87] [88] [89] . Although large aggregates can be detrimentally affected in ALI/ARDS, information on total surfactant pools is inconsistent, with both decreased [90] [91] [92] and unchanged [85, 93] amounts reported.

In assessing surfactant dysfunction in ALI/ARDS, it is important to realize that the pathology is not static. The contribution of surfactant dysfunction to ALI/ARDS is almost certainly dependent on the stage of disease, which commences with an exudative phase involving alveolar-capillary membrane damage and acute infl ammation but may evolve to fi broproliferation and fi brosis. The superimposition of iatrogenic factors such as ventilator-induced lung injury and hyperoxic injury during intensive care further confounds pathology, as does the multiorgan disease that is frequently present in patients with ALI/ARDS. The multifaceted pathology of lung injury is an important issue when evaluating the potential effi cacy of exogenous surfactant therapy in ALI/ARDS.

The existence of surfactant dysfunction in ALI/ARDS provides a conceptional rationale for the therapeutic use of exogenous surfactant, but the use of surfactant drugs having the greatest surface activity and ability to resist inhibition is clearly required. Moreover, to be effective in ALI/ARDS, exogenous surfactant must be delivered and distributed to injured alveoli in the necessary amounts despite the presence of edema and infl ammation. Similar to initial attempts to treat RDS in premature infants, the fi rst large controlled trial of surfactant replacement in ARDS using the aerosolized protein-free synthetic surfactant Exosurf® was an unequivocal failure [94] . This failure at least partly refl ects similar reasons, that is, the use of a surfactant with inadequate activity and an ineffective delivery method. However, surfactant therapy in ALI/ARDS faces more complex challenges than in the case of neonatal RDS, and this therapy remains investigational particularly for adults, as detailed next. 

Biophysical inactivation by inhibitory substances in edema or present as a result of inflammation Chemical degradation by lytic enzymes or by reactive oxygen/nitrogen species Depletion or detrimental alteration of active large aggregate surfactant subtypes Alveolar epithelial cell damage or alteration Type I cell injury and death leading to increased permeability of the alveolar epithelial barrier Type II cell injury and/or hyperplasia leading to altered surfactant synthesis, secretion, recycling Inflammation and microvascular dysfunction Capillary endothelial injury leading to increased microvascular permeability and interstitial or alveolar edema that contains surfactant inhibitors Multiple mediators and products produced by leukocytes and lung cells that affect the severity of injury and can directly or indirectly affect alveolar surfactant or type II cells See text for discussion. Surfactant dysfunction and its mechanisms in ALI/ARDS are reviewed in detail by Notter [12] and Wang et al. [81] . [17] , and Gross [81] .

Although the composition of endogenous surfactant is similar throughout mammalian species, this is not true of exogenous surfactant drugs. The degree of resemblance of pharmaceutical surfactants to native surfactant is highly variable and has direct consequences for surface and physiologic activity. Pharmaceutical surfactants can be divided into three functionally relevant groups: (1) organic solvent extracts of lavaged lung surfactant from animals, (2) organic solvent extracts of processed animal lung tissue with or without additional synthetic additives, and (3) synthetic preparations not containing surfactant material from animal lungs (Table 10 .7). Organic solvent extracts of lavaged alveolar surfactant (category I) contain all of the hydrophobic lipid and protein components of endogenous surfactant, although specifi c compositional details can vary depending on preparative methodology. Extracts of minced or homogenized lung tissue (category II) necessarily contain some nonsurfactant components and require more extensive processing that can further alter composition compared with native surfactant. The synthetic surfactants in category III that have been most widely studied are Exosurf® and ALEC® (artifi cial lung expanding compound). Exosurf is a mixture of DPPC : hexadecanol : tyloxapol (1 : 0.11 : 0.075 by weight), and ALEC is a mixture of 7 : 3 DPPC : egg phosphatidylglycerol (PG). These two preparations are no longer in active clinical use because they have been shown to have inferior activity compared with animal-derived surfactants [e.g., 12, [95] [96] [97] [98] [99] [100] . Two additional synthetic surfactants, KL4 (Surfaxin®) and recombinant SP-C surfactant (Venticute®), are currently undergoing clinical evaluation.

The compositions and activities of the exogenous surfactants listed in Table 10 .7, and their effi cacy in preventing or treating RDS in clinical trials in premature infants, are reviewed in detail by Notter [12] . Four exogenous surfactant preparations are currently licensed for clinical use in RDS in the United States: Infasurf®, Survanta®, Curosurf®, and Exosurf® (the latter is no longer used, as noted earlier). Infasurf® is a direct chloroform : methanol extract of large aggregate surfactant obtained by bronchoalveolar lavage from calf lungs [12, 56, 101] . Survanta® is made from an extract of minced bovine lung tissue to which DPPC, tripalmitin, and palmitic acid are added [12, 18] . Curosurf® is prepared from minced porcine lung tissue by a combination of washing, chloroformmethanol extraction, and liquid-gel chromatography [102] . Sur-faxin®, which is under active consideration for FDA approval, contains a 21 amino acid peptide (KL4) that has repeating units of one leucine (K) and four lysine (L) residues. This peptide is combined at 3% by weight with a 3 : 1 mixture of DPPC and palmitoyloleoyl phosphatidylglycerol (POPG) plus 15% palmitic acid [12] . Venticute® contains synthetic lipids and palmitic acid plus a 34 amino acid modifi ed human recombinant SP-C that has substitutions of phenylalanine for cysteine at two positions and isoleucine for methionine at another [12] .

The relative activities and effi cacies of surfactant drugs are crucial for evaluating and optimizing therapy. Differences in effi cacy among pharmaceutical surfactants have been demonstrated in comparison trials in premature infants and in retrospective metaanalyses (reviewed by Notter [12] ). These differences in surfactant activity can be directly linked to differences in composition. The fact that natural surfactants from animal lungs (categories I and II, Table 10 .7) have greater effi cacy than the protein-free synthetic surfactants Exosurf® and ALEC® refl ects the diffi culty of substituting for the highly active hydrophobic lung surfactant proteins SP-B/C in synthetic surfactants. The surface and physiologic activities of Exosurf® are signifi cantly increased by the addition of purifi ed bovine SP-B/SP-C, demonstrating that its synthetic components do not adequately replace these active apoproteins [95] . Animalderived clinical surfactants also differ markedly in their surface activity and ability to resist inhibitor-induced dysfunction based on their compositions.

Biophysical research demonstrates that the surface activity, inhibition resistance, and physiologic effects of extracts of lavaged animal surfactant (category I surfactant drugs, 18, 95, 96] . It has also been shown that differences in apoprotein content can help explain some of these differences in activity [14, 16, 18, 95, 103, 104] . For example, the activity and inhibition resistance of Infasurf® are substantially greater than those of Survanta® in basic biophysical and animal research [18, 95, 96, 103] (see Figures  10.5 to 10.7) , and these differences correlate directly with the content of SP-B in the two preparations [18, 103, 105] . Survanta® contains only 0.044% SP-B by weight relative to phospholipid because of losses during processing of lung tissue [18] . In contrast, Infasurf® has a specifi c SP-B content of 0.9% by weight (and a total hydrophobic protein content of 1.7% by weight) equivalent to lavaged calf lung surfactant [18] . As described earlier, SP-B is the most active of the hydrophobic surfactant proteins in enhancing the adsorption and overall dynamic surface activities of phospholipids [14] [15] [16] 18, 106, 107] . The addition of SP-B or synthetic SP-B peptides to Survanta® signifi cantly improves its activity toward that of natural surfactant [18, 103, 104] (e.g., Figure 10 .7), indicating that the lack of SP-B in this exogenous surfactant is functionally important. Even without SP-B, however, Survanta® still has Note: Infasurf® (ONY, Inc., and Forest Laboratories), Survanta® (Abbott/Ross Laboratories), and Curosurf® (Chesi Farmaceutici and Dey Laboratories) are currently FDA approved in the United States, and Surfaxin® (KL4) is under clinical evaluation. Exosurf® (Glaxo-Wellcome) is also FDA approved but is no longer used. Details on the compositions, activities, and efficacies of these exogenous surfactants in neonatal RDS are reviewed by Notter [12] , and their use in ALI/ARDS is discussed in the text. Source: Adapted from Notter [12] and Enhorning et al. [72] .

signifi cantly better activity than protein-free surfactants like Exosurf® because of its content of SP-C and other ingredients [12] .

Animal models of ALI/ARDS in which exogenous surfactant therapy has been shown to improve respiratory function or mechanics include acid aspiration [108] [109] [110] , meconium aspiration [111] [112] [113] [114] , anti-lung serum [115] , bacterial or endotoxin injury [116] [117] [118] [119] [120] [121] , vagotomy [122] , hyperoxia , in vivo lavage [104, [128] [129] [130] [131] [132] , N-nitroso-N-methylurethane (NNNMU) injury [133] [134] [135] , and viral pneumonia [136, 137] . In addition to demonstrating that surfactant therapy has potential benefi t in ALI/ARDS, animal studies are also important in comparing surfactant activity under reproducible conditions, as well as in examining other variables of interest for clinical therapy. These variables include the method of surfactant delivery (instillation versus aerosolization), the timing of administration, the effects of different modes of ventilation, the effects of dose, and so on. For example, animal studies indicate that direct airway instillation is more effective than current aerosol techniques in delivering exogenous surfactant to the alveoli and that early therapy is preferable to later therapy in terms of distributing surfactant to injured lungs (reviewed by Notter [12] ). However, despite their utility for assessing the acute effects of exogenous surfactants and comparing preparations and delivery methods, animal models offer limited insight into longer term morbidity or mortality. For this, one must ultimately turn to human studies.

Multiple clinical studies have reported benefi ts following the instillation of exogenous surfactants to term infants, children, or adults with ALI/ARDS or related acute respiratory failure [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] (Table  10 .8). However, many of these are small case series or pilot studies and found improvements in only acute lung function (oxygenation). Controlled trials of surfactant therapy in patients with ALI/ ARDS have met with mixed success, particularly in studies with adults [94, 155] . The clinical experiences with exogenous surfactant therapy in term infants, children and adults are summarized next.

The best-studied application of surfactant therapy in term infants with acute pulmonary injury is in meconium aspiration syndrome [148] [149] [150] [151] [152] . Meconium obstructs and injures the lungs when aspirated and is known to cause surfactant dysfunction [156, 157] . Auten et al. [148] , Khammash et al. [151] , and Findlay et al. [152] have all reported signifi cant improvement from surfactant administration in infants with meconium aspiration. The randomized study of Findlay et al. [152] found reductions in the incidence of pneumothorax, duration of mechanical ventilation and oxygen therapy, time of hospitalization, and requirements for extracorporeal membrane oxygenation (ECMO) in 20 term infants treated with Survanta® compared with controls. Lotze et al. [149, 150] also reported favorable results using Survanta® in a controlled trial in term infants referred for ECMO because of severe respiratory failure (meconium aspiration was a prevalent diagnosis in both studies). Twenty-eight infants treated with four doses of Survanta® (150 mg/kg) had improved pulmonary mechanics, decreased duration of ECMO treatment, and a lower incidence of complications after ECMO than control infants [149] . A subsequent multicenter controlled trial with 328 term infants also reported signifi cant improvements in respiratory status and the need for ECMO following surfactant treatment [150] . Exogenous surfactant is now used in many institutions to treat respiratory failure in term infants with meconium aspiration or pneumonia, although fewer controlled studies are available for the latter condition. Surfactant therapy has also been studied in infants with congenital diaphragmatic hernia, but its use remains somewhat controversial in this context [158, 159] .

Studies of surfactant in children and adults with ALI/ARDS have followed the general pattern of initial positive case reports or series followed by more equivocal results in randomized prospective studies. The fi rst large prospective, controlled study of surfactant therapy for adults with ARDS was defi nitively negative. Anzueto et al [94] administered nebulized Exosurf® versus placebo to 725 adults with ARDS secondary to sepsis and found no improvement in any measure of oxygenation and no effect on morbidity or mortality. As described earlier, Exosurf® is no longer used clinically in the United States because of its lower activity compared with animal-derived surfactants, and aerosolization is currently not as effective as airway instillation in delivering surfactant. Gregory et al. [155] reported small benefi ts in oxygenation in a controlled trial in adults with ARDS who received four 100 mg/kg doses of Sur-vanta® but with no overall advantage in survival in the 43 surfactant-treated patients studied. A recent study by Spragg et al. [160] using recombinant SP-C surfactant (Venticute®) in adults with ARDS showed immediate improvements in oxygenation but no longer term improvement in duration of mechanical ventilation, lengths of stay, or mortality. Post hoc analysis did suggest, however, that the response in the subgroup of patients with ARDS caused by direct lung injury was quite positive, and a follow-up prospective study with this group of patients is currently underway.

Controlled studies of surfactant therapy in children with ALI/ ARDS have been more encouraging. A randomized but unblinded trial by Willson et al. [143] in 42 children at eight centers with ALI/ARDS showed that those receiving Infasurf® (70 mg/kg) had immediate improvement in oxygenation and fewer ventilator days and days in intensive care. This trial followed an initial open-label trial by the same group demonstrating improved oxygenation in 29 children (0.1-16 years) treated with instilled Infasurf® [142] . Luchetti et al. [153, 154] have reported two small controlled studies showing that treatment with porcine surfactant (Curosurf®, 50 mg/ kg) led to improved gas exchange as well as reduced time on mechanical ventilation and in intensive care for infants with bronchiolitis. A study by Moller et al. [161] found that children with [139] Adult (10) ARDS from sepsis Alveofact Improved oxygenation Spragg et al. [140] Adult (6) ARDS from multiple causes Curosurf Improved oxygenation a and biophysical function Wiswell et al. [141] Adults (12) ARDS from multiple causes Surfaxin Improved oxygenation Willson et al. [142, 143] Children (29, 42) ARDS from multiple causes Infasurf Improved oxygenation Willson et al. [144] Children (152) ARDS from multiple causes Infasurf Improved survival, and improved ventilation Lopez-Herce et al. [145] Children (20) ARDS + postop cardiac Curosurf Improved oxygenation Hermon et al. [146] Children (19) ARDS + postop cardiac Curosurf or Alveofact Improved oxygenation Herting et al. [147] Children (8) Pneumonia Curosurf Improved oxygenation Auten et al. [148] Infants (14) Meconium aspiration or pneumonia Infasurf (CLSE) Improved oxygenation Lotze et al. [149, 150] Infants (28, 328) ECMO, multiple indications Survanta Improved oxygenation, decreased ECMO Khammash et al. [151] Infants (20) Meconium aspiration bLES Improved oxygenation in 75% of patients Findlay et al. [152] Infants (40) Meconium aspiration Survanta Improved oxygenation, decreased pneumothorax and mechanical ventilation Luchetti et al. [153, 154] Infants ( The Future of Surfactant Therapy and Related Combination Therapies

As described in preceding sections, surfactant replacement therapy is standard in the prevention and treatment of RDS in premature infants, and there is basic science and clinical evidence supporting its use in some forms of lung injury-associated respiratory failure. Clinical evidence of the effi cacy of surfactant therapy for term infants with meconium aspiration is suffi ciently strong that this approach is now frequently used in neonatal intensive care units (and is also being applied to other forms of neonatal respiratory failure, such as pneumonia). Controlled trials of surfactant therapy for children with ALI/ARDS also suggest signifi cant benefi ts, with survival advantages shown in a recent trial [144] . It can be argued that evidence of surfactant dysfunction in ALI/ARDS, along with favorable results for surfactant treatment in animal models and evidence for effi cacy in humans without signifi cant adverse effects, makes a strong rationale for considering surfactant therapy for any pediatric patient with pulmonary injury and ALI/ARDS. From this perspective, the major downside of the therapy is its considerable expense. However, it would be ideal if additional questions about the therapy were addressed in research before its indiscriminate adoption.

As emphasized in this chapter, some exogenous surfactants are more active and have better inhibition resistance than others, and this, along with effective delivery, will impact the success of surfactant therapy for ALI/ARDS. It is also likely that surfactant therapy is more applicable for some types of pulmonary injury than others. It is important to note that post hoc analyses in the studies of both Spragg et al. [160] and Willson et al. [144] suggested greater effi cacy in direct lung injury (e.g., pneumonia, aspiration) as opposed to indirect lung injury (e.g., sepsis, systemic infl ammatory response syndrome). It would obviously be helpful to focus surfactant therapy on the types of lung injury where it has maximal benefi t. Also, neonatal data suggest that early surfactant administration generates improved responses compared with delayed administration [e.g., 162], possibly as a result of better intrapulmonary drug distribution coupled with minimized ventilator-induced lung injury. Intuitively, similar advantages might accompany early surfactant administration in patients with ALI/ARDS.

Finally, a major issue with regard to surfactant therapy in ALI/ ARDS involves its potential use in combination with agents or interventions that target additional aspects of the complex pathophysiology of acute pulmonary injury. This kind of combination therapy approach may be particularly important for adults with ALI/ARDS, whose responses to exogenous surfactant have so far been disappointing. The use of multiple therapeutic agents or interventions based on specifi c rationales for potential synergy has the potential to signifi cantly enhance patient outcomes in complex disease processes such as those involving infl ammatory lung injury. The potential use of exogenous surfactant therapy in the context of specifi c combined-modality interventions is described in detail elsewhere [163, 164] . Examples of agents that might be synergistic with exogenous surfactant in ALI/ARDS include antiinfl ammatory antibodies or receptor antagonists, antioxidants, and vasoactive drugs such as inhaled nitric oxide (iNO). In addition, specifi c ventilator modalities or ventilation strategies that reduce iatrogenic lung injury may be equally important to consider in conjunction with surfactant therapy. Given the known importance of surfactant dysfunction in infl ammatory lung injury, it is likely that ongoing research will continue to identify specifi c populations of patients with ALI/ARDS or related acute respiratory failure who can benefi t from exogenous surfactant therapy, with or without complementary agents or interventions. [144] .

Neue auffassungen uber einen grundbegriff der atemmechanik. Dieretraktionskraft der lunge, abhangig von der oberfl achenspannung in den alveolen

Surface tension as a factor in the resistance of neonatal lungs to aeration

Surface tension as a factor in pulmonary volume-pressure hysteresis

Properties, function, and origin of the alveolar lining layer

Surface tension of lung extracts

Lung area from surface tension effects

Properties, function and origin of the alveolar lining layer

Surface properties in relation to atelectasis and hyaline membrane disease

Microaerosol administration of synthetic b,g-dipalmitoyl-L-alecithin in the respiratory distress syndrome: a preliminary report

The pulmonary hypoperfusion syndrome

Neonatal pulmonary ischemia. Clinical and physiologic studies

Lung Surfactants: Basic Science and Clinical Applications

Artifi cial surfactant therapy in hyaline membrane disease

Content-dependent activity of lung surfactant protein B (SP-B) in mixtures with lipids

Differential activity and lack of synergy of lung surfactant proteins SP-B and SP-C in surface-active interactions with phospholipids

Differential sensitivity to fi brinogen inhibition of SP-C-vs. SP-B-based surfactants

Pulmonary surfactant: physical chemistry, physiology and replacement

Component-specifi c surface and physiological activity in bovine-derived lung surfactants

Human surfactant protein B structure, function, regulation, and genetic disease

Molecular and phenotypic variability in the congenital alveolar proteinosis syndrome associated with inherited surfactant protein B defi ciency

A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds

Allelic heterogeneity in hereditary surfactant protein B (SP-B) defi ciency

A mutation in the surfactant protein C gene associated with familial interstitial lung disease

Surfactant proteins A and D and pulmonary host defense

The roles of surfactant proteins A and D in innate immunity

Surfactant protein A and surfactant protein D in health and disease

Immunomodulatory functions of surfactant

Surfactant protein A defi cient mice are susceptible to group B streptococcal infection

Surfactant protein A-defi cient mice are susceptible to Pseudomonas aeruginosa infection

Surfactant protein D regulates surfactant phospholipid homeostasis in vivo

Expression of the carbohydrate recognition domain of lung surfactant protein D and demonstration of its binding to lipopolysaccharides of Gram-negative bacteria

Surfactant protein D binds to Mycobacterium tuberculosis bacilli and liparabinomannan via carbohydrate-lectin interactions resulting in reduced phagocytosis of the bacteria by the macrophages

Clearance and recycling of pulmonary surfactant

Surfactant phospholipids: synthesis and storage

Surfactant: composition, structure, and metabolism

The pulmonary collectins and surfactant metabolism

Metabolism of lipids

Synthesis and assembly of lung surfactant

The proteins of the surfactant system

Molecular and cellular processing of lung surfactant

The pulmonary surfactant protein genes and their regulation in fetal lung

Surfactant protein composition of lamellar bodies isolated from rat lung

Requirement of the collagenous domain for carbohydrate processing and secretion of a surfactant protein, SP-A

Uptake of pulmonary surfactant protein C into adult rat lung lamellar bodies

Immunocytochemical localization of the major surfactant proteins in type II cells, Clara cells, and alveolar macrophages of rat lungs

Processing of hydrophobic pulmonary surfactant protein B in rat type II cells

Immunocytochemical localization of surfactant protein D (SP-D) in type II cell, Clara cells, and alveolar macrophages of rat lung

Conversion of lamellar body membranes into tubular myelin in alveoli of fetal rat lungs

Ultrastructure of tubular myelin and lamellar bodies in fast-frozen rat lung

Changes in lipid structure produced by surfactant proteins

Reconstitution of tubular myelin from synthetic lipids and proteins associated with pig lung surfactant

Metabolism and turnover of lung surfactant

Surfactant metabolism

Uptake of lectins by alveolar type II cells: subsequent deposition into lamellar bodies

Uptake of lung surfactant subfractions into lamellar bodies of adult rabbit lungs

Surfactant apoprotein Mr = 26,000-36,000 enhances uptake of liposomes by type II cells

Cellular uptake and processing of surfactant lipids and apoprotein SP-A by rat lung

An ethanol/ether soluble apoprotein from rat lung surfactant augments liposomes uptake by isolated granular pneumocytes

Surfactant peptides stimulate uptake of phosphatidylcholine by isolated cells

Lung Injury: Mechanisms, Pathophysiology, and Therapy

Acute respiratory distress in adults

The adult respiratory distress syndrome. Clinical features, factors infl uencing prognosis and principles of management

Characteristics of pulmonary surfactant in adult respiratory distress syndrome associated with trauma and shock

Surfactant activity and dysfunction in lung injury

A biophysical mechanism by which plasma proteins inhibit lung surfactant activity

Multiple mechanisms of lung surfactant inhibition

Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity

Additivity of protein and non-protein inhibitors of lung surfactant activity

Inhibition of pulmonary surfactant by oleic acid: mechanisms and characteristics

Proteolytic inactivation of dog lung surfactant-associated proteins by neutrophil elastase

Phospholipases introduced into the hypophase affect the surfactant fi lm outlining a bubble

Surface activity of a synthetic lung surfactant containing a phospholipase-resistant phosphonolipid analog of dipalmitoyl phosphatidylcholine

Subfractionation of lung surfactant: implications for metabolism and surface activity

Protein composition of rabbit alveolar surfactant subfractions

Surfactant subtypes in mice: characterization and quantitation

Changes in subphase surfactant aggregates in rabbits injured by free fatty acid

Surface activity of rabbit pulmonary surfactant subfractions at different concentrations in a captive bubble

Surface properties, morphology and protein composition of pulmonary surfactant subtypes

Surface-area cycling of different surfactant preparations: SP-A and SP-B are essential for large aggregate integrity

Extracellular metabolism of pulmonary surfactant: the role of a new serine protease

Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema

Pulmonary surfactant subfractions in patients with the acute respiratory distress syndrome

Pulmonary surfactant in health and human lung diseases: state of the art

Surfactant abnormalities in patients with respiratory failure after multiple trauma

Altered surfactant function and metabolism in rabbits with acute lung injury

Pulmonary surfactant subtype metabolism is altered after short-term ozone exposure

P. carinii induces selective alterations in component expression and biophysical activity of lung surfactant

Surfactant alterations in acute infl ammatory lung injury from aspiration of acid and gastric particulates

Surfactant abnormalities and adult respiratory failure

Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome

Altered pulmonary surfactant in uncomplicated and septicemia-complicated courses of acute respiratory failure

Evidence of lung surfactant abnormality in respiratory failure

Exosurf ARDS Sepsis Study Group. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome

Importance of hydrophobic apoproteins as constituents of clinical exogenous surfactants

Surfactant inhibition by plasma proteins: differential sensitivity of various surfactant preparations

Riddlesberger MM, Montogomery P, 21 Center Group. A multicenter randomized masked comparison of natural vs synthetic surfactant for the treatment of respiratory distress syndrome

A multicenter randomized masked comparison trial of synthetic surfactant versus calf lung surfactant extract in the prevention of neonatal respiratory distress syndrome

A multicenter randomized trial comparing synthetic surfactant with modifi ed bovine surfactant extract in the treatment of neonatal respiratory distress syndrome

A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome

Porcine-Derived Lung Surfactant. A review of the therapeutic effi cacy and clinical tolerability of a natural surfactant preparation (Curosurf) in neonatal respiratory distress syndrome

Surfactant protein-B supplementation improves in vivo function of a modifi ed natural surfactant

Spiking Survanta with synthetic surfactant peptides improves oxygenation in surfactant-defi cient rats

Surfactant protein B defi ciency: antenatal diagnosis and prospective treatment with surfactant replacement

Comparative studies on the biophysical activities of the low-molecular-weight hydrophobic proteins purifi ed from bovine pulmonary surfactant

Lipid mixing is mediated by the hydrophobic surfactant protein SP-B but not by SP-C

Lung lavage and surfactant replacement for hydrochloric acid aspiration in rabbits

Exogenous surfactant with PEEP reduces pulmonary edema and improves lung function in canine aspiration pneumonitis

Experimental aspiration trauma: comparison of steroid treatment versus exogenous natural surfactant

Improved oxygenation with exogenous surfactant administration in experimental meconium aspiration syndrome

Exogenous surfactant improves ventilation effi ciency and alveolar expansion in rats with meconium aspiration

Bronchoalveolar lavage with KL4-surfactant in models of meconium aspiration syndrome

Surfactant improves lung function and morphology in newborn rabbits with meconium aspiration

Respiratory failure following anti-lung serum: study on mechanisms associated with surfactant system damage

Surfactant replacement in the treatment of sepsis-induced adult respiratory distress syndrome in pigs

Aerosolized surfactant improves pulmonary function in endotoxin-induced lung injury

Exogenous surfactant and positive end-expiratory pressure in the treatment of endotoxin-induced lung injury

Surfactant replacement reverses respiratory failure induced by intratracheal endotoxin in rats

Effect of surfactant replacement on Pneumocystis carinii pneumonia in rats

Effect of different surfactants on pulmonary group B streptococcal infection in premature rabbits

Respiratory distress and surfactant inhibition following vagotomy in rabbits

Mitigation of pulmonary hyperoxic injury by administration of exogenous surfactant

Alveolar hyperoxic injury in rabbits receiving exogenous surfactant

Surfactant replacement attenuates the increase in alveolar permeability in hyperoxia

Sublethal hyperoxic injury to the alveolar epithelium and the pulmonary surfactant system

Hyperoxic lung injury reduces exogenous surfactant clearance in vitro

Surfactant replacement therapy in experimental adult respiratory distress syndrome (ARDS)

Effect of surfactant supplementation and end expiratory pressure in lung-lavaged rabbits

Gas exchange and lung morphology after surfactant replacement in experimental adult respiratory distress induced by repeated lung lavage

Evaluation of exogenous surfactant treatment strategies in an adult model of acute lung injury

Protein composition of synthetic surfactant affects gas exchange in surfactantdefi cient rats

Effect of exogenous surfactant instillation on experimental acute lung injury

Metabolism of exogenously administered surfactant in the acutely injured lungs of adult rabbits

Nebulized vs. instilled exogenous surfactant in an adult lung injury model

Intratracheal surfactant administration restores gas exchange in experimental adult respiratory distress syndrome associated with viral pneumonia

Surfactant replacement therapy improves pulmonary mechanics in end-stage infl uenza A pneumonia in mice

Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on biophysical and biochemical surfactant properties

Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis

Acute effects of a single dose of porcine surfactant on patients with acute respiratory distress syndrome

Bronchopulmonary segmental lavage with Surfaxin (KL(4)-surfactant) for acute respiratory distress syndrome

Calf lung surfactant extract in acute hypoxemic respiratory failure in children

Instillation of calf lung surfactant extract (calfactant) is benefi cial in pediatric acute hypoxemic respiratory failure

Pediatric Acute Lung Injury and Sepsis Investigators. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial

Surfactant treatment for acute respiratory distress syndrome

Surfactant therapy in infants and children: three years experience in a pediatric intensive care unit

Surfactant improves oxygenation in infants and children with pneumonia and acute respiratory distress syndrome

Surfactant treatment of full-term newborns with respiratory failure

Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation

Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure

Surfactant therapy in full-term neonates with severe respiratory failure

Surfactant replacement therapy for meconium aspiration syndrome

Porcinederived surfactant treatment of severe bronchiolitis

Multicenter, randomized, controlled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure

Bovine surfactant therapy for patients with acute respiratory distress syndrome

Surfactant displacement by meconium free fatty acids: an alternative explanation for atelectasis in meconium aspiration syndrome

Inhibition of pulmonary surfactant function by meconium

New approaches to managing congenital diaphragmatic hernia

The Congenital Diaphragmatic Hernia Study Group. Is surfactant therapy benefi cial in the treatment of the term newborn infants with congenital diaphragmatic hernia?

Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant

with the Surfactant ARDS Study Group. Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study

A comparison of surfactant as immediate prophylaxis and as rescue therapy in newborns of less than 30 weeks gestation

Surfactant therapy and its potential use with other agents in term infants, children and adults with acute lung injury

Combination therapies for lung injury