Surfactant biology and clinical application

Surfactant biology and clinical application

Sue E. Poynter, MD, Ann Marie LeVine, MD*

Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center,

3333 Burnet Avenue, Cincinnati, OH 45229, USA

Pulmonary surfactant is a highly surface-active material that lines the alveolar

surface of the lung. The major function of pulmonary surfactant is the reduction

of surface tension at the air-water interface of the terminal airways, decreasing the

tendency for alveolar collapse. This ability to reduce surface tension significantly

and to increase compliance in the lung led to the initial discovery of surfactant in

the 1920s by Von Neergaard [1]. In 1959, Avery and Mead [2] reported that

saline extracts of lungs from premature infants who died from respiratory distress

syndrome were deficient in surfactant when compared with infants dying of other

causes, providing clinical evidence of pulmonary surfactant’s crucial role in

pulmonary function. In addition to lowering surface tension, surfactant seems to

play a role in pulmonary host defense [3]. Early work on surfactant and host

defense was published more than 30 years ago. A resurgence of interest in this

subject occurred with the discovery that two of the surfactant proteins, surfactant

protein A (SP-A) and surfactant protein D (SP-D), are members of a family of

proteins called collectins that are involved in the innate host defense system of

the lung [3]. This article discusses surfactant biology, alterations of surfactant in

disease, and potential clinical applications.

Biophysical functions of surfactant

Von Neergaard, in 1929 [1], was the first to report that surface tension is more

important than tissue elastic forces for the retractive force of the lungs at all levels

of inflation. The surface tension of the alveolar air-water interface provides the

retractive force opposing lung inflation. The law of Laplace illustrates that the

difference in pressure between the airspace and the lining (DP) depends only on

0749-0704/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S0749-0704(03)00011-3

The work was supported by a grant from the National Institutes of Health KO8 HL-03905

(A.M.L.) and the Pediatric Scientist Development Program/NICHD K12-HD00850 (S.E.P.)

* Corresponding author.

E-mail address: [email protected] (A.M. LeVine).

Crit Care Clin 19 (2003) 459–472

the surface tension (T) and the radius of the alveoli (DP = 2T/r) [4]. Forces as

great as 70 dynes/cm2 are generated at the air-liquid interface in the alveoli and

would quickly lead to alveolar collapse and respiratory failure if unopposed [4,5].

The presence of surfactant, creating a fluid phospholipid film, can lower air-water

surface tensions to values near zero [6], ensuring that the alveolar space remains

open during the entire respiratory cycle and maintains residual lung volume at

end-expiration. Low surface tension also ensures that net fluid flow is from the

alveolar space into the interstitium. A lack of surfactant leads to accumulation of

fluid in the alveolar space. Surfactant also plays a role in improving mucociliary

clearance and removal of particulate material from the lung [3–5].

Pulmonary surfactant composition

Pulmonary surfactant is a complex mixture composed of approximately 90%

lipids and 10% protein secreted by the alveolar type II cells in the lung [4–6].

The overall lipid and phospholipid compositions of surfactants isolated from a

variety of animal species are remarkably similar in composition. In humans,

phosphatidylcholine comprises almost 80% of the total lipids, about half of which

is dipalmitoylphosphatidylcholine (DPPC). This saturated phospholipid seems to

be the most critical component for decreased surface tension of the airways [6].

Phosphatidylglycerol and phosphatidylinositol account for about 10% of the total

lipids, and lesser amounts of phosphatidylserine, phosphatidylethanolamine,

sphingomyelin, and glycolipids are also present [6]. During the respiratory cycle,

the surfactant surface film is compressed and re-expanded, leading to dense

packing of lipid material such as DPPC and very low surface tension values.

Surfactant contains two types of specific surfactant proteins, hydrophilic SP-A

and surfactant protein D (SP-D) and hydrophobic SP-B and surfactant protein C

(SP-C). Surfactant proteins play an important role in surfactant function and

metabolism and host defense of the lung. [4] Surfactant protein B is a small,

homodimeric protein found tightly associated with surfactant lipids in the

alveolar space. Surfactant protein B is a 79 aa homodimer of about 8.8 kDa

encoded by a gene on chromosome 2 and expressed in type II cells and Clara

cells in the lung. Surfactant protein B is first transcribed into a larger monomeric

proprotein of 42 kDa. The proprotein is N-glycosylated at the regions flanking

the mature SP-B sequence. The flanking arms are cleaved to release mature SP-B

by unknown proteases, and dimerization does not occur until cleavage of the

flanking arms is complete [7]. The 23 aa signal peptide of SP-B, located at the

N-terminus, mediates translocation of SP-B into the lumen of the endoplasmic

reticulum. Cleavage of the signal peptide results in a propeptide consisting of an

NH2-terminal propeptide (aa 24–200), the 79 aa mature peptide (aa 201–279),

and a C-terminal propeptide (aa 280–381) [7]. Surfactant protein B has a

homologous tertiary structure of six cysteine residues paired as disulfides and

an additional set of nine hydrophobic residues as seen in the family of saposinlike

proteins (sphingolipid activation proteins) [7]. Surfactant protein B plays a role in

S.E. Poynter, A.M. LeVine / Crit Care Clin 19 (2003) 459–472460

membrane binding, membrane lysis, membrane fusion, and promotion of lipid

adsorption to air-liquid surfaces [7]. Surfactant protein B, together with SP-A,

lipids, and calcium, helps construct tubular myelin [7,9].

Surfactant protein C is a hydrophobic protein that contains more than 70% non-

polar residues. The major form of SP-C is a 35 aa peptide with two thioester-linked

palmitoyl groups and a molecular mass of 4.3 kDa [7]. It contains a nonpolar

transmembrane domain and is encoded by a gene on chromosome 8. Surfactant

protein C is expressed exclusively by type II cells in the lung alveoli. The

organization of the SP-C proprotein is similar to the proprotein of SP-B. The 35 aa

mature peptide (aa 24–58) is flanked by an N-terminal propeptide (aa 1–24) and a

C-terminal propeptide (aa 59–197) [7]. Surfactant protein C is a type-II integral

membrane protein with the N-terminus located in the cytoplasm and the

C-terminus located in the lumen of the endoplasmic reticulum. The transmem-

brane domain of SP-C encodes the major part of the biologically active propeptide.

Most SP-C activities overlap the activities of SP-B. In addition to the functions

already described, SP-C seems to be important for monolayer film stability [7,9].

Surfactant protein A, the most abundant surfactant protein, is found as a

hydrophilic, 26-kDa, glycoprotein monomer. Surfactant protein A belongs to the

collectin family of proteins, which are known to function as antibody-indepen-

dent opsonins [3,8]. The primary structure of SP-A is characterized by four

structural domains: a signal sequence that is cleaved during processing, an

N-terminal collagenlike region, a hydrophobic neck domain, and a C-terminal

carbohydrate recognition domain (CRD) with a high degree of homology with

several members of the calcium-dependent (C-type) mammalian lectins [8,11].

The combination of a collagenlike region and a C-type lectin domain are the

structural features of the collectin family of proteins [8]. The mature peptide

forms trimers that assemble into octadecamers in the primary airway form.

Surfactant protein A has been shown to act cooperatively with SP-B in formation

of a surface film and in formation of tubular myelin [9]. Surfactant protein A,

however, does not seem to have an essential role in reduction of surface tension,

because transgenic mice deficient in SP-A survive and have normal compliance

and lung volumes [10]. The ability of surfactant isolated from these SP-A–

deficient mice to reduce surface tension at low concentrations is decreased [10].

Surfactant protein A is believed to be a molecule of the innate immune system

through its ability to recognize a broad spectrum of pathogens, enhance

phagocytosis by acting as an opsonin, or directly stimulate macrophages and

modulate cytokine production [3,8].

Surfactant protein D, similar to SP-A, is a member of the collectin family of

mammalian lectins and is expressed in type II cells and Clara cells. Surfactant

protein D is encoded by a single gene located on chromosome 10 in close

proximity to SP-A and other members of the collectin family. The collagenlike

domain of SP-D is larger than that of SP-A and is attached directly to the CRD

domain without a connecting region [11,12]. In its native form in the lung, SP-D

consists of 12 distinct 43-kDa SP-D monomers, arranged into four trimers. A role

for SP-D in the surface tension–reducing properties of surfactant has not been

S.E. Poynter, A.M. LeVine / Crit Care Clin 19 (2003) 459–472 461

defined, and SP-D does not seem to sediment with lipids as readily as does SP-A

[12]. Observations that support a role for SP-D in surfactant metabolism include

(1) SP-D may be associated with lipids under some conditions [11], (2) SP-D

binds to phosphatidylinositol, [13], and (3) SP-D–deficient mice have altered

surfactant lipid homeostasis [14]. Surfactant protein D also has a role in innate

host defense of the lung by binding pathogens, enhancing phagocytosis and

killing of some organisms, and modulating the inflammatory response to bacterial

and viral infection [3,12].

Synthesis and secretion of surfactant

Pulmonary surfactant is synthesized in the alveolar type II cell, one of only two

types of cells that comprise the alveolar epithelium. Surfactant phospholipids are

packaged with surfactant proteins B and C in the form of lamellar bodies that are

secreted into the airspace by exocytosis (Fig. 1). Extracellularly, phospholipids

and lamellar bodies interact with SP-A and calcium to produce tubular myelin, a

highly organized, lipid-rich material from which phospholipid films, consisting of

monolayers and multilayers, are generated at the air-liquid interface [6,9]. The

monomolecular film reduces the surface tension forces tending to collapse the

lung. Under normal conditions, most surfactant present in the alveolar space is in

Fig. 1. Surfactant life cycle. Type II cells synthesize surfactant. All surfactant components except

surfactant protein D (SP-D) are stored in the type II secretory organelle, the lamellar body, and

surfactant is secreted into liquid hypophase that covers alveoli. A unique latticelike structure called

tubular myelin is generated. Dipalmitoylphosphatidylcholine (DPPC) forms a monomolecular film at

air-liquid interface, reducing surface tension and the work of breathing. Surfactant is cleared by uptake

by the type II cell or is degraded by alveolar macrophages.


the form of functionally active large aggregates (LA), with the remainder being

found in the form of small surfactant vesicles or small aggregates (SA) containing

degradation products [9]. Surfactant is cleared by uptake by the type II cell, which

both degrades and then reuses surfactant components. A significant fraction of

surfactant is degraded by alveolar macrophages, with minor amounts moving up

the airways and across the epithelial-endothelial barrier [9].

Surfactant protein deficiencies

In vivo studies in gene-targeted mice lacking SP-B and in infants with

hereditary SP-B deficiency demonstrate the critical role of SP-B in surfactant

function, homeostasis, and lung function. Targeted disruption of the mouse SP-B

gene caused respiratory failure at birth. Although the lung structure in newborn

SP-B–deficient mice was normal, the mice failed to inflate their lungs

postnatally [15,16]. At the electron microscopic level, SP-B–deficient mice

failed to produce lamellar bodies or tubular myelin. Large multivesicular bodies

accumulated in the type II cells of SP-B–deficient mice, and the proteolytic

processing of proSP-C was disrupted [7]. These observations are consistent with

observations in infants suffering from hereditary SP-B deficiency [17,18,] Most

of these infants die from respiratory distress in the early neonatal period,

although mutations leading to partial SP-B function have been associated with

chronic lung disease in infants [18].

Surfactant protein C–deficient mice survive perinatally and postnatally, but

physiologic studies demonstrated abnormalities in lung function, particularly at

low lung volumes [19,20]. Composition and concentration of surfactant is

unaltered in the SP-C–deficient mice in vivo; however, surfactant isolated from

the SP-C–deficient mice is unstable during bubble surfactometry [20]. These

findings indicate that SP-C may play a critical role in recruiting and maintaining

lipid concentration in lipid films. Recent studies have identified a number of

families carrying mutations in the SP-C gene [21]. Surfactant protein C mutations

were identified in several families with familial interstitial lung disease, which

presents as varying degrees of interstitial lung disease in childhood and

adulthood. Lung pathology consists of thickened interstitium, infiltration with

inflammatory cells and macrophages, fibrosis, and abnormalities of the respira-

tory epithelium associated with severe lung disease [21].

Surfactant protein A–deficient mice have normal survival without changes in

surfactant composition, function, secretion, reuptake, and stability; however,

there is lack of tubular myelin in the alveoli [22]. Despite relatively normal lung

function, SP-A–deficient mice are highly susceptible to various bacterial (group B

Streptococcus, Haemophilus influenzae, Pseudomonas aeruginosa) and viral

(respiratory syncytial virus, influenza A virus) pathogens in vivo [3,22,23]. There

are currently no documented genetic deficiencies of SP-A or SP-D in humans;

however, polymorphisms in the human genes for these proteins affecting their

function have been discovered [24,25]. Humans with these polymorphisms have


increased susceptibility to infections with respiratory syncytial virus and Myco-

bacterium tuberculosis.

Surfactant D–deficient mice develop increased surfactant lipid pools in the

lung with relatively normal secretion and catabolic rates of surfactant lipids,

suggesting that SP-D plays a critical role in the regulation of surfactant ho-

meostasis [3,26]. In addition, SP-D–deficient mice accumulate foamy activated

macrophages in the lung and spontaneously develop emphysema because of

increased oxidant and metalloproteinase expression, suggesting that SP-D regu-

lates alveolar macrophage function [26]. Surfactant D–deficient mice are also

highly susceptible to infection by influenza A and respiratory syncytial viruses,

providing evidence for a role of SP-D in innate host defense of the lung [23,25].

Surfactant levels in lung disease

Alterations of surfactant composition or levels have been found in nearly

every form of lung disease including chronic, acute, infectious, inflammatory,

obstructive, and interstitial lung diseases. Surfactant replacement is being

studied as possible adjunctive therapy for pulmonary diseases associated with

surfactant abnormalities.

Obstructive lung disease

Chronic obstructive pulmonary disease

Tobacco smoke plays a role in airway inflammation and alveolar damage and is

associated with alterations in surfactant levels and function. Bronchoalveolar

lavage (BAL) fluid from smokers had decreased phospholipids with impaired

surface activity of surfactant. In chronic smokers, the levels of SP-A and SP-D in

BAL fluid are also reduced (Table 1). These findings may partly explain the

Table 1

Levels of surfactant/lipids in lung disease

Disease Surfactant protein levels Lipid levels

Obstructive

COPD/Smoking [27–29] # SP-A and SP-D # total phospholipid

Cystic fibrosis [27,34,35] " SP-A early, then # later # DPPC

Asthma [27,30,31] # SP-A # phosphatidylcholine

Pneumonia/ bacterial [27,32] # SP-A # phosphatidylcholine

RSV bronchiolitis [27,32,33] # SP-A and SP-D # DPPC

Interstitial

IPF [27,36,37] # SP-A, " SP-D # total phospholipid

Neonatal RDS [27,39–41] # SP-A #phospholipid/phosphatidylglycerolARDS [27,44–49] ## SP-A, # SP-B, later # SP-D # total phospholipid

Abbreviations: ARDS, acute respiratory disease syndrome; COPD, chronic obstructive pulmonary

disease; DPPC, dipalmitoyl phosphatidylcholine; RDS, respiratory disease syndrome; RSV, respiratory

syncytial virus; SP, surfactant protein.


increased rate of respiratory infections in smokers. Cigarette smoking results in

airway inflammation that may affect surfactant function by activating neutrophils

to release secretory products such as elastase and oxygen radicals. These

byproducts may directly inhibit surfactant function or production [27]. Similar

abnormalities in surfactant have been observed in patients with chronic obstructive

pulmonary disease (COPD), which is often a result of chronic cigarette smoking.

Patients with COPD and chronic bronchitis treated with surfactant phospholipids

showed modest improvement in lung function compared with controls [29].

Asthma

In patients with asthma, phosphatidylcholine and SP-A levels are decreased in

BAL fluid (Table 1). In addition, surface activity of surfactant is decreased during

acute asthma attacks, possibly because of increased protein leak into the air

spaces or increased inflammatory mediators in the lung. Decreased LA surfactant,

the functional surfactant form, has been shown in animal models of asthma

[27,30,31]. In two separate studies, aerosolized surfactant was used in adults and

children during acute asthmatic attacks with mixed results. The adult subjects

showed improvement in pulmonary function, whereas pulmonary function in

children did not improve [30,31].

Infections

Pneumonia

Changes in pulmonary surfactant with bacterial pneumonia include reduced

phosphatidylcholine, alterations in fatty acid composition, decreased SP-A, and

decreased surface activity (Table 1). Surfactant abnormalities have also been

observed in infants with respiratory failure from viral pneumonia with decreased

SP-A, SP-D, and DPPC levels in BAL fluid (Table 1). Treatment of infants with

respiratory failure secondary to bronchiolitis with exogenous surfactant resulted

in improved oxygenation, lung compliance, and decreased need for ventilator

support [33].

Cystic fibrosis

Bronchoalveolar lavage studies in patients with cystic fibrosis demonstrate an

extremely decreased phosphatidylcholine content. In young patients with cystic

fibrosis, no difference was observed in SP-A levels in BAL fluid; however, with

the early development of inflammation, SP-A levels increased (Table 1). In older

patients with more chronic cystic fibrosis disease, decreased SP-A and DPPC

levels in BAL fluid have been reported (Table 1). In the lungs of patients with

cystic fibrosis, decreased levels of SP-A may result in decreased host bacterial

defense and increased susceptibility to infections. In addition, reduced levels of

phospholipids may impair the ability of surfactant to reduce surface tension. In a

double-blinded, placebo-controlled trial using nebulized bovine surfactant

(Alveofact, Thomae GmbH, Biberach/Riss, Germany) in patients with moderate

to severe cystic fibrosis, no improvement in lung function or oxygenation was


observed, possibly because of the small dose of surfactant administered by

nebulization [27,35].

Interstitial lung disease

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a general term that includes the diagnosis of

interstitial pneumonia. Surfactant phospholipids, LA surfactant, and SP-A are

decreased in BAL fluid of patients with idiopathic pulmonary fibrosis (Table 1).

Elevated SP-D levels have been reported to correlate with the decline of

pulmonary function tests, whereas decreased SP-A levels were predictive of

non-survival [37,38]. Studies have not yet been performed to examine the effects

of surfactant administration in patients with idiopathic pulmonary fibrosis. Recent

data show a link between mutations in the SP-C gene and the development of

interstitial lung disease and may guide surfactant therapy in these disease

processes [21].

Neonatal respiratory distress syndrome

More than 40 years ago, investigators recognized the critical role of surfactant

in reducing surface tension at the air-liquid interface and in the pathogenesis of

respiratory distress syndrome in preterm infants [2]. Surfactant deficiency in

respiratory distress syndrome is characterized by atelectasis, alveolar collapse,

and hypoxemia. Intratracheal administration of exogenous surfactant mixtures

containing SP-B, SP-C, and phospholipids has become the criterion standard of

treatment for infants with respiratory distress syndrome [40,41]. These surfactant

mixtures act quickly to increase compliance and lung volumes, resulting in

decreased requirements for oxygen and positive-pressure ventilation. The effec-

tiveness of surfactant treatment is probably secondary to the immediate reduction

in surface tension and the reuptake of the surfactant particles by the respiratory

epithelium. The long-term results of surfactant therapy have been decreased

morbidity and mortality, with significantly less barotrauma and chronic lung

disease [39–41].

Acute respiratory distress syndrome

The term acute respiratory distress syndrome (ARDS) describes an over-

whelming inflammatory reaction within the pulmonary parenchyma leading to

global lung dysfunction. Acute respiratory distress syndrome is defined by an

acute onset, a PaO2/FiO2 ratio below 200, bilateral infiltrates on chest radiograph,

and a pulmonary capillary wedge pressure of less than 18 mm Hg or absence of

clinical evidence for left-sided heart failure [5]. The etiology of ARDS is

multifactorial; ARDS can occur in association with lung injury secondary to


scenarios such as trauma, sepsis, aspiration, pneumonia, massive blood trans-

fusions, or near-drowning [5]. It is a relatively common disease in the ICU, found

in 15% to 20% of all patients requiring mechanical ventilation in the adult ICU

and in 1% to 4.5% of patients in the pediatric ICU [5]. Unfortunately, despite

recent advances in delineating the pathophysiology and developing treatment

options, ARDS still has a high mortality rate of 40% to 50% [5,42–44].

Significant impairment of surfactant production and composition has been

demonstrated in the lungs of patients with ARDS [4,5]. This impairment of

surfactant can result from inhibition, degradation, or decreased production. A

characteristic finding in ARDS is increased permeability of the microvasculature

leading to leakage of protein and fluid, which may inactivate surfactant by

dilution and competition for the interface [42]. Plasma proteins known to inhibit

surfactant function include serum albumin, globulin, fibrinogen, and C-reactive

protein. In addition to proteins, phospholipases A2 and C and their products can

inhibit surfactant activity in vitro, perhaps by disrupting lipid organization at the

interface [42,43]. Epithelial cell injury by inflammatory mediators may also

contribute to surfactant deficiency because of decreased surfactant production.

Surfactant is present in two subtypes, a LA fraction and an SA fraction in the

alveolar space. Under normal conditions in the lung, 80% to 90% of surfactant is

present in the LA fraction that is characterized by a high SP-B content and high

surface activity [4,5]. In ARDS, an increase in SA fraction has been found,

consistent with a loss of SP-B and surface activity in the LA fraction [5,47].

These small aggregates possess much less surface activity and represent degrada-

tion products. The mechanism for this imbalance in the distribution of the

subtypes is unknown. Potential mechanisms include decreased secretion of newly

synthesized or recycled material by type II cells, degradation of the LA by

inflammatory mediators, or increased conversion of large surfactant aggregates to

small surfactant aggregates [4,5,42,43,47].

The composition of surfactant is also altered in other ways during ARDS

[5,44–49]. Bronchoalveolar lavage fluid from patients with ARDS demonstrates

reduced phospholipid content, abnormal phospholipid composition, and reduced

DPPC to half the level of controls [44–49]. Surfactant protein A, SP-B, and SP-C,

were decreased in BAL fluid from patients with ARDS. In addition, SP-A and SP-B

levels remained low for at least 14 days after the onset of ARDS [5,44,46]. Changes

in surfactant composition of phospholipids, fatty acids, and proteins probably

represent alveolar type II cell injury with altered metabolism, secretion, or

recycling of components by these cells.

In a study by Greene and colleagues [44], SP-A and SP-B concentrations were

also reduced in the lungs of patients at risk for ARDS, even before the onset of

clinically defined lung injury, and remained low in patients who developed

ARDS. In contrast, SP-D levels in BAL fluid remained normal, except in a

subgroup of patients who later died. Patients who progressed to death had

decreased BAL levels of SP-D on days one and three of ARDS. Levels of SP-A

in BAL fluid were much lower in patients who developed ARDS and may serve

as a marker to identify patients at risk for ARDS. Another potential marker for


disease severity is SP-D; deficiencies in SP-D may correlate with more severe

epithelial injury in the lungs [44–49]. Decreased SP-D levels in BAL fluid were

85.7% sensitive and 74% specific in predicting death secondary to ARDS [44].

The discovery that surfactant protein levels correlate with the onset of ARDS,

disease severity, and mortality may be useful in the future for predicting the

course of ARDS [44–49].

Host defense properties of the lung may be impaired because of surfactant

alterations in ARDS. Surfactant protein A and SP-D, two pulmonary collectins,

are known to participate in host defense by binding microorganisms, enhancing

phagocytosis, stimulating macrophage functions, and modulating cytokine pro-

duction in the lungs [3,23]. Because SP-A and SP-D levels may be decreased in

ARDS, patients may be predisposed to secondary infections, further exacerbating

the lung disease. Alterations in surfactant lipids may also be important in host

defense of the lung. Surfactant lipids suppress immune cell functions, such as

activation and proliferation of macrophages and lymphocytes, and may promote

bacterial lysis [3,23]. Although the exact role of each surfactant component in

host defense is unknown, alterations in surfactant levels and composition may

affect the immune response in the lung.

Surfactant treatment for acute respiratory distress syndrome

Acute respiratory distress syndrome is still a significant therapeutic challenge

for intensivists despite recent advances in understanding pathophysiology and

new treatment modalities. It is well established that surfactant content and

composition are altered in ARDS, resulting in decreased surface activity that

manifests as atelectasis and decreased lung compliance [4,5,44–49]. In preterm

infants with acute respiratory distress syndrome, intratracheal surfactant replace-

ment greatly improves gas exchange and oxygenation [39–41]. In ARDS

administration of surfactant has been shown to improve gas exchange but to a

lesser degree than seen with respiratory distress syndrome [50–57]. Because

ARDS is characterized by surfactant inactivation rather than deficiency, the

presence of surfactant inhibitors such as plasma proteins and inflammatory

mediators can inactivate exogenous surfactant and may decrease the efficacy of

treatment [42,43]. Several recent pilot studies in adults and children have

examined the efficacy of surfactant therapy in ARDS [50–57]. Standardizing

the results of these studies has been difficult because of the use of different types

of surfactant, different dosages, and different methods of delivery.

Adults with ARDS treated with Survanta (Ross Products, Abbott Laboratories,

Columbus, OH), a natural bovine surfactant preparation, had significant improve-

ment in gas exchange and a trend toward decreasedmortality [50]. Spragg et al [51]

examined the efficacy of bronchoscopic administration of Alveofact, another

bovine surfactant preparation, in adult patients with ARDS [51]. A surfactant dose

of 300 mg/kg was delivered by flexible bronchoscope in divided doses to each lung

segment. Patients demonstrated improved gas exchange, recruitment of collapsed


alveoli, and improved V/Q mismatch as shown by multiple inert gas elimination

technique (MIGET). A phase II study in Europe recently examined the efficacy of

intratracheal administration of a recombinant SP-C preparation (Venticute, Byk

Gulden, Konstanz, Germany) in ARDS patients [52]. The patients were randomly

assigned to receive either standard therapy alone or standard therapy plus

recombinant SP-C surfactant at two different doses. The SP-C groups were

subdivided into mid-dosage groups, receiving 200 mg/kg in four doses or high-

dosage groups, receiving 500 mg/kg in four doses. The mid-dosage groups showed

significant improvement in oxygenation index and were weaned more rapidly from

the ventilator than the receiving standard therapy alone. The high-dosage group

was not different from the group receiving standard therapy alone. Mortality was

29% in the mid-dosage group and 33% in the group receiving standard therapy

alone. A phase III trial using this recombinant SP-C surfactant was recently

completed, and preliminary results did not show difference in mortality or in days

of mechanical ventilation [53].

Children with ARDS or acute lung injury were also treated with Infasurf (ONY,

Inc., Amherst, NY), a calf lung surfactant, resulting in improved oxygenation,

decreased ventilator days, and earlier discharge from the pediatric ICU [54]. In a

retrospective chart review of children with ARDS who received either Curosurf

(Chiesi Farmaceutici, Parma, Italy) or Alveofact, a single dose of 50 to 100 mg/kg

improved pulmonary function measured by oxygenation index and hypoxemia

score [55]. A second dose did not further improve lung function. In a separate

study, 20 pediatric patients with ARDS were treated with Curosurf with moderate

improvement in oxygenation [56]. Lotze and colleagues [57] found significant

improvement in oxygenation and a decreased need for extracorporeal membrane

oxygenation (ECMO) in a study of 328 full-term infants with respiratory failure

treated with four 100 mg/kg doses of Survanta [57].

In contrast with the studies showing benefit from surfactant treatment in

ARDS, Anzueto et al [58] did not report any significant benefit from aerosolized

Exosurf, a synthetic surfactant preparation, in a large study of 725 adult patients

with sepsis-induced ARDS. Delivery of Exosurf (Glaxo-Wellcome, Burgwedel,

Germany) was by aerosolization, however, which decreases the deposition of

surfactant in the airways. The authors report that only 4.5% of the surfactant

reached the lungs, yielding a dose of only 5 mg/kg, several magnitudes lower than

the dose used with beneficial effects in the other studies cited [50–58].

Summary

There is strong evidence that alterations in the pulmonary surfactant system

play an important role in the pathophysiology of lung disease, including ARDS

[27–41,45–49]. Although it is still unclear whether mortality and morbidity of

ARDS will be reduced, surfactant replacement therapy has been shown to

improve oxygenation, improve lung compliance, and decrease the need for

ventilatory support [50–52,54–56]. The critical need for more standardized


studies with one type of intratracheal surfactant and uniform measurements of

surfactant proteins and phospholipids by BAL is evident. Further studies will also

be needed to elucidate the optimal timing and dosage regimen for different

disease processes. Some evidence supports the measurements of surfactant

protein levels as markers for predicting the onset and outcome of ARDS and

perhaps providing a window for early treatment of patients at risk to develop

ARDS [44]. Continued investigation into the role of surfactant in the immune

regulation of the lung may also provide additional information to support the

efficacy of surfactant replacement in lung disease.

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Surfactant biology and clinical application

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