The acute respiratory distress syndrome (ARDS) is a frequent, life-threatening disease in which a marked increase in alveolar surface tension has been repeatedly observed. It is caused by factors including a lack of surface-active compounds, changes in the phospholipid, fatty acid, neutral lipid, and surfactant apoprotein composition, imbalance of the extracellular surfactant subtype distribution, inhibition of surfactant function by plasma protein leakage, incorporation of surfactant phospholipids and apoproteins into polymerizing fibrin, and damage/inhibition of surfactant compounds by inflammatory mediators. There is now good evidence that these surfactant abnormalities promote alveolar instability and collapse and, consequently, loss of compliance and the profound gas exchange abnormalities seen in ARDS. An acute improvement of gas exchange properties together with a far-reaching restoration of surfactant properties was encountered in recently performed pilot studies. Here we summarize what is known about the kind and severity of surfactant changes occuring in ARDS, the contribution of these changes to lung failure, and the role of surfactant administration for therapy of ARDS.
Acute respiratory distress syndrome
The acute respiratory distress syndrome (ARDS) describes an overwhelming inflammatory reaction within the pulmonary parenchyma leading to life-threatening disturbances in pulmonary vasomotion, alveolar ventilation, and gas exchange. Originally, this syndrome was described in 1967 by Ashbaugh and collegues . According to the recent American–European Consensus Conference , ARDS is defined by an acute onset (catastrophic event), an oxygenation index (ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen [PaO2/FiO2 ]) < 200 mmHg, bilateral infiltrates on chest radiography, and a pulmonary capillary wedge pressure <18 mmHg or absence of clinical evidence for left-sided heart failure. When the PaO2/FiO2 ratio is between 200 and 300 mmHg and the other above-mentioned criteria are met, the term 'acute lung injury' (ALI) should be used instead of ARDS. ARDS is a frequent disease (incidence between 13.5  and 75 per 100,000 ), thus affecting about 16–18% of all patients ventilated in the intensive care unit . Despite recent progress in the understanding of the disease and numerous efforts to develop causative or symptomatic treatment options, ARDS still has a high mortality rate of about 30–40% .
ARDS may develop after a direct injurious attack on the lung parenchyma (direct ARDS) or may result from inflammatory processes carried into the lung via the pulmonary vasculature (indirect, 'classic' ARDS; see Supplementary Table 1). Inhaled or aspirated noxious agents, e.g. toxic gases or gastric contents, induce an inflammatory response in the epithelial and later the interstitial and endothelial compartments of the lung. On the other hand, numerous systemic disorders may induce an overwhelming inflammatory response that may be transferred to the lungs via cellular and humoral mediators entering the pulmonary circulation . One such trigger mechanism is sepsis, leading to respiratory distress in about 43% of these sepsis patients .
In the early, exudative, phase of ARDS, the massive, self-perpetuating inflammatory process involves the entire gas exchange unit (see Supplementary Fig. 1). Pathophysiologically, this phase has four characteristics: an increase in capillary endothelial and/or alveolar epithelial permeability; leakage of plasma protein, with flow of edematous fluid into the interstitial and, later, the alveolar spaces; vasoconstriction and microembolism or microthrombosis in the vascular compartment, and thus increased pulmonary vascular resistance, with maldistribution of pulmonary perfusion; and an increase in alveolar surface tension favoring alveolar instability with formation of atelectasis and ventila-tory inhomogeneities. As a consequence, a profound ventilation/perfusion (V/Q) mismatch, with extensive intrapulmonary shunt flow and highly impaired gas exchange, is regularly seen. This exudative phase may persist for about a week, during which full recovery without persistent loss of lung function is very possible  (see Supplementary Fig. 1). However, new inflammatory events, such as recurrent sepsis or acquisition of secondary (nosocomial) pneumonia, may repetitively worsen the state of lung function and then progressively favor proliferative processes characterized by mesenchymal cell activation and ongoing lung fibrosis  (see Supplementary Fig. 1). Fibroproliferative events such as increased collagen matrix production occur early in the course of ARDS (about 5 to 7 days after the onset ) and may lead to irreversible, restrictive abnormalities of lung function. In addition, the development of pulmonary fibrosis and deposition of extracellular collagen in the alveolar space correlates with an increased risk of death in ARDS [11,12] (see Supplementary Fig. 1).
Pulmonary surfactant system
Pulmonary surfactant is a lipoprotein complex covering the alveolar surface of all mammalian lungs . By profoundly reducing the surface tension at the air–water interface, it makes alveolar ventilation and gas exchange feasible at physiologic transpulmonary pressures and prevents alveoli from collapsing, in particular during expiration.
Pulmonary surfactant consists of about 90% lipids and about 10% proteins. Of the lipids, about 10–20% are neutral. The rest (80–90%) are phospholipids (PLs), of which about 80% are phosphatidylcholine, which contains an unusually large amount of palmitic acid residues (about 50–60% of all phosphatidylcholine molecules are dipalmitoylated [DPPC]) and about 10% are phosphatidylglycerol. Other PLs regularly found in low percentages are phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and sphingomyelin.
Four surfactant-specific apoproteins have been discovered so far, called surfactant apoprotein (SP)-A, SP-B, SP-C , and SP-D . SP-B and SP-C are extremely hydrophobic, low-molecular-weight proteins, whereas SP-A and SP-D are hydrophilic, high-molecular-weight proteins belonging to the family of collectins (C-type lectins). Upon the inspiratory stretch of the alveolar cell layer, alveolar type II pneumocytes secrete surfactant-containing lamellar bodies into the alveolar hypophase, which are then reorganized into the highly surface-active tubular myelin  and large, multilamellar vesicles. Lamellar bodies, tubular myelin, and large, multilamellar vesicles are called large surfactant aggregates (LAs). Adsorption of PLs to the air–water interface results in the formation of a stable PL film. During breathing, when the surface film is compressed and re-expanded, film compounds are squeezed out, leading to a dense packing of 'rigid' lipid material such as DPPC and thus to extremely low surface tension values (near 0 mN/m). Next to DPPC and phosphatidylglycerol, the hydrophobic apoproteins SP-B and SP-C seem to play an essential role for these adsorption facilities and dynamic surface-tension-lowering properties . Additional functions of the alveolar surfactant system include prevention of alveolar edema  and a pronounced influence, especially of the collectins SP-A and SP-D, on pulmonary host defense mechanisms (reviewed [18,19]).
Surfactant deficiency has been established as the primary cause of the respiratory failure in infant respiratory distress syndrome (IRDS) , and transbronchial application of surfactant preparations has become the gold standard for the treatment of this disorder . In ARDS, however, surfactant deficiency seems not to be of major importance; rather, a broad spectrum of biochemical and biophysical surfactant abnormalities contributes to respiratory failure.
Alteration of the pulmonary surfactant system in acute respiratory distress syndrome
The first, indirect, evidence of a severe impairment of surfactant function in ARDS was provided in 1979 by Petty and co-workers, who examined lungs from patients who had died from respiratory failure . In more recent studies, using bronchoalveolar lavage fluid (BALF) from ARDS patients, impairment of the surface-tension-lowering properties was consistently noted [23,24,25,26], with minimum surface tension values being increased to 15–20 mN/m, instead of <5 mN/m as observed in healthy volunteers (Fig. 2). Similarly elevated values were found for surfactant samples obtained from patients at risk of ARDS . Unlike the case in IRDS, in which the initial lack of surface-active material triggers the pathophysiologic sequelae, more complex changes of the biophysical and biochemical surfactant properties were noticed: these included alteration of the PL and fatty acid profile, decreased levels of surfactant apoproteins, reduced content of LA, inhibition of surfactant function by leaked plasma proteins, and inhibition by inflammatory mediators.
Lack of surface-active compounds and alteration of phospholipid, fatty acid, and apoprotein profiles
Clinical studies addressing the PL composition of BALF samples from patients with ARDS [23,24,25,26] revealed three important features (Table 1). Firstly, in two of four studies, the overall PL content was reduced. Secondly, a significant change in the relative distribution of the PL classes was noted throughout, including a marked decrease in phosphatidylglycerol levels (by >80% in three of the studies) and a compensatory increase in the relative amounts of the minor components (phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, sphin-gomyelin). However, phosphatidylcholine, the most abundant PL, was reduced only moderately throughout the studies. Thirdly, the relative amount of palmitic acid, the major fatty acid of phosphatidylcholine, was significantly decreased, to about 80% of control values, whereas the relative amount of unsaturated fatty acids in this PL was increased . The relative amount of DPPC, the most abundant single surfactant component, was dramatically reduced (to half that in controls).
Because of the late detection of surfactant apoproteins and – in the case of SP-B and SP-C – their extreme hydrophobic nature, appropriate analytical techniques for the quantification of these essential compounds under clinical conditions have only recently become available. Four studies measuring them in patients with ARDS demonstrated an impressive decline of SP-A, but not of SP-D [24,25,26,28] (Table 2). Concentrations of SP-B and SP-C were markedly reduced in the original BALF from ARDS patients  and particularly within the LA fraction [25,29]. SP-A and SP-B levels remained depressed for at least 14 days after the onset of ARDS . Interestingly, a decrease of these functionally important compounds was also observed in patients at risk for ARDS [25,28] (see Table 2).
The reported changes of the biochemical surfactant composition (PLs, fatty acids, apoproteins) in ARDS are likely to reflect injury of alveolar type II cells, with consequently altered metabolism or secretion of lipid and apoprotein by these cells.
Altered distribution of surfactant subtypes
Under physiologic conditions, some 80–90% of the extra-cellular surfactant material is recovered in the LA fraction that is characterized by a high SP-B content and excellent surface activity. However, in experimental lung injury  and in acute inflammatory lung diseases (severe pneumonia, ARDS) [26,29,31], an increase of small surfactant aggregates is is paralleled by a loss of SP-B and surface activity within the LA fraction. These small aggregates are far less surface-active and are considered to represent degradation products of the interfacial film.
The underlying reason for this imbalance in the distribution of surfactant subtypes is poorly understood. Decreased secretion of freshly synthesized or recycled surfactant material by alveolar type II cells, degradation of LAs due to inflammatory mediators, and accelerated large-to-small surfactant aggregate conversion are offered as putative mechanisms. Concerning the latter, the requirement of an enzymatic activity was proposed on the basis of inhibitor studies employing serine protease inhibitors . A diisopropylfluorophosphate-binding protein, later named 'convertase', was isolated from BALF, purified, and characterized as a member of the carboxylesterase family [33,34]. The physiologic substrate of the esterase, however, is presently unknown. Because of the broad substrate specificity of carboxylesterases, lipids and proteins could both be targets. The assumption that DPPC, the most abundant and biophysically most important PL, is the substrate was recently disproved . Other data suggest that SP-B may be a candidate for the convertase attack, thereby promoting LA conversion [29,36]. At present, there is no information available as to the regulation of the convertase in acute or chronic inflammatory lung diseases (see Supplementary Fig. 3).
Inhibition of surfactant function by plasma protein leakage
Leakage of plasma proteins into the alveolar space because of impaired function of the air–blood barrier consisting of capillary endothelium and alveolar epithelium is a very early event in the pathogenesis of ARDS and may substantially contribute to surfactant alterations in ARDS. Experimental studies in vitro and in vivo have shown that admixture of blood, serum, plasma, or alveolar washings obtained during states of plasma leakage may severely compromise biophysical surfactant function. Among the proteins involved, albumin [37,38,39], hemoglobin , and in particular fibrinogen or fibrin monomers [37,38,39,41,42] possess strong surfactant inhibitory properties. These studies also showed that the degree of inhibition of surfactant function by fibrinogen depends on the surfactant apoprotein profile. Surfactant preparations lacking the hydrophobic apoproteins are extremely sensitive to fibrinogen inhibition, and less sensitivity is noted in the presence of SP-B and SP-C in near-physiologic quantities [42,43]. In addition, further improvement in protein resistance is achieved by supplementation of PL- and hydrophobic-apoprotein-based surfactants with SP-A .
Incorporation of surfactant in fibrin/hyaline membranes
Accumulation of fibrin-rich material ('hyaline membranes') is commonly found in ARDS and other acute or chronic interstitial lung diseases [10,44,45]. In acute or chronic inflammatory conditions, the alveolar hemostatic balance is shifted towards predominance of a procoagulant activity, which is almost exclusively attributable to tissue factor and factor VII [46,47,48]. In contrast, the fibrinolytic activity of the alveolar space was found to be markedly reduced in these conditions, with reduced concentrations of urokinase, the predominant plasminogen activator in this compartment [46,48,49], but elevated activities of plasminogen activator inhibitor 1 (PAI-1) and α2-antiplasmin [46,47,49]. Hence, rapid fibrin formation is to be expected under these conditions. Recently, this group demonstrated loss of surfactant PLs from the soluble phase due to binding to or within fibrin strands when fibrin polymerized in the presence of surfactant material; this loss was paralleled by a virtually complete loss of surface activity  (Fig. 4). By this mechanism, the surfactant-inhibitory capacity of polymerizing fibrin was found to surpass that of soluble fibrin monomers or fibrinogen by more than two orders of magnitude, thus representing the most effective surfactant inhibitory mechanism hitherto described for plasma proteins. Overall, the findings obviously suggest that PLs and hydrophobic apoproteins are incorporated into the growing fibrin matrix, with severe loss of biophysically important surfactant compounds in areas with alveolar fibrin and hyaline membrane formation. In addition, fibrin clots embedding natural surfactant display markedly altered mechanical properties  and reduced susceptibility to proteolytic degradation . Surface activity can be largely restored by application of fibrinolytic agents in vitro  and in vivo , with the release of formerly incorporated surfactant material into the soluble phase (see Fig. 4).
Damage of surfactant compounds by inflammatory mediators
A complex network of humoral or cellular effector systems contributes to the inflammatory response in ARDS. Proinflammatory mediators may be produced locally in the alveolar compartment by activated neutrophils and macrophages, lung epithelial cells, or fibroblasts. Free elastase and collagenase activities [55,56], oxidative inhibition of the alveolar α1-proteinase inhibitor indicating oxygen radical generation, and increased levels of lysophospholipids (in particular lysophosphatidylcholine)  suggesting increased phospholipolytic activity have been encountered in BALF from patients with ARDS. Degradation of SP-A in BALF from ARDS patients was recently observed , indicating a high proteolytic activity in the alveolar compartment under inflammatory conditions. In addition, as summarized in Table 3, a variety of in vitro studies demonstrated a direct surfactant inhibitory effect for various mediators.
Pathophysiologic consequences of surfactant alterations in acute respiratory distress syndrome
As described above, severe alterations of the pulmonary surfactant system have been observed in the course of ARDS, favoring an increase in alveolar surface tension. Thus, the question arises, whether and to what extent these surfactant abnormalities contribute to pathophysiologic events encountered in ARDS.
Alteration in lung mechanics
Loss of surface activity leading to an increased alveolar surface tension is assumed to cause alveolar instability and atelectasis. According to the law of Laplace (p = 2 × γ × r-1; where p = pressure, γ = surface tension, and r = radius), an increase in surface tension should result in a marked decrease of lung compliance. This basic finding was described in early reports of altered lung mechanics in patients who died with ARDS . In addition, a marked decrease in compliance was observed in a variety of experimental animal models of ARDS, including disorders induced by administration of oleic acid, N-nitroso-N-methylurethane, or hydrochloric acid, by experimental induction of pneumonia or sepsis, and by repetitive lung lavage [58,59,60,61,62,63,64]. Transbronchial application of surfactant completely or partially restored physiologic lung compliance in some of these models. In patients with severe ARDS, however, lung compliance is still difficult to measure reliably, mostly because of uncertainties concerning lung volume and transpulmonary pressures.
Impairment of gas exchange: V/Q mismatch and shunt flow
In preterm babies with IRDS, where a lack of surface-active material triggers the pathophysiologic sequelae, transbronchial surfactant replacement dramatically improves gas exchange and arterial oxygenation . In experimental removal of endogenous surfactant from the lung (repetitive lavage models)  or surfactant inactivation with detergent , gas exchange properties deteriorated severely, and transbronchial application of exogenous surfactant material restored gas exchange and improved V/Q matching.
In more realistic models of ARDS, starting with induction of microvascular or alveolar injury, matters are more complex. Shunt flow (perfusion of atelectatic regions) and blood flow through lung areas with low V/Q ratios (dystelectatic lung regions) may well be related to an acute impairment of the alveolar surfactant system. Transbronchial surfactant application was found to improve gas exchange in models with protein-rich edema formation due to cervical vagatomy , hydrochloric acid aspiration [58,60], pneumonia [63,64], and application of N-nitroso-N-methylurethane  or oleic acid . The most obvious explanation for this improvement under experimental and also clinical conditions is the recruitment of formerly collapsed lung regions, with reduction of shunt flow and of V/Q mismatch . However, in these models in which lung inflammation is induced, the efficacy of surfactant replacement is less impressive than in IRDS or IRDS-like models, in which the surfactant depletion is primary. The difference is most likely due to the presence of surfactant-inhibitory agents including leaked plasma proteins and inflammatory mediators, as discussed above. Much larger amounts of exogenous surfactant are needed to overcome such inhibitory capacities.
Formation of lung edema
The importance of both epithelial and endothelial injury in the development of alveolar edema has been established. Surfactant alterations, however, also may contribute to the edema. Any increase in surface tension may result in a decrease in interstitial and thus perivascular pressures. Transendothelial and, later, transepithelial fluid movement into the interstitial and, later, alveolar space may increase. Several experimental studies described formation of extensive lung edema due to inhibition of surfactant function in vivo by transbronchially applied detergent , intratra-cheally injected bile acid , cooling and ventilating at low functional residual capacity , or plasma lavage . In some of the studies, transbronchially applied surfactant reduced alveolar flooding . Concerning patients with ARDS, however, there is at present no conclusive evidence that surfactant abnormalities affect lung fluid balance in patients with ARDS.
Reduction in host defense competence?
Nosocomial infection/ventilator-associated pneumonia is a common complication of ARDS (incidences range from 36.5% to 60%) that adversely affects the prognosis [72,73]. As pulmonary surfactant participates in the alveolar host defense system, alterations of the surfactant system may contribute to an increased susceptibility of these patients to secondary lung infection. At present, the host defense properties of pulmonary surfactant are not fully understood. Suggested mechanisms include direct interaction of surfactant components with pathogens (viruses, bacteria) or their products (e.g. endotoxin, viral glycoproteins); stimulation of phagocytosis by surfactant components (as an opsonin or active ligand); influence of the chemotaxis of immune-competent cells; and regulation of cytokine release and reactive oxygen production by macrophages (reviewed ). The hydrophilic surfactant apoproteins SP-A and SP-D have distinct functions in the innate immune response to microbial challenge. Studies with SP-A knockout mice revealed that these animals are more sensitive to infection with Haemophilus influenzae group B streptococci and Pseudomonas aeruginosa . In addition, the surfactant lipids suppress a variety of immune cell functions, including activation, proliferation, and immune response of lymphoctes, granulocytes, and alveolar macrophages [75,76] and can even promote bacterial lysis .
Changes in the protein and/or lipid composition of surfactant may thus effect immunomodulation in the lung. As indicated above, the exact contribution of each surfactant component to the alveolar host defense system remains uncertain. Nevertheless, the marked decrease in SP-A levels [24,25,26,28] and the proof of degradation of SP-A in vivo in the lungs of ARDS patients  suggest a loss of opsonizing capacity and increased susceptibilty to nosocomial infections.
'Collapse induration', mesenchymal cell proliferation, and fibrosis
During the acute phase of ARDS, full recovery without persistent loss of lung function is possible . However, some patients progress to a fibroproliferative phase, characterized by mesenchymal cell activation and proliferation, with synthesis of extracellular matrix components such as collagen, formation of new blood vessels, and bronchiolization . Within a few weeks, structural remodelling of the lung leads to widespread lung fibrosis and honeycombing. The onset of the fibroproliferative response is an early event in ARDS [78,79] and correlates with the outcome. The pathologic mechanisms underlying such a rapid fibroproliferative response to an acute inflammatory event have not been fully elucidated. In addition to inflammatory cells , cytokines [81,82] and growth factors (in particular transforming growth factor β ), abnormalities of the pulmonary surfactant system, and deposition of fibrin in the alveoli may contribute to the development of fibrosis and honeycombing (Fig. 4). According to the concept of 'collapse induration' as suggested by Burkhardt , lung fibrosis preferentially occurs at sites of persistent atelectasis due to extensive loss of alveolar surfactant function and to 'glueing' of adjacent septae by generation of alveolar fibrin. This specialized alveolar fibrin matrix serves as a nidus for fibroblast invasion, resulting in the deposition of excess extracellular matrix and irreversible loss of alveolar space. Thick, indurated septae (or conglomerates of several septae) may exist adjacent to dilated alveoli, providing the typical morphological image of fibrosis and honeycombing . Additionally, thrombin [84,85], fibrinopeptides A/B , and fibrin(ogen) scission products  have been shown to serve as potent fibroblast mitogens.
Surfactant replacement in acute respiratory distress syndrome
Against this background of surfactant abnormalities and their contribution to the pathophysiology of ARDS, improvement of alveolar surfactant function appears to be a reasonable approach to restore gas exchange properties and lung compliance. Such attempts may include pharmacological approaches to stimulate secretion of intact surfactant material from type II cells, protection from degradation of surfactant compounds, and inhibition of large-to-small aggregate conversion, but evidence that these approaches are effective in acute respiratory failure is still lacking. As in IRDS, transbronchial application of exogenous surfactant may be used in ARDS to restore surfactant function in inflamed lungs, but larger quantities may be needed to overcome the inhibitory (proteinaceous) burden in the alveolar compartment. A further rationale for such an approach is provided by various animal models of acute lung injury in which treatment with surfactant improved gas exchange and outcome. So far, six pilot studies addressing the safety and efficacy of transbronchial surfactant administration in ARDS have been completed (Table 4).
Upon repeated intratracheal administration of Survanta®, a natural bovine surfactant preparation, with cumulative doses between 400 and 800 mg/kg body weight (b.w.), Gregory et al. noted significant improvement in gas exchange and obtained a trend towards reduced mortality in adults with acute respiratory failure . BALF analysis revealed partially improved surfactant functions.
The safety and efficacy of a bronchoscopic application of another bovine surfactant preparation (Alveofact®) were studied in 10 patients with severe, sepsis-induced ARDS, in an uncontrolled, multicenter study . The surfactant, 300 mg/kg b.w., was delivered through a flexible bronchoscope in divided doses to each segment of the lung. In response to the first administration, the PaO2/FiO2 increased from 85 to 200 mmHg (Fig. 5). In some patients, this improvement in gas exchange was already evident during the application procedure (Fig. 6). Analysis of V/Q characteristics (multiple inert gas elimination technique, MIGET) revealed that treatment resulted in recruitment of formerly collapsed alveoli, reducing the intrapulmonary shunt flow (from 41.7% at baseline to 19.8% post surfactant) and increasing blood flow through regions with low and normal V/Q ratios. Patients in whom the initial increase in PaO2/FiO2 was partially lost received a second, smaller, dose of surfactant, resulting in prolonged improvement of arterial oxygenation. In addition, the treatment produced a far-reaching, though incomplete, restoration of the severely altered biochemical and biophysical surfactant properties.
In a more recent, phase II, study in Europe and South Africa, the feasibility and efficacy of a tracheal application of a surfactant preparation based on recombinant SP-C (Venticute®) was studied in patients with ARDS . Patients were randomized to receive either standard therapy alone (STD group) or standard therapy plus recombinant SP-C surfactant (MID group, up to 200 mg/kg total PL, in four doses; HIGH group, up to 500 mg/kg total PL, in four doses). The MID group showed marked improvements in the oxygenation index (mean PaO2/FiO2 184, vs 139 mmHg in STD), ventilator-free days (mean 10.9, vs 1.8 in STD), and percentage of successfully weaned patients (57, vs 25 in STD). Finally, mortality was 29% in the MID and 33% in the STD group. No differences were observed between the HIGH and STD groups. Very recently, a phase III trial using this recombinant SP-C-based surfactant was finished. Astonishingly, surfactant treatment did not result in a significant reduction of ventilator-free days or mortality (28 days). However, the detailed analysis of this study is not completed yet.
In another controlled, randomized, unblinded study, the efficacy of a calf-lung surfactant extract (Infasurf®) was investigated in 42 children with acute respiratory failure , most of them fulfilling ARDS criteria. A rapid improvement in oxygenation, reduced duration of mechanical ventilation, and an earlier discharge from the pediatric intensive care unit was observed in the surfactant group.
In contrast to these studies, Anzueto and collegues  found no benefit from an aerosol of a synthetic surfactant preparation (Exosurf®) in a large, randomized, placebo-controlled study enrolling 725 patients with sepsis-induced ARDS. However, there are important criticisms. Firstly, the aerosolization technique used did not ascertain a pulmonary deposition of suitably large amounts of surfactant. As measured by the authors themselves, only 4.5% of the applied material reached the lungs, thus yielding a daily dose of 5 mg/kg b.w. This dose is two orders of magnitude below that possibly effective under conditions of a high alveolar protein burden  in ARDS and one order of magnitude below that currently used in IRDS. Secondly, Exosurf® is a fully synthetic surfactant preparation lacking the hydrophobic apoproteins. Apoprotein-free surfactant preparations have been repeatedly shown to be less effective in animal studies and IRDS  than natural surfactant preparations and are extremely prone to inhibition by plasma proteins . In addition, in an attempt to withdraw the inhibitory plasma proteins from the alveolar space, Wiswell and colleagues performed a broncho-alveolar segmental lavage in 12 ARDS patients. For this purpose surfactant based on a synthetic peptide (KL4), mimicking SP-B, was used. In essence, the authors observed an improvement of oxygenation status and positive end-expiratory pressure (PEEP) level after 72 hours. However, the lavage procedure resulted in a temporary (24 hour) deterioration of gas exchange and a need for higher PEEP levels. These early deleterious effects were as pronounced as the later beneficial effects .
There is good evidence that severe abnormalities of the pulmonary surfactant system in ARDS contribute to the pathophysiologic sequelae of the disease. Transbronchial application of exogenous surfactant material may offer a feasible and safe approach to improve gas exchange in ARDS and to restore biochemical and biophysical properties of the endogenous surfactant pool. However, a high or repetitive dosage regimen seems needed to overcome the inhibitory capacities of the inflamed alveolar space and to achieve a prolonged recruitment of formerly collapsed lung regions. Further studies will be needed to elucidate the optimum timing, dosage regimen, and application technique, and to establish whether such therapy can reduce mortality in patients with ARDS. Furthermore, the impact of surfactant on inflammation, host defense, and the fibroproliferative response in the alveolar compartment will have to be addressed critically.
acute respiratory distress syndrome
bronchoalveolar lavage fluid
fraction of inspired oxygen
- γ min:
minimum surface tension after 5 min of film oscillation
infant respiratory distress syndrome
large surfactant aggregate
partial pressure of arterial oxygen
surfactant apoprotein A/B/C/D
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE: Acute respiratory distress in adults. Lancet. 1967, 2: 319-323.
Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R: The American–European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994, 149: 818-824.
Luhr OR, Antonsen K, Karlsson M, Aardal S, Thorsteinsson A, Frostell CG, Bonde J: Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir Crit Care Med. 1999, 159: 1849-1861.
Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med. 2000, 342: 1334-1349.
The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000, 342: 1301-1308.
Seeger W, Lasch HG: Septic lung. Rev Infect Dis. 1987, 9 (suppl): S570-S579.
Hudson LD, Milberg JA, Anardi D, Maunder RJ: Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995, 151: 293-301.
McHugh LG, Milberg JA, Whitcomb ME, Schoene RB, Maunder RJ, Hudson LD: Recovery of function in survivors of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1994, 150: 90-94.
Fukuda Y, Ishizaki M, Masuda Y, Kimura G, Kawanami O, Masugi Y: The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. Am J Pathol. 1987, 126: 171-182.
Bachofen M, Weibel ER: Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med. 1982, 3: 35-56.
Martin C, Papazian L, Payan MJ, Saux P, Gouin F: Pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome. A study in mechanically ventilated patients. Chest. 1995, 107: 196-200.
Chesnutt AN, Matthay MA, Tibayan FA, Clark JG: Early detection of type III procollagen peptide in acute lung injury. Pathogenetic and prognostic significance. Am J Respir Crit Care Med. 1997, 156: 840-845.
Creuwels LA, van Golde LM, Haagsman HP: The pulmonary surfactant system: biochemical and clinical aspects. Lung. 1997, 175: 1-39.
Possmayer F: A proposed nomenclature for pulmonary surfactant-associated proteins. Am Rev Respir Dis. 1988, 138: 990-998.
Persson A, Chang D, Rust K, Moxley M, Longmore W, Crouch E: Purification and biochemical characterization of CP4 (SP-D), a collagenous surfactant-associated protein. Biochemistry. 1989, 28: 6361-6367.
Williams MC, Hawgood S, Hamilton RL: Changes in lipid structure produced by surfactant proteins SP-A, SP-B, and SP-C. Am J Respir Cell Mol Biol. 1991, 5: 41-50.
Nieman GF, Bredenberg CE: High surface tension pulmonary edema induced by detergent aerosol. J Appl Physiol. 1985, 58: 129-136.
Wright JR: Immunomodulatory functions of surfactant. Physiol Rev. 1997, 77: 931-962.
Crouch E, Wright JR: Surfactant proteins A and D and pulmonary host defense. Annu Rev Physiol. 2001, 63: 521-524.
Jobe AH: Pulmonary surfactant therapy. N Engl J Med. 1993, 328: 861-868.
Soll RF: Clinical trials of surfactant therapy in the newborn. In Surfactant Therapy for Lung Disease. Edited by Robertson B, Taeusch HW. New York: Marcel Dekker,. 1995, 407-442.
Petty TL, Silvers GW, Paul GW, Stanford RE: Abnormalities in lung elastic properties and surfactant function in adult respiratory distress syndrome. Chest. 1979, 75: 571-574.
Hallman M, Spragg R, Harrell JH, Moser KM, Gluck L: Evidence of lung surfactant abnormality in respiratory failure. Study of bronchoalveolar lavage phospholipids, surface activity, phospholipase activity, and plasma myoinositol. J Clin Invest. 1982, 70: 673-683.
Pison U, Seeger W, Buchhorn R, Joka T, Brand M, Obertacke U, Neuhof H, Schmit Neuerburg KP: Surfactant abnormalities in patients with respiratory failure after multiple trauma. Am Rev Respir Dis. 1989, 140: 1033-1039.
Gregory TJ, Longmore WJ, Moxley MA, Whitsett JA, Reed CR, Fowler AA, Hudson LD, Maunder RJ, Crim C, Hyers TM: Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome. J Clin Invest. 1991, 88: 1976-1981.
Günther A, Siebert C, Schmidt R, Ziegler S, Grimminger F, Yabut M, Temmesfeld B, Walmrath D, Morr H, Seeger W: Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema. Am J Respir Crit Care Med. 1996, 153: 176-184.
Schmidt R, Meier U, Yabut-Perez M, Walmrath D, Grimminger F, Seeger W, Günther A: Alteration of fatty acid profiles in different pulmonary surfactant phospholipids in acute respiratory distress syndrome and severe pneumonia. Am J Respir Crit Care Med. 2001, 163: 95-100.
Greene KE, Wright JR, Steinberg KP, Ruzinski JT, Caldwell E, Wong WB, Hull W, Whitsett JA, Akino T, Kuroki Y, Nagae H, Hudson LD, Martin TR: Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med. 1999, 160: 1843-1850.
Günther A, Schmidt R, Feustel A, Meier U, Pucker C, Ermert M, Seeger W: Surfactant subtype conversion is related to loss of surfactant apoprotein B and surface activity in large surfactant aggregates. Experimental and clinical studies. Am J Respir Crit Care Med. 1999, 159: 244-251.
Lewis JF, Veldhuizen R, Possmayer F, Sibbald W, Whitsett J, Qanbar R, McCaig L: Altered alveolar surfactant is an early marker of acute lung injury in septic adult sheep. Am J Respir Crit Care Med. 1994, 150: 123-130.
Veldhuizen RA, McCaig LA, Akino T, Lewis JF: Pulmonary surfactant subfractions in patients with the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995, 152: 1867-1871.
Gross NJ, Schultz RM: Serine proteinase requirement for the extra-cellular metabolism of pulmonary surfactant. Biochim Biophys Acta. 1990, 1044: 222-230.
Krishnasamy S, Gross NJ, Teng AL, Schultz RM, Dhand R: Lung "surfactant convertase" is a member of the carboxylesterase family. Biochem Biophys Res Commun. 1997, 235: 180-184. 10.1006/bbrc.1997.6719.
Krishnasamy S, Teng AL, Dhand R, Schultz RM, Gross NJ: Molecular cloning, characterization, and differential expression pattern of mouse lung surfactant convertase. Am J Physiol. 1998, 275: L969-L975.
Dhand R, Young J, Teng A, Krishnasamy S, Gross NJ: Is dipalmi-toylphosphatidylcholine a substrate for convertase?. Am J Physiol Lung Cell Mol Physiol. 2000, 278: L19-L24.
Veldhuizen RA, Hearn SA, Lewis JF, Possmayer F: Surface-area cycling of different surfactant preparations: SP-A and SP-B are essential for large-aggregate integrity. Biochem J. 1994, 300: 519-524.
Seeger W, Stöhr G, Wolf HR, Neuhof H: Alteration of surfactant function due to protein leakage: special interaction with fibrin monomer. J Appl Physiol. 1985, 58: 326-338.
Fuchimukai T, Fujiwara T, Takahashi A, Enhorning G: Artificial pulmonary surfactant inhibited by proteins. J Appl Physiol. 1987, 62: 429-437.
Cockshutt AM, Weitz J, Possmayer F: Pulmonary surfactant-associated protein A enhances the surface activity of lipid extract surfactant and reverses inhibition by blood proteins in vitro. Biochemistry. 1990, 29: 8424-8429.
Holm BA, Notter RH: Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity. J Appl Physiol. 1987, 63: 1434-1442.
Seeger W, Thede C, Günther A, Grube C: Surface properties and sensitivity to protein-inhibition of a recombinant apoprotein C-based phospholipid mixture in vitro-comparison to natural surfactant. Biochim Biophys Acta. 1991, 1081: 45-52.
Seeger W, Günther A, Thede C: Differential sensitivity to fibrinogen inhibition of SP-C- vs. SP-B-based surfactants. Am J Physiol. 1992, 262: L286-L291.
Venkitaraman AR, Baatz JE, Whitsett JA, Hall SB, Notter RH: Biophysical inhibition of synthetic phospholipid-lung surfactant apoprotein admixtures by plasma proteins. Chem Phys Lipids. 1991, 57: 49-57.
Burkhardt A: Alveolitis and collapse in the pathogenesis of pulmonary fibrosis. Am Rev Respir Dis. 1989, 140: 513-524.
Chapman HA, Allen CL, Stone OL: Abnormalities in pathways of alveolar fibrin turnover among patients with interstitial lung disease. Am Rev Respir Dis. 1986, 133: 437-443.
Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, Martin TR, McLarty J, Fair DS: Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest. 1989, 84: 695-705.
Idell S, Koenig KB, Fair DS, Martin TR, McLarty J, Maunder RJ: Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome. Am J Physiol. 1991, 261: L240-L248.
Günther A, Mosavi P, Heinemann S, Ruppert C, Muth H, Markart P, Grimminger F, Walmrath D, Temmesfeld Wollbrück B, Seeger W: Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. Comparison with the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2000, 161: 454-462.
Bertozzi P, Astedt B, Zenzius L, Lynch K, LeMaire F, Zapol W, Chapman HA: Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med. 1990, 322: 890-897.
Seeger W, Elssner A, Günther A, Krämer HJ, Kalinowski HO: Lung surfactant phospholipids associate with polymerizing fibrin: loss of surface activity. Am J Respir Cell Mol Biol. 1993, 9: 213-220.
Günther A, Kalinowski M, Rosseau S, Seeger W: Surfactant incorporation markedly alters mechanical properties of a fibrin clot. Am J Respir Cell Mol Biol. 1995, 13: 712-718.
Günther A, Kalinowski M, Elssner A, Seeger W: Clot-embedded natural surfactant: kinetics of fibrinolysis and surface activity. Am J Physiol. 1994, 267: L618-L624.
Günther A, Markart P, Kalinowski M, Ruppert C, Grimminger F, Seeger W: Cleavage of surfactant-incorporating fibrin by different fibrinolytic agents. Kinetics of lysis and rescue of surface activity. Am J Respir Cell Mol Biol. 1999, 21: 738-745.
Schermuly RT, Günther A, Ermert M, Ermert L, Ghofrani HA, Weissmann N, Grimminger F, Seeger W, Walmrath D: Conebulization of surfactant and urokinase restores gas exchange in perfused lungs with alveolar fibrin formation. Am J Physiol Lung Cell Mol Physiol. 2001, 280: L792-L800.
Christner P, Fein A, Goldberg S, Lippmann M, Abrams W, Weinbaum G: Collagenase in the lower respiratory tract of patients with adult respiratory distress syndrome. Am Rev Respir Dis. 1985, 131: 690-695.
Lee CT, Fein AM, Lippmann M, Holtzman H, Kimbel P, Weinbaum G: Elastolytic activity in pulmonary lavage fluid from patients with adult respiratory-distress syndrome. N Engl J Med. 1981, 304: 192-196.
Baker CS, Evans TW, Randle BJ, Haslam PL: Damage to surfactant-specific protein in acute respiratory distress syndrome. Lancet. 1999, 353: 1232-1237.
Lamm WJ, Albert RK: Surfactant replacement improves lung recoil in rabbit lungs after acid aspiration. Am Rev Respir Dis. 1990, 142: 1279-1283.
Lewis J, Ikegami M, Higuchi R, Jobe A, Absolom D: Nebulized vs. instilled exogenous surfactant in an adult lung injury model. J Appl Physiol. 1991, 71: 1270-1276.
Strohmaier W, Redl H, Schlag G: Studies of the potential role of a semisynthetic surfactant preparation in an experimental aspiration trauma in rabbits. Exp Lung Res. 1990, 16: 101-110.
Zelter M, Escudier BJ, Hoeffel JM, Murray JF: Effects of aerosolized artificial surfactant on repeated oleic acid injury in sheep. Am Rev Respir Dis. 1990, 141: 1014-1019.
Lewis JF, Tabor B, Ikegami M, Jobe AH, Joseph M, Absolom D: Lung function and surfactant distribution in saline-lavaged sheep given instilled vs. nebulized surfactant. J Appl Physiol. 1993, 74: 1256-1264.
Van Daal GJ, Bos JA, Eijking EP, Gommers D, Hannappel E, Lachmann B: Surfactant replacement therapy improves pulmonary mechanics in end-stage influenza A pneumonia in mice. Am Rev Respir Dis. 1992, 145: 859-863.
Song GW, Robertson B, Curstedt T, Gan XZ, Huang WX: Surfactant treatment in experimental Escherichia coli pneumonia. Acta Anaesthesiol Scand. 1996, 40: 1154-1160.
Schermuly RT, Günther A, Weissmann N, Ghofrani HA, Seeger W, Grimminger F, Walmrath D: Differential impact of ultrasonically nebulized versus tracheal-instilled surfactant on ventilation-perfusion (VA/Q) mismatch in a model of acute lung injury. Am J Respir Crit Care Med. 2000, 161: 152-159.
Schermuly R, Schmehl T, Günther A, Grimminger F, Seeger W, Walmrath D: Ultrasonic nebulization for efficient delivery of surfactant in a model of acute lung injury. Impact on gas exchange. Am J Respir Crit Care Med. 1997, 156: 445-453.
Berry D, Ikegami M, Jobe A: Respiratory distress and surfactant inhibition following vagotomy in rabbits. J Appl Physiol. 1986, 61: 1741-1748.
Walmrath D, Günther A, Ghofrani HA, Schermuly R, Schneider T, Grimminger F, Seeger W: Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis. Am J Respir Crit Care Med. 1996, 154: 57-62.
Kaneko T, Sato T, Katsuya H, Miyauchi Y: Surfactant therapy for pulmonary edema due to intratracheally injected bile acid. Crit Care Med. 1990, 18: 77-83.
Albert RK, Lakshminarayan S, Hildebrandt J, Kirk W, Butler J: Increased surface tension favors pulmonary edema formation in anesthetized dogs' lungs. J Clin Invest. 1979, 63: 1015-1018.
Nieman GF, Goyette D, Paskanik A, Brendenberg C: Surfactant displacement by plasma lavage results in pulmonary edema. Surgery. 1990, 107: 677-683.
Markowicz P, Wolff M, Djedaini K, Cohen Y, Chastre J, Delclaux C, Merrer J, Herman B, Veber B, Fontaine A, Dreyfuss D: Multi-center prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome. Incidence, prognosis, and risk factors. ARDS Study Group. Am J Respir Crit Care Med. 2000, 161: 1942-1948.
Chastre J, Trouillet JL, Vuagnat A, Joly Guillou ML, Clavier H, Dombret MC, Gibert C: Nosocomial pneumonia in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1998, 157: 1165-1172.
Korfhagen TR, LeVine AM, Whitsett JA: Surfactant protein A (SP-A) gene targeted mice. Biochim Biophys Acta. 1998, 1408: 296-302.
Hayakawa H, Myrvik QN, St Clair RW: Pulmonary surfactant inhibits priming of rabbit alveolar macrophage. Evidence that surfactant suppresses the oxidative burst of alveolar macrophage in infant rabbits. Am Rev Respir Dis. 1989, 140: 1390-1397.
Speer CP, Gotze B, Curstedt T, Robertson B: Phagocytic functions and tumor necrosis factor secretion of human monocytes exposed to natural porcine surfactant (Curosurf). Pediatr Res. 1991, 30: 69-74.
Coonrod JD, Lester RL, Hsu LC: Characterization of the extra-cellular bactericidal factors of rat alveolar lining material. J Clin Invest. 1984, 74: 1269-1279.
Armstrong L, Thickett DR, Mansell JP, Ionescu M, Hoyle E, Billinghurst RC, Poole AR, Millar AB: Changes in collagen turnover in early acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999, 160: 1910-1915.
Marshall RP, Bellingan G, Webb S, Puddicombe A, Goldsack N, McAnulty RJ, Laurent GJ: Fibroproliferation occurs early in the acute respiratory distress syndrome and impacts on outcome. Am J Respir Crit Care Med. 2000, 162: 1783-1788.
Jones HA, Schofield JB, Krausz T, Boobis AR, Haslett C: Pulmonary fibrosis correlates with duration of tissue neutrophil activation. Am J Respir Crit Care Med. 1998, 158: 620-628.
Zhang K, Gharaee Kermani M, McGarry B, Remick D, Phan SH: TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis. J Immunol. 1997, 158: 954-959.
Martinet Y, Menard O, Vaillant P, Vignaud JM, Martinet N: Cytokines in human lung fibrosis. Arch Toxicol Suppl. 1996, 18: 127-139.
Coker RK, Laurent GJ, Shahzeidi S, Lympany PA, du Bois RM, Jeffery PK, McAnulty RJ: Transforming growth factors-beta 1, -beta 2, and -beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis. Am J Pathol. 1997, 150: 981-991.
Hernandez Rodriguez NA, Cambrey AD, Harrison NK, Chambers RC, Gray AJ, Southcott AM, duBois RM, Black CM, Scully MF, McAnulty RJ, et al: Role of thrombin in pulmonary fibrosis. Lancet. 1995, 346: 1071-1073.
Ohba T, McDonald JK, Silver RM, Strange C, LeRoy EC, Ludwicka A: Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptor. Am J Respir Cell Mol Biol. 1994, 10: 405-412.
Gray AJ, Reeves JT, Harrison NK, Winlove P, Laurent GJ: Growth factors for human fibroblasts in the solute remaining after clot formation. J Cell Sci. 1990, 96: 271-274.
Gray AJ, Bishop JE, Reeves JT, Mecham RP, Laurent GJ: Partially degraded fibrin(ogen) stimulates fibroblast proliferation in vitro. Am J Respir Cell Mol Biol. 1995, 12: 684-690.
Gregory TJ, Steinberg KP, Spragg R, Gadek JE, Hyers TM, Long-more WJ, Moxley MA, Cai GZ, Hite RD, Smith RM, Hudson LD, Crim C, Newton P, Mitchell BR, Gold AJ: Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997, 155: 1309-1315.
Walmrath D, De Vaal JB, Bruining HA, Kilian JG, Papazian L, Hohlfeld J, Vogelmeier C, Wurst W, Schaffer P, Rathgeb F, Grim-minger F, Seeger W: Treatment of ARDS with a recombinant SP-C (rSP-C) based synthetic surfactant [abstract]. Am J Respir Crit Care Med. 2000, 161: A379-
Willson DF, Zaritsky A, Bauman LA, Dockery K, James RL, Conrad D, Craft H, Novotny WE, Egan EA, Dalton H: Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure. Members of the Mid-Atlantic Pediatric Critical Care Network. Crit Care Med. 1999, 27: 188-195.
Anzueto A, Baughman RP, Guntupalli KK, Weg JG, Wiedemann HP, Raventos AA, Lemaire F, Long W, Zaccardelli DS, Pattishall EN: Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. N Engl J Med. 1996, 334: 1417-1421.
Ainsworth SB, Beresford MW, Milligan DW, Shaw NJ, Matthews JN, Fenton AC, Ward Platt MP: Pumactant and poractant alfa for treatment of respiratory distress syndrome in neonates born at 25–29 weeks' gestation: a randomised trial. Lancet. 2000, 355: 1387-1392.
Seeger W, Grube C, Günther A, Schmidt R: Surfactant inhibition by plasma proteins: differential sensitivity of various surfactant preparations. Eur Respir J. 1993, 6: 971-977.
Holm BA, Keicher L, Liu MY, Sokolowski J, Enhorning G: Inhibition of pulmonary surfactant function by phospholipases. J Appl Physiol. 1991, 71: 317-321.
Hallman M: Lung surfactant in respiratory distress syndrome. Acta Anaesthesiol Scand. 1991, 95(suppl): 15-20.
Cockshutt AM, Possmayer F: Lysophosphatidylcholine sensitizes lipid extracts of pulmonary surfactant to inhibition by serum proteins. Biochim Biophys Acta. 1991, 1086: 63-71.
Wispe JR, Clark JC, Warner BB, Fajardo D, Hull WE, Holtzman RB, Whitsett JA: Tumor necrosis factor-alpha inhibits expression of pulmonary surfactant protein. J Clin Invest. 1990, 86: 1954-1960.
Pison U, Tam EK, Caughey GH, Hawgood S: Proteolytic inactivation of dog lung surfactant-associated proteins by neutrophil elastase. Biochim Biophys Acta. 1989, 992: 251-257.
Liau DF, Yin NX, Huang J, Ryan SF: Effects of human polymorphonuclear leukocyte elastase upon surfactant proteins in vitro. Biochim Biophys Acta. 1996, 1302: 117-128.
Ryan SF, Ghassibi Y, Liau DF: Effects of activated polymorphonuclear leukocytes upon pulmonary surfactant in vitro. Am J Respir Cell Mol Biol. 1991, 4: 33-41.
Seeger W, Lepper H, Wolf HR, Neuhof H: Alteration of alveolar surfactant function after exposure to oxidative stress and to oxygenated and native arachidonic acid in vitro. Biochim Biophys Acta. 1985, 835: 58-67.
Oosting RS, van Greevenbroek MM, Verhoef J, van Golde LM, Haagsman HP: Structural and functional changes of surfactant protein A induced by ozone. Am J Physiol. 1991, 261: L77-L83.
Spragg RG, Gilliard N, Richman P, Smith RM, Hite RD, Pappert D, Robertson B, Curstedt T, Strayer D: Acute effects of a single dose of porcine surfactant on patients with the adult respiratory distress syndrome. Chest. 1994, 105: 195-202.
Wiswell TE, Smith RM, Katz LB, Mastroianni L, Wong DY, Willms D, Heard S, Wilson M, Hite RD, Anzueto A, Revak S, Cochrane CG: Bronchopulmonary segmental lavage with Surfaxin (KL4-Surfactant) for acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999, 160: 1188-1195.
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (SFB 547 'Kardiopulmonales Gefäβsystem' and Gu 405/3-1).
About this article
Cite this article
Günther, A., Ruppert, C., Schmidt, R. et al. Surfactant alteration and replacement in acute respiratory distress syndrome. Respir Res 2, 353 (2001). https://doi.org/10.1186/rr86
- acute lung injury
- pulmonary surfactant
- surfactant replacement