Intensive Care Med (2001) 27: 1699±1717 DOI 10.1007/s00134-001-1121-5
RE VIEW
Pulmonary surfactant: functions, abnormalities and therapeutic options
Ilka Frerking Andreas Günther Werner Seeger Ulrich Pison
Received: 27 August 2001 Final revision received: 27 August 2001 Accepted: 4 September 2001 Published online: 30 October 2001 Springer-Verlag 2001
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I. Frerking ´ U. Pison ( ) Department of Anaesthesiology and Intensive Care Medicine, CharitØ, Campus Virchow-Klinikum, Humboldt University, 13353 Berlin, Germany E-mail:
[email protected] Phone: +49-30-4 50 55 10 01 Fax: +49-30-4 50 55 19 00 A. Günther ´ W. Seeger Department of Internal Medicine, Justus-Liebig University, 35385 Giessen, Germany
Abstract The first successful clinical pilot studies of surfactant replacement were published about 20 years ago as a logical extension of experimental studies showing beneficial effects in pre-term animals. The efficacy of this therapy for immature new-borns has been confirmed in various controlled trials and surfactant therapy is now part of the routine management of the infant respiratory distress syndrome. During the last decade there has been growing insight into the functional role of surfactant components and the mechanisms by which exogenous surfactant exerts its therapeutic effects on lung mechanics, gas exchange and host defence. Of particular interest in this context is the essential role that surfactant-associated proteins play in the surface
Introduction Although our understanding of the composition, structure and function of pulmonary surfactant has advanced greatly over the last decade, the precise molecular mechanisms and interactions by which lung surfactant contributes to lung function in health and disease remain to be elucidated. Nonetheless, surfactant replacement therapy has been introduced into clinical practice with considerable success, and has been a driving force to improve knowledge of the basic science of pulmonary surfactant [1]. The purpose of this article is to present an overview of the current knowledge of the pulmonary surfactant system with emphasis on its basic functions and possible clinical implications for
tension-limiting ability of surfactant, as well as their contribution to pulmonary defence. Indications for surfactant replacement have widened in recent years and promising results have been obtained for adult conditions such as the acute respiratory distress syndrome (ARDS), pneumonia, chronic obstructive and allergic lung diseases. This review outlines the complexity of the surfactant system and describes its basic biophysics, physiology and biochemistry. Problems related to the development of exogenous surfactant preparations, the exploration of clinical targets for surfactant therapy and pathophysiological mechanisms interfering with surfactant function in various forms of lung disease will be discussed.
pulmonary medicine. Current uncertainties will be highlighted.
Basic functions of pulmonary surfactant Pulmonary surfactant affects lung mechanics, gas exchange and host defence (Table 1). While the contribution of surfactant components to lung mechanics and gas exchange via its surface tension-lowering ability has been studied extensively, its role in alveolar host defence remains more hypothetical.
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Table 1 Classic and ªnon-surfactantº functions of pulmonary surfactant Classic surfactant functions
ªNon-surfactantº functions
± Lung mechanics ± Non-specific host defence ± Reduction of surface tension ± Maintaining the surfactant in relation to surface area film stability as a pathogen barrier ± Stabilising lung volume at ± Facilitating mucociliary translow transpulmonary port pressures ± Prevention of lung collapse and atelectasis
± Antioxidant activity
± Prevention of lung oedema ± Gas exchange
± Antibacterial/antiviral activity ± Specific host defence role
± Maintaining the gas exchange area of the lung
± SP-A and SP-D are ªcollectinsº with a pathogen recognition function
± Reduction of pulmonary shunt flow
± SP-A and SP-D serve as opsonins, modulating chemotaxis and phagocytosis ± SP-A interacts with alveolar macrophages through a specific receptor (C1q-receptor) ± Alteration of cytokine/inflammatory mediator release
Lung mechanics Surfactant has a vital role in maintaining the alveolar/ capillary interface. Its primary function is to decrease surface tension in the alveoli, thereby stabilising lung volume at low trans-pulmonary pressures. In 1929 von Neergard observed that the pressure needed to fill a lung was much higher for air than liquid [2]. His frontier-breaking conclusion was that a substantial part of the resistance towards lung expansion was due to the naturally high surface tension of the air/water interface. However, it took more than 25 years before Pattle and Clements independently reported the properties of the alveolar lining layer and the alveolar material that reduced surface tension [3, 4]. Surfactant is a complex mixture of lipids and proteins, whose composition is fairly constant among mammalian species [5, 6]. Based on the analysis of lung fluid extracts obtained by bronchoalveolar lavage (BAL) techniques, surfactant is composed of approximately 80 % phospholipids, 8 % other lipids (cholesterol, triacylglycerol and free fatty acids) and 12 % protein. The principal classes of phospholipids are approximately 85 % phosphatidylcholine (PC) compounds (of which 40±55 % are dipalmitoyl±PC (16:0/16:0), 9±12 % palmitoylmyristoyl-PC (16:0/14:0), 8 % palmitoylpalmitoleoyl-PC (16:0/16:1), 10 % palmitoyloleoyl-
PC (16:0/18:1) and 6 % palmitoyllinoleoyl-PC (16:0/ 18:2), 9 % is phosphatidylglycerol (PG), 3 % phosphatidylethanolamine (PE) and 2 % phosphatidylinositol (PI) [7, 8, 9]. Approximately half of the proteins recovered by bronchoalveolar lavage are serum proteins that are considered to be contaminants. The remaining half consists of four surfactant-associated proteins (SP), designated SP-A, SP-B, SP-C [10] and a recently discovered protein, named SP-D [11]. SP-A (28±36 kDa, variably glycosylated) and SP-D (43 kDa) easily dissociate from lipids and are water-soluble [12]. Both enhance phagocytosis of bacteria and viruses and exert regulatory effects on type II pneumocytes. SP-B (8 kDa) and SP-C (4 kDa) are small, extremely hydrophobic proteins that are important in surfactant dynamics within the terminal air spaces and in the reduction of surface tension [13]. According to the laws of Young and Laplace (Dp = 2s/r) a higher pressure (p) is required to ventilate alveoli with a smaller radius (r), if the surface tension (s) does not vary. Because of the greater retractive force of surface tension on smaller alveoli, the result would be collapse of small alveoli in favour of larger alveoli, resulting in unequal alveolar ventilation. Due to its ability to adsorb to an air/liquid interface, surfactant reduces surface tension (s) to near-zero values at minimum alveolar radius. This allows the opening of collapsed lung regions with minimal inspiratory pressures, thereby preventing atelectasis [14]. The function of surfactant is thus to minimise and equalise retractive forces, independent of alveolar size. As a result, the work of breathing is reduced and alveoli with different sizes are able to coexist [12]. The most important surfactant component for reducing surface tension is dipalmitoylated phosphatidylcholine (DPPC) [15]. Compared to other biological membrane preparations, DPPC appears in unusually high percentages in the surfactant material. DPPC and phospholipids in general are amphipathic molecules with a polar hydrophilic headgroup and a non-polar hydrophobic tail. Therefore, DPPC adsorbs to the pulmonary air/ liquid interface, with the hydrophobic fatty chains being orientated toward the gas phase and the hydrophilic head region toward the aqueous phase. Next to DPPC, a certain amount of unsaturated PC and charged phospholipids (PG, PI) is necessary to improve adsorption of the lipids. The hydrophobic apoproteins SP-B and SP-C are essential to enhance adsorption capacities and the film stability of surfactant [16] and to maintain a surfactant layer-associated pool. Recent data show that gene-targeted SP-B deficient mice die rapidly after birth [17], while SP-C deficient mice are viable and grow normally [18], but with less stable surfactant.
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Gas exchange Surfactant makes gas exchange feasible at low trans-pulmonary pressures through maintaining the huge gas exchange surface of the lungs [19]. A deficiency or dysfunction of surfactant leads to a ventilation-perfusion imbalance and intrapulmonary shunting with hypoxaemia. The most consistent response, reported in virtually all exogenous surfactant trials, is an improvement in oxygenation which can occur within minutes of treatment [20, 21, 22, 23, 24]. Surfactant therapy also results in a decreased need for ventilatory support within several hours, usually reported as a reduction in mean airway pressures [25, 26]. The most obvious reason for this observed improvement in gas exchange under both clinical and experimental conditions is the recruitment of formerly collapsed lung regions, with reduction of pulmonary shunt flow and, thus, improved matching of pulmonary perfusion to ventilation [27]. Whether or not surfactant components can directly facilitate gas exchange is not yet known. Host defence Apart from its biophysical properties, surfactant also plays an important role in pulmonary host defence and local immunomodulation through both non-specific and specific mechanisms [28]. Non-specific defence mechanisms Several non-specific mechanisms have been proposed for surfactant. It may enhance the stability of the film that floats on the alveolar lining layer, facilitate mucociliary transport, and may possess antioxidant activity and antibacterial/antiviral properties. Surfactant phospholipids form a very stable lipid film which may act as a non-specific barrier to adhesion and invasion of micro-organisms into the lung. The average thickness of the alveolar lining liquid layer in rat lungs is about 0.2 mm, with a variation of a few nanometres to several micrometres, and is continuous over the entire alveolar surface [29]. Attached to the surfactant film are stable bilayer lipid structures [30] and tubular myelin, lipid structures arising from lamellar bodies, the initial secreted form of surfactant [31]. This may serve as an extracellular surfactant reservoir which is non-susceptible to inactivation by inhaled particles, pathogens and transudated serum proteins [32]. Surfactant facilitates mucociliary transport via its viscoelastic, rheological properties [33]. It enhances particle clearance from the small airways [34], accelerates ciliary beat frequency [35] and conditions the viscosity of the mucus [36]. These effects may be mediated by
the stimulatory effect of surfactant on chloride ion transport across the airway epithelium [37]. The increased hydration of the airway mucus may influence the rheology of the alveolar lining layer, thereby promoting mucociliary clearance [38]. Production of oxygen radicals by phagocygotic cells and loss of surfactant have been implicated in the pathogenesis of acute lung injury. Natural, as well as synthetic, surfactant can modify the respiratory burst of polymorphonuclear leukocytes by inhibiting neutrophil superoxide production [39]. Surfactant may also possess antioxidant activity; by scavenging oxidant radicals it thus protects against hyperoxic lung injury [40, 41]. The presence of lipophilic antioxidants such as vitamin E in surfactant material may explain this property [42]. Both hydrophilic proteins SP-A and SP-D, which are ubiquitous among air breathing organisms, directly protect surfactant phospholipids from oxidative damage [43]. They may contribute to lung protection from oxidative stress due to atmospheric or supplemental oxygen, air pollutants or lung inflammation. However, in a preliminary study in primates, porcine surfactant did not protect against pulmonary oxygen injury [44]. Nevertheless, artificial surfactant did ameliorate the pulmonary response to hyperoxia, including protection against epithelial and endothelial cell destruction [45, 46, 47]. Surfactant may also possess direct bactericidal/antiviral properties. Studies of rat alveolar lining material identified long chain free fatty acids as bactericidal components, showing their ªantibioticº action against Streptococcus pneumoniae in vitro [48]. On the other hand, studies of human surfactant material obtained by BAL did not demonstrate antibacterial effects against Haemophilus influenzae [49]. With regard to its antiviral properties, the apoproteins, (especially SP-A and SPD) have been mainly investigated; addition of SP-A to cell cultures infected with the influenza A virus resulted in a reduction of virus-infected cells [50]. SP-A has also been shown to bind herpes simplex virus (HSV) and HSV-infected cells [51]. SP-D is important in limiting the extent of replication of influenza A virus within the lung [52, 53]. Specific influences on inflammatory target cells Surfactant components have been analysed regarding specific influences on inflammatory target cells. Collectins. These are a group of collagenous lectins (molecules with a collagen-like domain and a lectin domain) present in pulmonary secretions and mammalian serum. They have a role in first-line defence against a variety of pathogens by binding to specific microbial carbohydrate recognition domains [54, 55]. SP-A and SP-D are considered to be part of this group of collec-
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tins that target the carbohydrate structures on invading pathogens [56]. They represent a non-clonal and innate host defence system that is functional in the absence of, and/or prior to, the adaptive antibody-based immune system [57]. The fact that abundant SP-A and SP-D are detected in tracheal and bronchial glands and the epithelium of conducting airways led to the proposed predominant role of these hydrophilic surfactant proteins in host defence [58]. Pathogen recognition is mediated via the binding of C-type lectin domains of SP-A and SP-D to carbohydrate structures on the surface of the micro-organism [59], causing their agglutination, enhanced killing and clearance [60]. The surfactant-associated protein A / C1q receptor. Surfactant-associated protein A reacts with alveolar macrophages through a specific surface receptor [61], as demonstrated by electron microscopy [62]. Interestingly, the structural organisation of SP-A is reminiscent of that of C1q, part of the first complement cascade component C1 [56]. The hypothesis that receptors for C1q are also responsible for SP-A binding to monocytic cells [63] has been supported by two separate studies showing that C1q and SP-A bind to the same receptor [64, 65]. Several roles have been proposed for C1q, including antibody-dependent and independent immune functions [66]. It has been hypothesised that SPA might substitute for C1q in the lung, where concentrations of C1q are low. However, neither addition of SP-A nor SP-D was able to reconstitute classical pathway activity to C1q-depleted serum [67]. Nevertheless, a recombinant homotrimer of the neck region of SP-D and the C1q globular domain did inhibit classical complement activation [68]. The modular organisation of the six globular domains of C1q (gC1q) are similar to that found in the six globular domains of SP-A [69]. The gC1q modules are also found in a variety of non-complement proteins, including the C-terminal globular regions of human type VIII and X collagen, precerebellin, hibernation protein, multimerin, saccular collagen and Acrp-30 [70]. The crystal structure of the homotrimeric Acrp-30 suggests that gC1q modules may assemble as C-terminal appendages to the collagen regions in the same way as the carbohydrate recognition domains present in the collectin family [68]. Inflammatory target cells. Surfactant-associated protein A stimulates the chemotaxis [71] and response of alveolar macrophages [72]. Antibodies against SP-A abolish the response [73]. SP-A has also been shown to enhance the binding of E. coli lipopolysaccharide (LPS) to alveolar macrophages, to increase deacylation of LPS by 2.3fold [74] and to mediate the alveolar macrophage generation of peroxynitrite that is necessary for the killing of Mycoplasma pulmonis [75]. Ingestion of complexes of SP-A and Bacillus Calmette-Guerin (BCG) by rat mac-
rophages leads to the production of inflammatory mediators and increases mycobacterial killing [76]. However, another chemiluminescence study has shown that SP-A/ surface- as well as SP-A/macrophage-interactions are required to release oxygen radicals from alveolar macrophages in vitro [7]. This indicates that a ªdouble-bindingº situation is necessary for a ªfullº inflammatory response of alveolar macrophages. The ªdouble-bindingº hypothesis as a functional requirement for SP-A/macrophage interaction may protect alveoli from uncontrolled cell activation that would be harmful to the host in health. Surfactant-associated protein D also interacts with alveolar macrophages, stimulating release of oxygen radicals [78, 79]. SP-D has an important role in the first-line defence against Candida albicans, an important respiratory fungus [80]. Interestingly, SP-D is present on all mucosal surfaces of the human body [81], suggesting it may be the innate immune system counterpart of IgA in the adaptive immune system. SP-D and SP-A also increase calcium-dependent neutrophil uptake of the Gram-negative E. coli and the Gram-positive Pneumococcus and Staph. aureus [82]. The mechanism of opsonising activity of SP-D and SP-A differs in important aspects from those of opsonising antibodies, providing evidence that surfactant collectins promote neutrophil-mediated clearance of bacteria in the lung independently of antibody production. On the other hand, SP-A can suppress activation and proliferation of lymphocytes to local stimuli in a dosedependent fashion [16, 83]. SP-D will inhibit human Tlymphocyte proliferation [84]. Similar inhibitory effects on neutrophils have been shown for a bovine surfactant modified by the addition of DPPC [85]. Altered secretion of cytokines and other mediators. Human SP-A stimulates production of TNF-a, interleukin (IL)-1b and IL-6 [86], and activates transcription factor NF-kB in monocytic THP-1 cell lines [87]. However, SP-A decreased TNF-a activity in a medium of LPSstimulated macrophages, apparently via phagocyte interactions [88]. It also limited excessive proinflammatory cytokine release in human pulmonary macrophages [89]. Of interest, TNF-a accumulation in alveolar macrophages exposed to Pneumocystis decreased in the presence of SP-D [90]. The exact contribution of each surfactant component towards immunomodulation within the cytokine network remains unclear: Two functional human genes of SP-A have recently been characterised; even their two products (SP-A1 and SP-A2) react differently in their ability to stimulate TNF-a production in THP-1 cells [91].
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Table 2 Types of surfactant for substitution therapy Surfactant type
Advantage
Disadvantage
Human surfactant
± Contains all surfactant constituents
± Not readily available
Amniotic fluid
± Higher resistance to inactivation
± Sparse resource
Lipid-based synthetic surfactants
± No risk of disease transmission
± Lower resistance to inactivation
Exosurf ALEC (Pumactant)
± Less immunological rejection ± Inexpensive
± Lacks surface-active apoproteins ± Less rapid improvement in gas exchange
± Completely defined formulation Synthetic surfactants including lipids and surfactant proteins
± Contains selected surfactant apoproteins
± Not yet available
SP-B fragment plus lipids (KL4-Surfactant, Surfaxin)
± Completely defined formulation
rSP-C plus lipids (Venticute)
± Higher resistance to inactivation
Natural surfactant
± Contains surfactant apoproteins SP-B and SP-C
± Transmission risk
Bovine: ± Surfactant TA (Surfacten) ± Survanta (Beractant) ± Alveofact ± CLSE ± Infasurf
± Higher resistance to inactivation
± Unwanted constituents ± Immunological consequences possible
Porcine: ± Curosurf (Poractant alfa) ALEC artificial lung expanding compound, CLSE calf lung surfactant extract
Animal models / Surfactant-associated protein A ªknock-outº mice Specific interactions between surfactant and the host defence system have been studied in animal models, in particular using gene-targeted SP-A deficient mice (SP-A -/- mice). These mice are more susceptible to Pseudomonas aeruginosa infection [92]. Lung inflammation was also more severe in SP-A- as well as SP-Ddeficient mice compared to wild types in response to Group B Streptococcus (GBS) and H. influenzae infection [93]. The reason for this may lie in the observation that pulmonary clearance of intratracheally administered respiratory syncytial virus (RSV) [94], adenovirus [95] and GBS [96] was impaired in SP-A -/- mice. Exogenous SP-A administration restored clearance of RSV [94] and GBS [96] and decreased lung inflammation in SP-A -/- mice. Therefore, SP-A application may represent a strategy to prevent or treat viral and bacterial pulmonary infections.
Pulmonary surfactant for lung disease Premature new-borns and immature lungs (IRDS) The role of surfactant replacement therapy in the management of the infant respiratory distress syndrome
(IRDS) is now well established and has represented standard care for neonates requiring mechanical ventilation for IRDS since 1990 [97, 98]. Surfactant therapy constitutes a logical extension of the classical observation that the lungs of babies dying from IRDS lack surface active material and the possibility of compensating for this deficit by administering the missing material or an equivalent substance via the airways [99]. In 1959 Avery and Mead reported that saline extracts from the lungs of pre-term infants with IRDS lacked the low surface tension characteristic of pulmonary surfactant [100]. The clinical era of surfactant replacement therapy opened with the pilot study of Fujiwara et al. in 1980, showing dramatic improvement of lung function in babies with severe disease after treatment with a large dose of modified natural surfactant instilled directly into the airways [101]. Surfactant can be used prophylactically or therapeutically. Prophylactic administration is more effective than rescue treatment of IRDS, especially in infants under 30 weeks of gestation and a birth weight less than 1000 g [102, 103, 104, 105]. As a consequence, ventilation is required less frequently and mortality is reduced [106]. Despite these reports in favour of prophylactic surfactant for neonates at high risk for IRDS, rescue therapy is normally applied [73]. Its advantages are less use of surfactant and, hence, lower cost.
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Surfactants for IRDS are of two general types: (a) those processed from animal lungs or human amniotic fluid and (b) those containing only synthetic components (Table 2). The issue of choice of surfactant is still not completely resolved. The advantages promoted for surfactants from animal (porcine or bovine) lungs are their better biophysical properties, as they contain the hydrophobic surfactant proteins SP-B and SP-C [107, 108, 109, 110]. Surfactants with these proteins produce more rapid improvement in infants and are less sensitive to inhibition by serum proteins and other substances that accumulate in injured lungs [97]. Fully synthetic surfactant may be less effective, especially when the alveolar lining layer is disturbed with destruction of the barrier between the alveolar compartment and the circulation with its inhibitory proteins. A recent study in 212 premature neonates comparing ALEC (Pumactant) and Curosurf (Poractant alpha) demonstrated significantly lower mortality with Curosurf (14.1 versus 31.0 %, p = 0.006) [111]. On the other hand, synthetic surfactants such as ALEC and Exosurf have been promoted as being more uniform in composition and safer, as there is no transmission risk of diseases such as bovine spongiform encephalopathy (BSE), or the potential of allergic sensitisation to animal SP-B or SP-C. In addition, the differences in short-term physiological response and long-term outcome have been less striking than expected when comparing animal source and synthetic surfactants [108]. A new kind of surfactant is being developed, combining recombinant peptides or proteins based on human surfactant protein sequences with synthetic lipids such as KL-4 (Surfaxin) and rSP-C surfactant (Venticute). This shows promising results in animal studies [112, 113, 114, 115, 116]. Controlled trials in humans have been performed with KL-4, showing efficacy and safety [117, 118]. Trials using rSP-C are necessary to demonstrate efficacy in humans. Surfactant treatment usually consists of 1±2 doses. In clinical trials 25 to 200 mg phospholipids per kg body weight (b.w.) have been used as single doses. It is likely that the phospholipid dose needed for prophylaxis is smaller than for treatment of IRDS, when inhibitory proteins are present in the air spaces. For prophylaxis a dose of 100 mg/kg b.w. seems an appropriate dose for re-treatment after 6±12 h if the infant remains ventilator-dependent and needs more than 30 % oxygen [119]. Multiple doses are thought to be useful because of their ability to overcome the functional inactivation of surfactant by proteins, an effect considered to be significant [120, 121, 122, 123, 124, 125]. A two-dose treatment schedule was equivalent to a four-dose regimen in a large study of 6757 infants treated with a synthetic surfactant [126]. The only consistent pulmonary complication of surfactant treatment is pulmonary haemorrhage; this oc-
curs mostly in small neonates and can happen many hours after successful treatment [127], though it may well be related to ventilator settings rather than surfactant therapy. As yet there is no definite association with intracranial haemorrhage, the major cause of later cerebral palsy in very low birth weight infants [128]. In longterm follow-up, infants treated with surfactant generally performed as well or better than control infants [129]. Overall, surfactant replacement therapy has decreased the frequency and severity of IRDS. When administered prophylactically or at the onset of IRDS, surfactant decreases neonatal mortality and the frequency of pneumothorax [1, 25, 130]. Surfactant treatment was introduced into general clinical use in 1989; this coincided with a decline in the general infant mortality curve in the United States from 8.5 % in 1989 to 6.3 % in 1990 [131]. Acute respiratory distress syndrome (ARDS) In 1967 Ashbaugh et al. described the development of acute respiratory failure in 12 patients with progressive dyspnoea and hypoxaemia who did not respond to an increase in inspired oxygen [132]. Post-mortem examination revealed a severe reduction in lung compliance and histological signs of atelectasis, haemorrhage, pulmonary oedema and hyaline membrane formation. As the clinical and pathological features resembled those seen in neonates with IRDS, the term ªadult respiratory distress syndromeº (ARDS) was coined [133]. It was renamed the ªacute respiratory distress syndromeº by an American-European Consensus conference on ARDS [134] which defined it as a preceding catastrophic event, a PaO2/FIO2 ratio less than 200 mmHg, bilateral infiltrates on chest X-ray and a pulmonary capillary wedge pressure below 18 mmHg or no clinical evidence of increased left atrial pressure. Because of the observed similarities between IRDS and ARDS, Petty and Ashbaugh postulated that the surface active material of the lung is abnormal in ARDS and that this defective surfactant may possibly contribute to the pathophysiology of the respiratory failure [132]. Although, in contrast to IRDS, the deficiency of surfactant material is not the initiating problem in ARDS, a broad range of biophysical and biochemical abnormalities of the pulmonary surfactant system have been observed, favouring alveolar collapse with ventilation/perfusion mismatch and, in particular, shunt flow [135, 136, 137, 138, 139, 140]. The biophysical and biochemical alterations of the surfactant system in ARDS include: · Increased surface tension to more than 15±20 mN/m, as compared to near zero in healthy controls (Fig. 1) [135, 136],
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· Alterations of the fatty acid composition with a marked reduction of the relative content of the saturated phospholipid fraction, especially palmitic acid [137, 141], · Decreased levels of surfactant apoproteins, as shown for SP-A [135, 136, 142] and SP-B [135, 136, 142, 143], · Reduced content of large surfactant aggregates, which are more active [143, 144], · Inhibition of surfactant function by plasma proteins [135, 145], · Inhibition of surfactant by inflammatory mediators, in particular proteases [146] and oxygen radicals released by inflammatory cells which may attack surfactant proteins [147] and exert phospholipolytic activity that degrades surfactant lipids [137]. Of particular interest is the possibility of increased reactive radical formation through treating patients with inhaled NO which may then interact with SP-A and surfactant lipids [148, 149, 150].
Fig. 1 Biophysical surfactant properties of large surfactant aggregates isolated from controls or patients with various lung diseases. Minimum surface tension (mN/m) was measured in a bubble surfactometer at 2 mg/ml phospholipid and at minimum bubble size after 5 min of film oscillation (g min) (control healthy volunteers, CLE cardiogenic lung oedema, ARDS ARDS without lung infection, ARDS+PNEU ARDS with lung infection, PNEU severe pneumonia necessitating mechanical ventilation). Data are indicated for single values (*), mean value (D) and median value (&); * p < 0.05, ** p < 0.01, *** p < 0.001 as compared to control. Reprinted from [135] with permission
· Alterations of the phospholipid profile with reduction of the relative percentages of phosphatidylcholine and phosphatidylglycerol and an increase in the relative percentages of phosphatidylinositol, phosphatidylethanolamine and sphingomyelin [135, 136, 137, 139],
One large randomised multi-centre study has investigated the efficacy of aerosolised Exosurf, a synthetic surfactant preparation [151] (Table 3). In addition, several pilot studies have examined the safety and efficacy of both natural and synthetic surfactant preparations in ARDS. In one study, repetitive intratracheal application of the bovine preparation Survanta was given to adults with acute respiratory failure, with cumulative doses between 300 and 800 mg/kg b.w. An improvement of gas exchange and a trend towards an increase in survival were noted [152]. Similar positive effects were seen with the porcine preparation Curosurf [153]. Bronchoscopic application of a bovine surfactant extract (Alveofact) to ten patients with severe sepsis-induced ARDS at a total dose of 300 mg/kg b.w.[27] resulted in an increase in mean PaO2/FIO2 ratio from less than 90 mmHg to approximately 200 mmHg (Fig. 2). A restoration of composition and surface activity was also seen, with a profound improvement in the phospholipid (PL):protein ratio, the relative content of large surfactant aggregates and phosphatidylcholine, and the minimum surface tension in both the absence and presence of the BALF proteins (Table 4). A recent study performed in Europe and South Africa investigated the feasibility and efficacy of a tracheal application of a recombinant SP-C-based surfactant preparation (Venticute) [154]. Patients were randomised to receive standard therapy alone (STD, n = 12) or standard therapy plus rSP-C surfactant. Two different surfactant doses were investigated: a MID group (n = 14) received a total of 200 mg/kg phospholipids, and a HIGH group (n = 15) received 500 mg/kg phospholipids. Twenty-four hours after treatment, the PaO2/FIO2 ratio was 184 64 mmHg in the MID group versus 139 59 mmHg in the STD group. Fifty-seven
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Table 3 Pilot studies addressing efficacy and safety of surfactant administration in ARDS: data of one multicentre study with a synthetic surfactant containing only phospholipis (Exosurf), one pilot study with a synthetic surfactant containing a SP-B fragment and
phospholipis (KL-4), three pilot studies with natural surfactant (bovine: Survanta, Alveofact, porcine: Curosurf) and one pilot study with a synthetic surfactant containing recombinant SP-C (rSP-C) plus phospholipids (Venticute) (PL total phospholipids)
Surfactant
Application
Dosage (mg/kg b.w.)]
PaO2/FIO2 (mmHg) pre-treatment
PaO2/FIO2 (mmHg) post-treatment
Reference
Exosurf
Constant aerosolisation (5 days)
Control: none
140 64
[151]
Exosurf: approximately 5/day
145 82
approximately 35 % increase approximately 45 % increase
KL-4
Bronchopulmonary segmental lavage
143 46
150 0.11
[118]
Survanta
Intratracheal instillation
30 ml of 2.5 mg/ml or 10 mg/ml Surfaxin per lung segment up to 3 times Control: none Survanta 8 50 4 100 8 100
128
133
[152]
98 124 133
161 182 162
Curosurf
Bronchoscopic
50
Data not given
49 16 % increasea
[153]
Alveofact Venticute
Bronchoscopic Intratracheal instillation
300±500 Control: none Venticute 4 1 rSP-C+200 PL
85 7 Data not given
200 20b 139 59
[27] [154]
Data not given
184 64
a
b
p < 0.05, p < 0.001 as compared to pre-treatment
percent of the MID group patients were successfully weaned by day 28 compared to only 25 % in the STD group. Accordingly, ventilator-free days were 10.9 (mean) and 14 (median) in the MID group and 1.8 (mean) and 0 (median) in the STD group. Mortality was 29 % in the MID and 33 % in the STD group. No differences were observed in the HIGH, compared to the STD, group. Intratracheal application of a recombinant based SP-C surfactant may thus offer a feasible and safe approach for replacement of surfactant in patients with ARDS. Another pilot study of 12 ARDS patients sought to cleanse injured lungs by sequential bronchopulmonary segmental lavage containing a dilute synthetic surfactant (KL-4, Surfaxin) [118]. The subjects were assigned to one of three treatment regimens with escalating doses of the artificial compound. Although there were no serious adverse consequences from the procedure, three of the five ARDS patients with sepsis died. By day 28, the two survivors were off mechanical ventilation for an average of 2.8 days and neither had been discharged. In contrast, the seven non-septic ARDS patients had been off mechanical ventilation for an average of 20 days and all had been discharged. This study provides the first attempt to cleanse the lungs of ARDS patients in order to provide sufficient functional surfactant to assist in gas exchange. After instillation, patients showed improved oxygenation and required lower ventilator settings.
In contrast, Anzueto et al. [151, 155] could not demonstrate any beneficial effect of aerosolised Exosurf in sepsis-induced ARDS in a large (725 patients), multicentre, randomised, placebo-controlled study. However, three important criticisms can be levelled: Exosurf is a synthetic surfactant preparation lacking surfactant proteins. In vitro, Exosurf displays reasonable surface activity but is clearly less active compared to natural surfactant preparations in animal studies and IRDS patients. Moreover, Exosurf is extremely sensitive whereas other natural surfactant preparations are rather resistant towards inhibition by plasma proteins. One obvious reason is the complete absence of the hydrophobic surfactant apoproteins SP-B and SP-C, which are known to enhance resistance of surfactant towards inhibition by plasma proteins [156]. Furthermore, due to the aerosolisation technique used, the dosage of surfactant material in this study may have been far too low to gain any significant effect. As the authors themselves showed, the relative pulmonary deposition rate was 4±5 %. Thus, their patients received an average of 5 mg Exosurf per kg b.w. per day. This dosage is about one order of magnitude below that of the current IRDS treatment recommendations and is probably yet another order of magnitude below the dosage that may be effective in ARDS, where exogenous surfactant material has to face the high burden of inhibitors [124, 135]. In summary, there is good evidence that severe abnormalities of the pulmonary surfactant system occur
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Fig. 2 Time course of PaO2/FIO2 upon surfactant administration in ARDS. Data are means SEM. A total of 300 mg/kg Alveofact was delivered bronchoscopically in separate doses into each segment of both lungs in ten patients (time zero, n = 10). In five patients, in whom the increase in arterial oxygenation was partially lost within the following hours, a second dose of 200 mg/kg Alveofact was applied 18±24 h later. The maximum PaO2/FIO2 value is given for each day, and for every 12 h within the first 2 days. The number of surviving patients is indicated (n). *** p < 0.001 for comparison of the PaO2/FIO2 values before and after the first surfactant application. From [27] with permission
in ARDS and that they contribute to the pathophysiology of this disease. Attempts to apply intact exogenous surfactant material have been successful in some pilot studies with regard to feasibility and safety. Along with a marked restoration of physiological surfactant properties, there was an acute and significant improvement in gas exchange. Obviously, much higher doses were necessary to yield clinical effects as compared to IRDS; this appears related to the presence of surfactant inhibitory compounds in the alveolar compartment of ARDS patients. Controlled studies on larger patient populations are currently underway; these may help to clarify whether surfactant therapy can reduce the mortality of ARDS or have any impact upon inflammation, host-defence and mesenchymal cell proliferation. Due to the very complex nature of ARDS, it may be necessary to combine different treatment strategies, e.g. surfactant replacement therapy plus inhaled application of vasodilator agents such as nitric oxide [157, 158], prostacyclin (PGI2) [159] or fibrinolytic agents such as urokinase [160], plus ventilator strategies that reduce shear stress on damaged lung tissue [161].
Lung infection, asthma, chronic obstructive pulmonary disease (COPD) and emphysema Surfactant replacement may also be applicable to other lung diseases such as infection, asthma, COPD and emphysema. Lung infection/pneumonia Abnormalities in both the phospholipid and apoprotein fractions of surfactant have been described in association with a wide variety of pathogens, including bacteria [135, 162, 163, 164], viruses and fungi [165, 166]. Trials of surfactant replacement in models of viral pneumonia have shown controversial results. In a mice model of influenza A pneumonia, surfactant therapy produced a significant increase in lung compliance and volume [167]. On the other hand, a second study using the same viral pneumonia model demonstrated an exacerbation of infection after intranasal administration of surfactant, causing fatal disease even in mice with a small amount of inoculated virus [168]. Therefore, caution might be warranted for this treatment in humans. Case reports of surfactant therapy for pneumonia in humans are rare and controlled studies are not yet available. One report showed a positive effect of intrabronchial surfactant instillation in an adult patient with lobar pneumonia and hypoxaemia [169]. A bovine surfactant instillation was shown to be safe in a case-control study of 41 pre-term infants with respiratory failure due to pneumonia [170]. The precise mechanism by which surfactant improves respiratory failure due to pneumonia is unclear. It may overcome a quantitative deficiency of
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Table 4 Surfactant parameters in bronchoalveolar lavage fluid (BAL) obtained from ARDS patients (n = 10) before (pre-) and 15±21 h after (post-) surfactant replacement (300±500 mg/kg Alveofact), from healthy controls (n = 10) and for the surfactant material used for replacement therapy (Alveofact, n = 3) (PPR phosphoPPR LSA (% of PL) PC (% of PL) PG (% of PL) SM (% of PL) SP-A (% of PL) SP-B (% of PL) gads (mN/m) gmin (mN/m) gads + P (mN/m) gmin + P (mN/m)
lipid to protein ratio, LSA large surfactant aggregates, PL total phospholipids, PC phosphatidylcholine, PG phosphatidyglycerol, SM sphingomyelin, SP-A surfactant protein A, SP-B surfactant protein B, gads adsorption, gmin minimum surface tension, +P in the presence of supernatant protein)
ARDS patients pre-treatment
ARDS patients post-treatment
Controls
Alveofact
0.02 0.01 27.7 5.3 72.6 2.1 3.1 0.6 7.7 1.3 1.0 0.5 3.73 1.15 45.0 1.6 21.6 1.4 43.5 1.5 34.4 2.2
0.23 0.1 68.6 8.8a 85.3 1.0b 7.2 0.9b 2.4 0.5b 0.4 0.1 4.9 1.26 25.6 2.8b 9.2 2.8c 37.6 2.4 24.2 3.6
0.58 0.1 67.0 7.1 83.1 0.9 8.6 0.6 0.8 0.2 6.2 0.7 3.0 0.3 22.5 0.2 0.25 0.2 22.7 0.7 0.5 0.3
± > 90 87.8 0.4 7.6 0.1 0.8 0.1 ± 3.8 0.7 22.2 0.3 0.28 0.3 ± ±
Data are given as mean values standard error of the mean a p < 0.05, b p < 0.001, c p < 0.01 Taken from reference [27] with permission
endogenous surfactant due to the antagonistic effects of pulmonary exudates and reduced production following damage to type II pneumocytes. There are indications, however, that exogenous surfactant components may serve as nutrients for bacteria. The influence of three natural (Curosurf, Alveofact, Survanta) and two synthetic (Exosurf, Pumactant) surfactant preparations on the growth of bacteria frequently cultured from blood or tracheal aspirate fluid of newborns was recently compared [171]. Some surfactants had bactericidal properties while others seemed to promote bacterial growth for different bacterial species. This suggests that bacterial growth in different surfactant preparations is influenced by the microbial species and the composition and dose of surfactant. This finding might be important for future decision making by physicians. Surfactant therapy may also have immunological effects. One study in surfactant-treated babies showed a significant increase in polymorphonuclear lymphocytes without clinical or bacteriological evidence of infection [172]. Another study using a bovine surfactant observed high titres of induced anti-surfactant antibodies in animals [173], though a study of premature new-borns treated with a bovine surfactant did not detect any antibodies against surfactant apoproteins [174]. The immunogenicity and immunomodulatory activity of exogenous surfactant clearly needs to be investigated further. Asthma It is unclear whether surfactant actually participates in the allergic inflammation processes that are frequently seen in asthmatic patients. Bronchial asthma is recognis-
ed as a chronic inflammatory disorder of the airways, with increased bronchial responsiveness and reversible airway narrowing in response to a wide range of stimuli. The allergic airway inflammation is supposedly triggered by inhaled allergens, which cause an immediate hypersensitivity reaction by prompting mast cells to release histamine and other mediators. These mediators sustain the reaction by activating T lymphocytes to generate cytokines, such as IL-4, IL-5 and TNF-a [175]. IL4 and TNF-a-induced leukocyte recruitment, through up-regulation of adhesion molecules, may aggravate bronchial inflammation, thereby leading to oedema and leakage of plasma proteins into the airway spaces [176]. Surfactant dysfunction may also contribute to the characteristic airway obstruction of asthma. Since surfactant components influence the production of inflammatory mediators and cytokines, the application of exogenous surfactant may potentially influence the clinical picture of asthma. Surfactant suppressed the immune lung injury response to inhaled antigen in laboratory animals [177]. Exogenous surfactant application also prevented and partly reversed the increased airway resistance and surfactant dysfunction produced in allergen-challenged guinea pigs [178]. Enhörning et al. reported that lavage fluid from antigen-challenged human asthmatics contains agents inhibiting surface activity, particularly at reduced temperatures [179]. Airway inflammation may therefore cause surfactant to lose its ability to maintain the patency of narrow conducting airways, especially in cold weather. The surface activity in sputum during an acute asthma attack changes markedly [180]; nebulisation of surfactant was able to dramatically increase both vital capacity (VC) and FEV1 in adult asthmatics [181]. Surfactant function was inhibited by segmental allergen challenge
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in asthmatic humans [182, 183], while the reduced concentration of DPPC in BAL fluid correlated with an increase in protein content [184]. Another study in stable asthmatics revealed decreased DPPC only in sputum but not BAL fluid, without any change in protein concentration [185]. Surfactant-associated proteins have been investigated with respect to allergic diseases. Surfactant-associated proteins A and D. Surfactant-associated protein A levels in the BAL fluid of asthmatic patients are decreased compared with healthy controls [186]. This could reflect an impaired resistance against pulmonary inflammation, with further disturbance of the surfactant system. SP-A binds to allergenic glycoproteins from pollen grains [187], while both SP-A and SP-D inhibit binding of allergen-specific IgE to house dust mite extracts [188]. This suggests that the interaction of surfactant proteins with certain allergens may have a role in immediate-type hypersensitivity. SP-A and SP-D inhibit histamine release in the early phase of allergen provocation [188] and suppress lymphocyte proliferation in the late phase of bronchial inflammation [189]. These effects on the two essential steps in the development of asthmatic symptoms points to a possibly important protective role of these two proteins. The suppression of lymphocyte proliferation and histamine release may be mediated by two different mechanisms: SP-A and SP-D may bind to the allergen and hinder its interaction with surface-bound IgE molecules, reducing histamine release by sensitised basophils. Surfactant proteins may also bind to surface molecules on the cell membrane of lymphocytes, thus inducing inhibitory signals that affect the transduction of lymphocyte proliferation. Surfactant-associated protein C. In a murine asthma model, an allergen-induced down-regulation of the human SP-C promoter related to eosinophilic inflammation was noted [190]. Allergic airway inflammation is thus associated with down-regulation of a surfactant protein involved in maintaining airway patency. However, the delineation of the precise role of surfactant ± and replacement therapy ± in the immunoregulatory network of asthmatic airway inflammation awaits further study. Chronic obstructive pulmonary disease and emphysema Pulmonary surfactant is essential for normal lung function. Its components, particularly SP-A and SP-D, play an important role in the regulation of inflammatory processes within the lung. Because of the chronic lung inflammation seen in COPD and the surface destruction seen in emphysema, the surfactant system may be involved in the underlying pathophysiology.
Patients with COPD often have a combination of chronic obstructive bronchitis and pulmonary emphysema [191, 192]. The progressive destruction of alveolar structures characteristic of emphysema is thought to occur through an imbalance between the proteases (proteolytic enzymes) and antiproteases in the lower respiratory tract, leading to proteolytic destruction of lung elastin and tissue [193, 194]. Neutrophil and alveolar macrophage elastase, in particular, work unimpeded to destroy the alveolar elastin network. One of the earliest pathological abnormalities to develop within smokers' lungs is accumulation of alveolar macrophages within the alveoli [195, 196]. There are several possible interactions of surfactant and the progression of COPD and/or emphysema. Elastase-induced dysfunction of surfactant. In vitro studies by Pison et al. showed that neutrophil elastase is capable of cleaving surfactant-associated proteins, resulting in a reduced adsorption rate of surfactant to an air/ fluid interface [146]. This observation suggests an ability of elastolytic enzymes to interfere with surfactant function in vivo. Elastase is capable of removing the surfactant layer from the pores of Kohn, resulting in a significant stress increase on the elastin skeleton of the alveolar septa and enlargement of the pores [197]. Damage of surfactant by cigarette smoke. Cigarette smoke may alter the surface activity of pulmonary surfactant [198, 199]. Endobronchial washings from longterm cigarette smokers show a significant rise in minimum surface tension compared with non-smokers [200]. There are no clear data on the contents of phospholipids, the main surface tension-reducing constituent of surfactant, in the BAL fluid of smokers: Reports vary from lower total phospholipid content [201], no difference [202] and significantly higher levels in smokers compared with non-smokers [198]. Reduction of type II cells. Synthesis and secretion of surfactant is a function of the alveolar type II cell. Lower numbers of type II cells are present in emphysematous lungs [203]. This result is in line with the hypothesised protective effect of the type II cell and its secretory product surfactant against the development of emphysema. Accordingly, daily exposure to inhaled cigarette smoke resulted in emphysema in rabbits given a threshold dose of elastase [204]. Under these conditions the normal rate of proliferation and differentiation of type II cells may be unable to maintain a sufficient production of the surfactant lining layer. Endotracheal surfactant instillation had a protective effect on pancreatic elastase-induced airspace enlargement in mice [205]. Exogenous surfactant may substitute for the elastasedestroyed original surfactant film and prohibit the development of elastase-induced emphysema. Pre-treat-
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Table 5 Surfactant for lung disease Lung disease
Evidence for surfactant alteration
Rationale for surfactant replacement
IRDS
Lack of surfactant due to immature type II cells
Replacement of lacking surface active material
ARDS
Increased surface tension Replacement of dysfunctional surfactant Alterations of the phospholipid profile Overcome inactivation Decline in SP-A and SP-B Surfactant decreases pro-inflammatory cytokine release Decrease of large surfactant aggregates Inactivation by inhibitory proteins Cleavage by inflammatory mediators and proteases/elastase
Pneumonia
Decreased SP-A Reduction of surfactant pool Increased SP-A Change of fatty acid profile Increased phospholipids
Replacement of dysfunctional surfactant Antibacterial properties of surfactant
Asthma
Reduced surface activity / increased surface tension Decreased SP-A Altered phospholipid profile
Reduction of surface tension / work of breathing Anti-allergic properties of surfactant
COPD
Predisposing genetic polymorphisms of the SP-B gene
Reduction of surface tension Optimising the work of breathing
Emphysema
Lack of type II cells SP-D deficiency
Reduction of surface tension Prevention of lung collapse
ment as well as treatment with Neltenexine, a new drug affecting surfactant production, showed a significant reduction in the alveolar deformation induced by elastase in rats [206]. Impairment of surfactant proteins. Surfactant-associated proteins A and D play crucial roles in the host defence mechanisms and immunomodulation of the peripheral airways [51, 61, 71, 72, 76, 77, 78, 80]. The impairment in surfactant biophysical activity after exposure to neutrophil elastase may be due to proteolytic cleavage of SP-A [146, 207]. Indeed, the contents of SP-A and SPD in the BAL fluid from smokers was significantly decreased compared to that from non-smokers [208]. This reduction in SP-A and SP-D may attenuate the host defence functions of surfactant, and may lead to direct toxic injury of the lung followed by the development of COPD. Direct evidence for the impact of surfactant proteins for COPD and emphysema comes from genetargeted mice studies. Deletion of the SP-D gene in mice leads to spontaneous development of enlarged airspaces and abnormalities in both collagen and elastin [209]. This process is associated with an accumulation of activated macrophages, which affects the remodelling process [210, 211]. Therefore, SP-D might have a previously unknown function in the regulation of inflammation and pulmonary remodelling in vivo. Wert et al. noted a 10-fold increase in hydrogen peroxide production in isolated alveolar macrophages of SP-D -/- mice [212]. This indicates an antioxidant role of SP-D in the lung, which may influence oxygen radical production leading to inflammation and emphysema. The precise extent to which SP-D deficiency contributes to the de-
velopment of COPD and/or emphysema remains to be determined. Current studies of the genetic background of lung diseases such as COPD and emphysema raise novel and interesting perspectives. A recent study of genetic polymorphisms for SP-A, SP-B and SP-D in a human population with COPD compared to healthy smokers and non-smokers reported some alleles to be potential susceptibility factors for COPD [213]. These alleles may play a role in chronic obstructive lung disease by increasing the risk of, or protecting against, COPD when they are found in a certain genetic background or under the influence of a certain environment. Overall, there are many aspects supporting a protective role of alveolar type II cells and their secretory product, pulmonary surfactant, in the pathogenesis of COPD and emphysema. Further investigation is required to test the hypothesis that surfactant replacement therapy improves lung function and ultimately improves outcome and quality of life in patients with COPD and emphysema. Concluding remarks The great success of intratracheal surfactant instillation in neonatal IRDS has stimulated its potential utility in adult lung diseases with abnormalities of the surfactant system such as ARDS, pneumonia, asthma, COPD and emphysema (Table 5). Nonetheless, novel delivery techniques should still be considered. Could surfactant reach its site of action by venous application through a ªshuttle-systemº? Or
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could surfactant itself, due to its spreading ability, serve as a ªshuttleº for other medications to reach their site of action? There are several conceivable approaches through which surfactant function could be improved therapeutically. Pharmacological attempts to increase secretion of intact surfactant material by type II pneumocytes and/or inhibition of accelerated extracellular surfactant metabolism are just two examples. However, it is currently unclear if such attempts could be successfully performed in the diseased lung. In view of the heterogeneous pathophysiology of diseases such as ARDS, asthma and COPD, a more precise classification would be extremely important. Recent studies involving genetic alleles and backgrounds have begun to address this problem [213]. Genetic studies may also help to clarify why there are ªrespondersº and ªnon-respondersº to certain treatment strategies. While searching for the ªbestº surfactant preparation there have also been unexpected findings. Different lev-
els of platelet activating factor (PAF) have been discovered in several surfactants. Although PAF is considered to be highly toxic, administration of the surfactant material with more PAF content surprisingly resulted in a better outcome [214]. Perhaps destroying/losing PAF during manufacture of an exogenous surfactant for lung therapy may degrade key factors such as surfactant proteins. This could decrease efficacy, while any potentially toxic PAF would be degraded in vivo through PAF hydrolases, a significant amount of which is present in the alveolar lining layer synthesised by type II cells [215]. Another interesting recent finding is the previously unknown presence of antibacterial peptides in a porcine surfactant preparation [216]. The precise isolation and analysis of surfactant constituents still needs further investigation. Due to the complex nature of the pulmonary surfactant system and the heterogeneous character of patients with lung disease, there may well be more surprises in store for researchers and clinicians.
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