© 2007 American Thoracic Society DOI: 10.1165/rcmb.2007-0004ED
Surfactant for Acute Lung InjuryUniversity of California, San Diego, La Jolla, California Surfactant as treatment for acute lung injury (ALI) has been under investigation for almost two decades, and despite considerable effort, progress has been slow. While the rationale for this intervention is strong, the hurdles to demonstrating clinical efficacy are immense. These hurdles are not unique to studies of surfactant therapy, but face all treatments proposed for ALI. In fact, no pharmacologic therapy for that syndrome is of proven benefit despite evaluation in phase III trials of over a dozen candidates, and current treatment consists of supplemental oxygen and mechanical ventilation. Yet progress is being made in the attempt to establish the efficacy of surfactant therapy for patients with ALI. Pulmonary surfactant, a complex mixture of phospholipids, neutral lipids and proteins, results in a lowering of alveolar surface tension during ventilation, thereby markedly reducing the work of breathing. In addition, it helps maintain the patency of small airways, protects against formation of lung edema, and participates in local defense of the lung against infection. In the setting of acute lung injury (ALI), there are marked changes in lung surfactant that combine to result in a dramatic loss of function. These changes include: marked reduction in surfactant production by alveolar type II cells; inactivation by plasma proteins in alveolar edema fluid of the inflamed lung; and inactivating reaction of surfactant lipids and/or proteins with reactive nitrogen and oxygen species, proteases, and phospholipases. In addition, the extracellular conversion of large (functional) surfactant aggregates to small (inactive) aggregates is augmented. Loss of surfactant function results in decreased pulmonary compliance and functional residual capacity, atelectasis, increased right-to-left shunt and hypoxemia, and possibly enhanced edema formation. As these changes are all features of ALI, it is reasonable to postulate that loss of surfactant function may contribute to the pathophysiology of ALI. The jump to postulating that treatment with exogenous surfactant may improve survival rests on several observations. First, in a variety of animal models, loss of surfactant function results in an ALI-like syndrome, and treatment with exogenous surfactant results in improved gas exchange. Second, in phase III clinical trials, treatment of patients with ALI with exogenous surfactant resulted in improved gas exchange (1) and, in a study of pediatric patients, a suggestion of improved survival (2, 3). Third, the functional surfactant deficit seen in infants with respiratory distress syndrome (RDS) is effectively treated with exogenous surfactant. In this case, the deficit comes initially from an absolute lack of surfactant, but in established RDS many features of lung inflammation resemble those seen in ALI. Finally, a lack of functional surfactant may promote lung inflammation. By what mechanisms might surfactant therapy improve survival in the setting of ALI? While improvement in gas exchange and relief of fatal hypoxemia is one possible mechanism, it is unlikely to be of great importance, as only a minority of patients with ALI die of that cause. More likely, restoration of surface tension–lowering function might result in reduction of mechanical stress on components of the lung parenchyma. Reduction of mechanical stress was associated, in the NHLBI ARDS Network study of low volume and pressure ventilation, with a reduction in mortality from 30.1% to 20% (4). Why, then, have none of the controlled trials of surfactant replacement established the benefit of this intervention for treatment of patients with ALI? The list of hurdles that must be overcome is daunting (Table 1).
A large number of variables in clinical studies of ALI cannot be controlled or must be defined arbitrarily. Although phase II studies might address some of these hurdles and provide guidelines for rational design of phase III studies, pressures on the pharmaceutical sponsors to bring drugs to market often result in initiation of phase III studies based on limited knowledge. Nevertheless, some of the hurdles are slowly being overcome. We realize now that many patients with ALI have fatal comorbidities (e.g., sepsis) that are unlikely to benefit from surfactant treatment, and that treatment might better be focused on a responsive subgroup—for example, those with direct lung injury—rather than on all patients with ALI (1, 2). What surfactant preparation should be used to treat patients with direct lung injury? As noted by Wang and coworkers in this issue of the AJRCMB (pp. 387–394), there are substantive reasons to prefer a synthetic preparation (5). However, the optimal lipid and protein composition of such a preparation is unknown. The wide variety of surfactant compositions present in nature suggests that different surfactants may provide adaptation to different environments (6). Surfactant that is optimal for treatment of ALI might not have the same composition as native surfactant. A variety of novel surfactant preparations have been proposed, including ones based on modifications of surfactant proteins B or C (SP-B, SP-C) or on peptide or peptoid analogs of those proteins, and ones containing additives to improve function and/or resist inactivation. With the exception of the studies by Wang and colleagues, relatively little attention as been given to the lipid composition of synthetic surfactants, and investigators, relying on data of Tanaka and coworkers (7), have often used a mixture of dipalmitoylphosphatidylcholine, phosphatidylglycerol, and palmitate. In contrast, Wang and colleagues have studied a novel surfactant containing only a phospholipase-resistant diether phosphonolipid (DEPN-8) and the hydrophobic surfactant proteins SP-B and SP-C. Building on prior studies that included evaluation in a bubble surfactometer, they now show in lavaged excised rat lungs that this preparation has excellent biophysical properties equivalent to those of calf lung surfactant extract (CLSE). Unlike CLSE, DEPN-8+SP B/C surfactant is resistant to inhibition by phospholipase A2 or lysophosphatidylcholine (LPC). DEPN-8+SP B/C surfactant, like CLSE, is inhibited by bovine serum albumin (BSA). Studies demonstrating function of this surfactant in complex mixtures of native surfactant, BSA, and LPC would more closely mimic the alveolar milieu of ALI, and animal experiments are a clear necessity. While the role of surfactant—natural or synthetic—in the treatment of ALI remains unclear, progress is being made on many fronts. Use may be found in treatment of other lung diseases and in drug delivery. However, investigators must critically evaluate their contributions and contribute to discussion of criteria for advancing a novel surfactant to clinical trials. After applying these criteria, carefully designed clinical investigations based on adequate phase II trials will be essential for moving novel surfactants from bubble to bedside. Footnotes Conflict of Interest Statement: R.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. References
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