© 2004 American Thoracic Society
Lung Surfactant, Asthma, and AllergensA Story in EvolutionUniversity of Padua Padua, Italy A continuous film covers the mucosa of the lungs, extending from the alveoli to the larger airways. Surface tension is less than 2 mJ/m2 in alveoli on expiration and 32 mJ/m2 in the trachea, so there appears to be a gradient in surface tension between the alveoli and the central airways. The value of surface tension in regions between these extremes is unknown, although recent estimates indicate that it may be close to 15 mJ/m2 in the conducting airways, a value typical for surfactant in a compressed state (1). These findings lend support to the concept that surface tension is regulated all along the airways and that a dysfunction of surfactant may have adverse effects both on the alveolar region and on the conducting airways. A growing body of experimental evidence indicates that surfactant dysfunction may contribute to the airway obstruction of asthma. In fact, guinea pigs sensitized with ovalbumin and then challenged by aerosol exhibit altered performance of surfactant (2). Similarly, lung lavage fluid and sputum of patients with allergic asthma contain a surfactant with decreased surface activity (3, 4). Leakage of plasma proteins into the airways appears to play a fundamental role in surfactant inactivation (3, 5). Other invoked mechanisms include increased hydrolysis of surfactant phospholipids (6) and decreased synthesis of hydrophobic surfactant proteins (7).
How surfactant inactivation relates to airway obstruction in asthma remains unclear. Many assume that the inactivation of surfactant may cause accumulation of fluid in the terminal conducting airways (2). Others think that it may act by amplifying the bronchoconstrictor response of more central airways (8). In addition to the effects on surface tension, lipids and proteins of surfactant could affect airway patency in asthma by influencing the inflammatory response. Indeed, surfactant lipids suppress lymphocyte function and proliferation, inhibit the activation of neutrophils, decrease the production of superoxide anions, slow the release of proinflammatory mediators, and inhibit the activation of nuclear factor Surfactant administration could have favorable effects on asthma both by restoring surface activity and by modulating the immune response. Experiments with animal models of allergic asthma, all characterized by a violent influx of plasma proteins in the airways, indicate that surfactant administration may be beneficial. In fact, surfactant extracts, administered prophylactically or after challenge to guinea pigs immunized against ovalbumin, improved lung mechanics and gas exchange (11, 12). Studies with patients have given contrasting results. Kurashima and coworkers found that the inhalation of a surfactant extract by adult patients during an asthma attack improved lung mechanics (13). Oetomo and coworkers found no change in lung mechanics in children with asthma who inhaled a surfactant extract during a stable phase of their disease (14). Babu and coworkers found that the inhalation of a dry powdered synthetic phospholipid mixture abolished the early allergen-induced response in a group of adult subjects with mild atopic asthma (15). To date, no adverse effects of surfactant administration to patients with asthma have been reported.
Thus, the results of the study of Erpenbeck and coworkers (16) reported in this issue of the Journal (pp. 578–586) come as a surprise. These authors subjected patients with mild asthma and control subjects to a segmental allergen challenge immediately after exposing the same lung areas to saline solution or to a commercial pig lung surfactant extract. They found that pretreatment with the surfactant extract amplified the response to allergen exposure, increasing the concentration of eosinophils, eotaxin, and IL-5 in lung lavage fluid and decreasing the concentration of interferon- The argument, however, cannot be considered settled. In their mouse model, the authors used fluorescent dextran, a water-soluble compound that could move through the airways and be taken up by lung cells in ways radically different from those of the allergens administered to patients (grass pollen mix or Dermatophagoides pteronyssinus). Moreover, the amount of a substance taken up by a single type of cell does not necessarily reflect the spread and retention of that substance through the airways. Finally, mice received a fixed dose of dextran, while a dose–response study would have been more ideal. Thus the effect of surfactant administration on spreading, uptake, and clearance of inhaled allergen remains to be rigorously analyzed; the possibility that the effects observed by Erpenbeck and coworkers (16) were due to the action of the surfactant extract (Curosurf) on allergen distribution cannot be dismissed entirely. A link between surfactant and the response to inhaled allergens is reasonable, because low surface tension increases the immersion of inhaled particles in the aqueous layer that covers the airways and facilitates the interaction with lung cells (1). An immunological explanation for the observed results cannot be excluded. For example, surfactant lipids, present in large excess in the conducting airways after administration of the surfactant extract, could have bound resident molecules with inhibitory activity (10). This mechanism, however, remains to be proved, and the substances involved remain to be identified. The evidence presented by Erpenbeck and coworkers suggests that the final result of surfactant administration in asthma could depend upon a combination of effects on surface tension, allergen presentation, and immune response. We need to know much more about all this before considering surfactant for the treatment of asthma. FOOTNOTES Conflict of Interest Statement: A.B. has been consultant for Chiesi Farmaceutici Spa, Parma, Italy, the manifacturer of Curosurf. During the year 2000, he received $4,000 from Chiesi Farmceutici, to study the association of magnesium stearate with alveolar surfactant. REFERENCES
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B and L-selectin–induced signal transduction (
. The extract alone had no direct effect on eosinophil infiltration, chemotaxis, secretion of mediators, or expression of CCR3 receptors. Accordingly, the authors explored the possibility that the surfactant extract could have increased allergen spreading through the airways. To this end, they administered fluorescent dextran into the trachea of mice previously instilled with saline or the surfactant extract and measured the change over time of the fluorescence associated with alveolar macrophages. Finding no difference between the two groups of animals, the authors conclude that the surfactant extract augmented the inflammatory response after allergen exposure more likely through an immunomodulatory effect rather than by improving allergen distribution throughout the airways. 
