© 2005 American Thoracic Society doi: 10.1164/rccm.2411005
Oleic Acid Damages Ion Transport and Promotes Alveolar EdemaThe Dark Side of Healthy LivingDepartment of Anesthesiology University of Alabama at Birmingham Birmingham, Alabama Oleic acid is a monounsaturated fatty acid found in large quantities in olive oil. Numerous studies indicate that a diet rich in olive oil decreases the development of atherosclerosis and lowers serum cholesterol by diminishing oxidative stress and inflammatory mediators while promoting antioxidant defenses (1). Oleic acid is the main ingredient of Lorenzo's oil, which may delay the onset of adrenoleulodystrophy in young boys. Finally, olives (and thus oleic acid) are important ingredients of the healthy Mediterranean diet. On the other hand, patients with acute respiratory distress syndrome have elevated serum levels of oleic acid (2), and infusion of oleic acid in animals results in an acute lung injury–type syndrome (3). The deleterious effects of oleic acid have been attributed to increases in the permeability of both vascular and alveolar epithelium to solute, caused by changes in membrane fluidity and increases in intracellular calcium concentration (4–6). In this issue of the AJRCCM (pp. 469–479), Vadász and colleagues (6) used a variety of ex vivo and in vitro techniques to show that intravenous infusion of oleic acid, in concentrations likely to be encountered in the plasma of patients with acute respiratory distress syndrome, decreased active ion transport across the alveolar epithelium. Lungs treated with oleic acid were unable to clear intratracheally instilled saline, and became edematous. The authors speculated that oleic acid may be responsible, at least in part, for the development of permeability-type edema in patients with acute lung injury. Ion transport across the alveolar epithelium involves the coordinated movement of Na+, Cl–, and K+ ions. Na+ ions passively enter alveolar type I and II cells through apically located epithelial sodium channels, and are actively transported across the basolateral membrane by the energy-consuming, electrogenic Na,K-ATPase. Potassium ions, which are exchanged for Na+ in a 2:3 stoichiometry by the Na,K-ATPase, exit the cells via K+ channels located in the basolateral membranes. Chloride ions, which must follow Na+ ions to preserve electrical neutrality, enter cells through Cl– channels or cross through paracellular junctions. The coordinated movement of these ions creates an osmotic gradient, which favors the movement of fluid from the alveolar into the interstitial spaces (7). The classic studies of Matthay and colleagues (8) established the presence of active ion transport across alveolar epithelium in adult anesthetized animals and resected human lungs. There has been some skepticism as to whether the process of epithelial ion transport may have any physiologic significance. For active transport to occur, the epithelial barrier must be very tight to prevent backflow of Na+ ions across basolateral surfaces, thereby obviating the oncotic gradient. However, patients with acute lung injury who are still able to concentrate alveolar protein (as a result of active Na+ reabsorption) have a better prognosis than those who cannot (9, 10). Pharmacologic inhibition of lung epithelial sodium channels in rats exposed to hyperoxia results in increased lung extravascular water (11, 12). Conversely, instillation of adenoviral vectors containing Na,K-ATPase improves survival of animals following exposure to hyperoxia (13). It seems likely that active transport occurs across relatively unaffected regions of the alveolar epithelium and contributes to the reabsorption of pulmonary edema. As injury progresses, alveolar transport is compromised and edema worsens. Decreased active transport can result from post-translational modification of ion transporters (14), initiation of signaling events leading to their internalization (15), decreased gene transcription, or diminished paracellular resistance. Vadász and colleagues (6) demonstrated that oleic acid decreased the activity of Na+ channels (as shown by measurements of amiloride-sensitive Na+ currents in A549 cells patched in the whole cell mode) and of the Na,K-ATPase, as shown by direct measurements of functional and enzymatic Na,K-ATPase. This places the system in double jeopardy: agents that may restore one of these components (such as ß-agonists that increase Na+ channel activity) may not be able to reestablish active transport and alveolar fluid clearance across oleic acid–injured lungs. It was interesting to note that Vadász and colleagues (6) reported that epithelial permeability to solute was unaltered after oleic acid. This contrasts with previous experiments demonstrating large increases in epithelial permeability in oleic acid injury (4, 5), attributed at least in part to an increase of intracellular Ca+2. However, Davidson and coworkers (4) reported that the increase in alveolar permeability after infusion of oleic acid was transient, even though hypoxemia was persistent. It is possible that hypoxemia was the result of the inability of the animals to clear alveolar edema because active transport was compromised, as reported in the study by Vadász and coworkers (6).
One limitation of Vadász's study is that the mechanism by which oleic acid injures ion transporters was not elucidated. The authors did demonstrate that oleic acid associated covalently with subunits of both the epithelial Na+ channel and of the Na,K-ATPase. However, there was no direct proof that this association resulted in inhibition of function of these two transporters. Furthermore, the statement that cell surface expression of epithelial Na+ channels and Na,K-ATPase was unaltered by oleic acid is not supported by experimental evidence. In particular, Western blotting studies of biotinylated proteins of sham- and oleic acid–treated A549 cells showed similar levels of the ß subunit of the epithelium Na+ channels and Additional mechanistic studies are needed to explore the interesting observation that oleic acid directly affects epithelial ion transport. However, this study still offers new insights into a potential mechanism by which oleic acid may injure the alveolar epithelium and contribute to the development of acute respiratory distress syndrome. FOOTNOTES Conflict of Interest Statement: S.M. does not have a financial relationship with a commercial entity that has an interest in the subject of the manuscript; H.-L.J. does not have a financial relationship with a commercial entity that has an interest in the subject of the manuscript. REFERENCES
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subunit of the Na,K-ATPase. However, the epithelial Na+ channels consist of at least three different subunits (
alone) in Xenopus oocytes (