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Modulation of Alveolar Fluid Clearance by Acute Inflammation

The Plot Thickens

Allergy, Pulmonary, and Critical Care Medicine Vanderbilt University School of Medicine Nashville, Tennessee

Although many proinflammatory mediators have been measured in biological fluids from patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) (1), the pathophysiological significance of a given biological marker is not always apparent from isolated measures of concentrations or immunologic activity. A variety of factors can influence the biological activity of a proinflammatory mediator. For example, the simultaneous presence of inhibitors such as antiinflammatory cytokines, soluble receptors, receptor antagonists, or autoantibodies can markedly alter the biological activity of a given cytokine or other proinflammatory molecule (2). Effects of proinflammatory molecules may also vary depending on the target cell that is studied. Finally, proinflammatory mediators may have complex and unrecognized effects on other physiological systems in addition to their direct involvement in the inflammatory cascade. One example of this type of complex relationship is the increasingly recognized interplay between inflammation, coagulation, and fibrinolysis in sepsis and ALI/ARDS (3). Thus, moving from simple measures of biological markers to measures of biological activity both in vitro and in vivo has the potential to greatly enhance our understanding of the pathophysiology of clinical ALI/ARDS.

In this issue of the Journal (pp. 407–412), Sloniewsky and coworkers (4) take an important step in this direction with their investigation of the effect of the proinflammatory cysteinyl leukotriene, leukotriene D₄, on alveolar epithelial sodium transport and the activity of the alveolar epithelial Na,K-ATPase. Before this report, investigation of the role of leukotriene D₄ in the pathogenesis of ALI/ARDS has focused principally on its deleterious proinflammatory and permeability-enhancing effects. Sloniewsky and coworkers report that leukotriene D₄, found in substantial levels in the pulmonary edema fluid of patients with ALI/ARDS (5, 6), can increase alveolar epithelial fluid transport both in vitro and in the isolated perfused rat lung through increased activity and membrane localization of the Na,K-ATPase (4). This effect is mediated through the CysLT receptor 2, which they found is expressed by both A549 cells and rat alveolar epithelial type II cells. Importantly, the concentrations of leukotriene D₄ required for this effect in the isolated perfused lung (10 pM) are biologically relevant, because levels of leukotriene D₄ in the pulmonary edema fluid from patients both with ARDS (19.2 ± 25.6 nM) and hydrostatic pulmonary edema (2.2 ± 2.4 nM) were several logs higher (6). These findings suggest that in addition to its potent proinflammatory effects, leukotriene D₄ may play an important role in the regulation of alveolar epithelial fluid transport across the distal airspaces.

The active transport of fluid from the distal airspaces is driven by the vectorial transport of sodium and chloride across the alveolar and distal airway epithelium (7). Intact alveolar epithelial fluid transport is critical to the resolution of clinical pulmonary edema from a variety of causes (8–10) and it is postulated that therapies that improve the rate of alveolar epithelial fluid transport might be of clinical utility in the treatment of both cardiogenic and noncardiogenic pulmonary edema. Although catecholamine-dependent regulation of the rate of alveolar epithelial fluid transport is thought to play a major role in the physiologic regulation of alveolar fluid clearance, an increasing number of catecholamine-independent mechanisms have been identified (7). These include hormonal regulation by glucocorticoids, thyroid hormone, aldosterone and atrial natriuretic peptide and effects of growth hormones such as epidermal growth factor, transforming growth factor- and keratinocyte growth factor. Of major significance to the current findings, the proinflammatory cytokine, tumor necrosis factor-, has recently been demonstrated to upregulate alveolar epithelial fluid transport through both tumor necrosis factor- receptor–dependent (11) and –independent (12) mechanisms. Thus, leukotriene D₄ is the second proinflammatory mediator to be identified that potentially has protective effects that are mediated through upregulation of alveolar epithelial fluid transport.

Why do proinflammatory mediators, such as leukotriene D₄ and tumor necrosis factor-, upregulate alveolar epithelial sodium and fluid transport? Is this a teleologically important countereffect to the permeability-enhancing effects of these mediators? There are many issues that will need to be resolved before we can fully understand the pathogenetic significance of the apparent link between acute inflammation and modulation of alveolar epithelial fluid transport. One issue not addressed in the current study is what effect higher concentrations of leukotriene D₄, similar to those reported in the pulmonary edema fluid of patients (2–20 nM), would have in the isolated perfused lung. It will be important to determine whether more physiologic concentrations lead to permeability effects that outweigh any protective effect on alveolar fluid clearance. The concentration of leukotriene D₄ studied in the isolated perfused lung by Sloniewsky and coworkers did not alter permeability but was several logs lower than the concentrations measured clinically (5, 6). A second issue of major importance is whether the injured lung responds similarly to leukotriene D₄. Although ß-agonists are well known to stimulate alveolar fluid clearance in the uninjured lung, they have not been effective in some models of severe lung injury (13). Another issue is whether the effect of leukotriene D₄ on alveolar epithelial fluid transport is additive in the setting of other stimuli that modulate the activity of the Na,K-ATPase or the epithelial sodium channel. There are other instances where an additive effect of two stimuli has been reported. For example, both keratinocyte growth factor and ß-adrenergic agonists can upregulate alveolar fluid clearance and their effect is additive, likely because they act by entirely different mechanisms (14). Finally, do other proinflammatory cytokines and mediators have similar effects on the rate of alveolar epithelial fluid transport? An obvious question is whether other cysteinyl leukotrienes also have this effect on alveolar epithelial fluid transport since both leukotriene C₄ and leukotriene E₄ are found in relatively high concentrations in the pulmonary edema fluid of patients with ALI/ARDS or hydrostatic pulmonary edema (6). Although there is some evidence that other proinflammatory cytokines such as interferon- and interleukin-1ß can alter sodium transport in the intestinal and renal epithelium, they have yet to be studied in the alveolar epithelium. Thus, we have much to learn about the link between acute inflammation and the regulation of lung fluid balance. The report of Sloniewsky and coworkers is important and will help to stimulate many new areas of investigation.

FOOTNOTES

Conflict of Interest Statement: L.B.W. has no declared conflict of interest.

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