© 2003 American Thoracic Society
Tumor Necrosis Factor and Lung Edema ClearanceThe Tip of the Iceberg?Centre de Recherche Centre Hospitalier de l'Université de Montréal Montréal, Québec, Canada Because the severity of acute lung injury and its recovery depend in part on alveolar epithelial function, treatments aimed at improving epithelial function might accelerate recovery and decrease the mortality of patients with this condition (1). Although the alveolar epithelium has many important functions, its role in the clearance of alveolar edema is of particular significance because patients with acute lung injury and impaired alveolar liquid clearance have a poor prognosis (2). Alveolar liquid clearance is driven by epithelial sodium transport, and numerous treatments have been proposed to stimulate the process and hopefully hasten recovery from lung damage. (1, 3, 4). Although alveolar liquid clearance is mainly modulated by catecholamine-dependant mechanisms, it can be modulated in various models of lung injury by a catecholamine-independent pathway involving tumor necrosis factor (TNF) (3, 5, 6). These observations are quite surprising considering that TNF is a mediator of lung injury (7) and is cytotoxic to endothelial cells (8). In the current issue of the Journal (pp. 1043–1050), Elia and colleagues (9) provide exciting new data that help us to understand this paradoxical effect of TNF. The authors are proposing that TNF-enhanced alveolar liquid clearance is mediated by a different signaling system than the system leading to lung injury. Whereas the induction of lung injury by TNF is probably mediated by its binding with high-affinity receptors, its positive effect on alveolar liquid clearance would depend on lectin-like interactions. The presence in TNF of a lectin-like domain allows interaction with specific oligosaccharides expressed on the cell surface (10). Indeed, in a previously published paper, TNF stimulation of alveolar liquid clearance was shown to be absent when a TNF mutant lacking lectin-like activity was used (6). The new in vivo data of Elia and colleagues (9) support this hypothesis. They observed a stimulation of alveolar liquid clearance by TNF in mice genetically deficient in TNF receptors. Moreover, when they used a synthetic peptide (Ltip, named after the TNF domain to which it corresponds) that mimics the lectin-like domain of TNF, they could also enhance alveolar liquid clearance. Although I agree with the authors that Ltip might represent a novel therapeutic avenue for pulmonary edema, a number of questions need to be addressed before this molecule could be considered as a potential therapeutic agent. We do not have a clear picture of the cellular pathway involved in TNF-enhanced alveolar liquid clearance. Fukuda and colleagues (6) proposed that TNF stimulates amiloride-sensitive current in alveolar epithelial cells. Because amiloride has been shown to inhibit sodium transport, the presence of this current is suggestive of activation of sodium transport by TNF in these cells. The molecular identity involved in this sodium transport, however, is still unknown. Most probably, a nonselective cation channel, rather than the epithelial sodium channel, is involved because TNF-induced amiloride-sensitive current is observed not only in epithelial cells but also in macrophages and endothelial cells (11) where the epithelial sodium channel is unexpected. Although TNF can stimulate amiloride-sensitive current in all cellular systems studied, it is not clear whether this response is always related to the lectin-like activity of TNF. In macrophages and endothelial cells, the effect of TNF is most probably due to lectin-like activity because the effect can be seen in macrophages obtained from animals deficient in TNF receptors (11). Moreover, the effect could also be reproduced by the synthetic TNF peptide Ltip, which exerts lectin-like activity (11). In alveolar epithelial cells, the TNF effect on amiloride-sensitive current was also absent when the cells were incubated with a TNF mutant lacking lectin-binding capacity (6). Incubation with TNF receptor antibodies, however, inhibited amiloride-sensitive current, suggesting that the effect of TNF in alveolar epithelial cells might not be totally receptor-independent (6). Because toxicity is mainly related to the interaction between TNF and its receptors, this might be of concern (12). Furthermore, even if the effect is totally receptor-independent and related to the lectin-like activity of TNF, how can we be sure that the stimulation of amiloride-sensitive current is not the first step in a nonspecific response to changes in cell volume that is associated with cell swelling and cytotoxicity (13)? This possibility needs to be considered because the lectin-like activity of TNF was proposed to kill trypanosomes (10). Although the in vivo data from Elia and colleagues (9) are reassuring regarding the potential for Ltip toxicity, some findings suggest that Ltip might not be totally inoffensive. Although they did observe significantly less alveolar hemorrhage and alveolar edema in Ltip-treated lungs than in TNF-treated lungs, there was nonetheless recruitment of neutrophils in the alveolar space with Ltip. We have to wonder if the experimental protocol had enough power to clearly identify any potential Ltip toxicity. Finally, although Ltip stimulates alveolar liquid clearance in normal lungs, it may not be efficacious in injured lungs. It has been shown recently that ß-adrenergic agonists, which are known to stimulate alveolar liquid clearance in normal and mildly injured lungs, could not enhance alveolar liquid clearance in a more severe model of lung injury (14). It will be essential to establish Ltip efficiency not only in normal lungs but also in injured lungs. Because of unanswered questions, consideration of Ltip as a new therapeutic agent against pulmonary edema is premature. It is, however, surely an exciting avenue to explore. It would be a mistake to not further explore the mechanism of Ltip action on sodium transport or to avoid testing its potential toxicity and efficiency in different models of lung injury. If we understand its mechanism of action, we might have a better idea of how sodium transport is modulated in lung injury. This in itself might help us design new therapies for pulmonary edema. The data of Elia and colleagues (9) are taking us to an unexplored region of lung injury. We need to continue to explore this new exciting concept, and we should not forget that there might be more than we think under the tip of the iceberg. Acknowledgments The author acknowledges the editorial work done on this manuscript by Ovid Da Silva, Editor/Redactor of the Research Support Office of the Centre de Recherche du CHUM. FOOTNOTES Supported by grants from the Canadian Cystic Fibrosis Foundation and the Canadian Institute of Health Research. Conflict of Interest Statement: Y.B. was a consultant for the development of a clinical trial for BCY Lifesciences, Inc. He was also a coinvestigator in a cystic fibrosis clinical trial by BCY Lifesciences, Inc. The investigators received a $60,000 CDN to pay the research expenses to run the trial (personnel and lab work). REFERENCES
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. Am J Respir Crit Care Med 2003;168:1043–1050.
